Publications by authors named "Weizhou Zhang"

78 Publications

Body fatness and mTOR pathway activation of breast cancer in the Women's Circle of Health Study.

NPJ Breast Cancer 2020 Sep 21;6(1):45. Epub 2020 Sep 21.

Department of Cancer Prevention and Control, Roswell Park Comprehensive Cancer Center, Buffalo, NY, USA.

Energy imbalance has an important role in breast cancer prognosis. Hyperactive mechanistic Target of Rapamycin (mTOR) pathway is associated with breast tumor growth, but the extent to which body fatness is associated with mTOR pathway activities in breast cancer is unclear. We performed immunostaining for mTOR, phosphorylated (p)-mTOR, p-AKT, and p-p70S6K in tumor tissue from 590 women (464 African Americans/Blacks and 126 Whites) with newly diagnosed invasive breast cancer in the Women's Circle of Health Study. Anthropometric measures were taken by study staff, and body composition was measured by bioelectrical impedance analysis. Linear regressions were used to estimate percent differences in protein expression between categories of body mass index (BMI), waist circumference, waist/hip ratio, fat mass, fat mass index, and percent body fat. We observed that BMI ≥ 35.0 vs. <25 kg/m was associated with 108.3% (95% CI = 16.9%-270.9%) and 101.8% (95% CI = 17.0%-248.8%) higher expression in p-mTOR and normalized p-mTOR, i.e., p-mTOR/mTOR, respectively. Quartiles 4 vs. 1 of waist/hip ratio was associated with 41.8% (95% CI = 5.81%-89.9%) higher mTOR expression. Similar associations were observed for the body fat measurements, particularly in patients with estrogen receptor-negative (ER-) tumors, but not in those with ER+ tumors, although the differences in associations were not significant. This tumor-based study found positive associations between body fatness and mTOR pathway activation, evident by a p-mTOR expression, in breast cancer. Our findings suggest that mTOR inhibition can be a treatment strategy to prevent the recurrence of these tumors in obese individuals.
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http://dx.doi.org/10.1038/s41523-020-00187-4DOI Listing
September 2020

Intratumoral talimogene laherparepvec injection with concurrent preoperative radiation in patients with locally advanced soft-tissue sarcoma of the trunk and extremities: phase IB/II trial.

J Immunother Cancer 2021 Jul;9(7)

Internal Medicine, The University of Iowa Hospitals and Clinics, Iowa City, Iowa, USA.

Background: Soft-tissue sarcomas (STS) in the extremities and trunk treated with standard-of-care preoperative external beam radiation therapy (EBRT) followed by surgical resection are associated with local and distant relapses. In preclinical studies, oncolytic virotherapy in sarcoma has demonstrated antitumor effects via direct intratumoral oncolysis and cytotoxic T-cell-mediated immune responses. Talimogene laherparepvec (TVEC) is a replication-competent, immune-enhanced, oncolytic herpes simplex virus type 1 engineered for intratumoral injection; it has been approved by the FDA for the treatment of locally advanced and metastatic melanoma.

Methods: We explored a novel combination of TVEC with standard-of-care EBRT administered preoperatively in patients with locally advanced STS of the extremities and trunk in a phase IB/II clinical trial. Thirty patients with primary STS >5 cm for which EBRT was indicated to achieve negative margins were enrolled. FDA-approved TVEC doses were used. Immune correlative studies in peripheral blood, biopsy and resected tumor tissues were performed.

Results: No dose-limiting toxicity was observed. Adverse events were similar to those reported in prior studies with TVEC. One patient with myxoid liposarcoma exhibited a partial response. Seven of the 29 (24%) evaluable patients achieved 95% pathological necrosis. None of the patients developed a herpes infection due to the treatment. Eight of the 29 (27%) patients developed postoperative wound complications, which is consistent with previous studies. None of the patients developed local recurrence after surgical resection of the primary sarcoma. 2-year progression-free and overall survival were 57% and 88%, respectively. Caspase-3 demonstrated increased expression of both in TVEC-treated tissue samples as compared with control samples treated with radiation alone.

Conclusion: Preoperative intratumoral TVEC with concurrent EBRT for locally advanced STS is safe and well-tolerated. This combination treatment may enhance immune responses in some cases but did not increase the proposed rate of pathological necrosis. The Caspase-3 biomarker may be associated with a positive effect of TVEC in sarcoma tumor tissue and should be explored in future studies.

Trial Registration Number: NCT02453191.
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http://dx.doi.org/10.1136/jitc-2021-003119DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8327848PMC
July 2021

Body fatness and breast cancer risk in relation to phosphorylated mTOR expression in a sample of predominately Black women.

Breast Cancer Res 2021 07 30;23(1):77. Epub 2021 Jul 30.

Department of Cancer Prevention and Control, Roswell Park Comprehensive Cancer Center, Buffalo, NY, USA.

Background: The mechanistic target of rapamycin (mTOR) pathway promoted by positive energy imbalance and insulin-like growth factors can be a mechanism by which obesity influences breast cancer risk. We evaluated the associations of body fatness with the risk of breast cancer varied with phosphorylated (p)-mTOR protein expression, an indication of the pathway activation.

Methods: Women with newly diagnosed breast cancer (n = 715; 574 [80%] Black and 141 [20%] White) and non-cancer controls (n = 1983; 1280 [64%] Black and 713 [36%] White) were selected from the Women's Circle of Health Study. Surgical tumor samples among the cases were immunostained for p-mTOR (Ser2448) and classified as p-mTOR-overexpressed, if the expression level ≥ 75th percentile, or p-mTOR-negative/low otherwise. Anthropometrics were measured by trained staff, and body composition was determined by bioelectrical impedance analysis. Odds ratios (ORs) of p-mTOR-overexpressed tumors and p-mTOR-negative/low tumors compared to controls were estimated using polytomous logistic regression. The differences in the associations by the p-mTOR expression status were assessed by tests for heterogeneity.

Results: Cases with p-mTOR-overexpressed tumors, but not cases with p-mTOR-negative/low tumors, compared to controls were more likely to have higher body mass index (BMI), percent body fat, and fat mass index (P-heterogeneity < 0.05), although the OR estimates were not significant. For the measurement of central adiposity, cases with p-mTOR overexpressed tumors had a higher odds of being at the Q3 (OR = 2.52, 95% CI = 1.46 to 4.34) and Q4 (OR = 1.99, 95% CI = 1.12 to 3.50) of waist circumference (WC) compared to controls. Similarly, cases with p-mTOR overexpressed tumors had a higher odds of being at the Q3 (OR = 1.82, 95% CI = 1.11 to 2.98) and Q4 (OR = 1.81, 95% CI = 1.11 to 2.98) of WHR compared to controls. These associations of WC and waist-to-hip ratio (WHR) did not differ by tumor p-mTOR status (P-heterogeneity = 0.27 and 0.48, respectively).

Conclusions: Our findings suggest that in this population composed of predominately Black women, body fatness is associated with breast cancer differently for p-mTOR overexpression and p-mTOR negative/low expression. Whether mTOR plays a role in the obesity and breast cancer association warrants confirmation by prospective studies.
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http://dx.doi.org/10.1186/s13058-021-01458-zDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8325192PMC
July 2021

Blockade of the CD93 pathway normalizes tumor vasculature to facilitate drug delivery and immunotherapy.

Sci Transl Med 2021 07;13(604)

Department of Surgery, University of Colorado Anschutz Medical Campus, Aurora, CO 80045, USA.

The immature and dysfunctional vascular network within solid tumors poses a substantial obstacle to immunotherapy because it creates a hypoxic tumor microenvironment that actively limits immune cell infiltration. The molecular basis underpinning this vascular dysfunction is not fully understood. Using genome-scale receptor array technology, we showed here that insulin-like growth factor binding protein 7 (IGFBP7) interacts with its receptor CD93, and we subsequently demonstrated that this interaction contributes to abnormal tumor vasculature. Both CD93 and IGFBP7 were up-regulated in tumor-associated endothelial cells. IGFBP7 interacted with CD93 via a domain different from multimerin-2, the known ligand for CD93. In two mouse tumor models, blockade of the CD93/IGFBP7 interaction by monoclonal antibodies promoted vascular maturation to reduce leakage, leading to reduced tumor hypoxia and increased tumor perfusion. CD93 blockade in mice increased drug delivery, resulting in an improved antitumor response to gemcitabine or fluorouracil. Blockade of the CD93 pathway triggered a substantial increase in intratumoral effector T cells, thereby sensitizing mouse tumors to immune checkpoint therapy. Last, analysis of samples from patients with cancer under anti-programmed death 1/programmed death-ligand 1 treatment revealed that overexpression of the IGFBP7/CD93 pathway was associated with poor response to therapy. Thus, our study identified a molecular interaction involved in tumor vascular dysfunction and revealed an approach to promote a favorable tumor microenvironment for therapeutic intervention.
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http://dx.doi.org/10.1126/scitranslmed.abc8922DOI Listing
July 2021

The Diagnostic Performance of Early Sjögren's Syndrome Autoantibodies in Juvenile Sjögren's Syndrome: The University of Florida Pediatric Cohort Study.

Front Immunol 2021 25;12:704193. Epub 2021 Jun 25.

Center for Orphaned Autoimmune Disorders (COAD), College of Dentistry, University of Florida, Gainesville, FL, United States.

Objectives: The aim of this study was to evaluate the clinical validity of early Sjögren's syndrome (SS) autoantibodies (eSjA), which were originally marketed for early diagnosis of SS, for juvenile SS (JSS) in a recently identified pediatric cohort.

Methods: A total of 105 symptomatic subjects with eSjA results available were evaluated at the Center for Orphaned Autoimmune Disorders at the University of Florida and enrolled for this study. JSS diagnosis was based on the 2016 ACR/EULAR SS criteria. Demographic/clinical/laboratory parameters were compared between JSS (n = 27) and non-JSS (n = 78) for % positivity, sensitivity, and specificity of eSjA (SP1, anti-salivary protein; CA6, anti-carbonic anhydrase VI; PSP, anti-parotid secretory protein) and classic SS-autoantibodies (cSjA; ANA, SSA/SSB, RF, and others) either alone or in combination. Associations between eSjA and diagnostic/glandular parameters were also determined by Fisher's exact test.

Results: Compared to non-JSS, JSS patients exhibited sicca symptoms demonstrating reduced unstimulated salivary flow rate (USFR) and abnormal glandular features revealed by salivary gland ultrasound (SGUS). Among cSjA, ANA demonstrated the highest sensitivity of 69.2%, while SSA, SSB, and RF showed around 95% specificities for JSS diagnosis. The % positive-SSA was notably higher in JSS than non-JSS (56% vs. 5%). Of eSjA, anti-CA6 IgG was the most prevalent without differentiating JSS (37%) from non-JSS (32%). Sensitivity and specificity of eSjA were 55.6 and 26.9%, respectively. Autoantibodies with potentially applicable specificity/sensitivity for JSS were seen only in cSjA without a single eSjA included. There were no associations detected between eSjA and focus score (FS), USFR, SSA, SGUS, and parotitis/glandular swelling analyzed in the entire cohort, JSS, and non-JSS. However, a negative association between anti-PSP and parotitis/glandular swelling was found in a small group of positive-SSA (n = 19, p = 0.02) whereas no such association was found between anti-PSP-positive compared to anti-PSP-negative. JSS and non-JSS groups differed in FS, USFR, and EULAR SS Patient Reported Index Dryness/Mean in CA6/PSP/ANA, SP1, and SSA-positive groups, respectively. Additionally, a higher FS was found in RF-positive than RF-negative individuals.

Conclusions: eSjA underperformed cSjS in differentiating JSS from non-JSS. The discovery of clinical impact of eSjA on early diagnosis of JSS necessitates a longitudinal study.
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http://dx.doi.org/10.3389/fimmu.2021.704193DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8267463PMC
June 2021

BCL11B is positioned upstream of PLZF and RORγt to control thymic development of mucosal-associated invariant T cells and MAIT17 program.

iScience 2021 Apr 13;24(4):102307. Epub 2021 Mar 13.

Department of Anatomy and Cell Biology, College of Medicine, University of Florida, Gainesville, FL 32610, USA.

Mucosal-associated invariant T (MAIT) cells recognize microbial riboflavin metabolites presented by MR1 and play role in immune responses to microbial infections and tumors. We report here that absence of the transcription factor (TF) Bcl11b in mice alters predominantly MAIT17 cells in the thymus and further in the lung, both at steady state and following infection. Transcriptomics and ChIP-seq analyses show direct control of TCR signaling program and position BCL11B upstream of essential TFs of MAIT17 program, including RORγt, ZBTB16 (PLZF), and MAF. BCL11B binding at key MAIT17 and at TCR signaling program genes in human MAIT cells occurred mostly in regions enriched for H3K27Ac. Unexpectedly, in human MAIT cells, BCL11B also bound at MAIT1 program genes, at putative active enhancers, although this program was not affected in mouse MAIT cells in the absence of Bcl11b. These studies endorse BCL11B as an essential TF for MAIT cells both in mice and humans.
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http://dx.doi.org/10.1016/j.isci.2021.102307DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8042176PMC
April 2021

Proteolysis-targeting chimera against BCL-X destroys tumor-infiltrating regulatory T cells.

Nat Commun 2021 02 24;12(1):1281. Epub 2021 Feb 24.

Department of Pathology, Immunology, and Laboratory Medicine, College of Medicine, University of Florida, Gainesville, FL, USA.

Regulatory T cells (Tregs) play an important role in maintaining immune homeostasis and, within tumors, their upregulation is common and promotes an immunosuppressive microenvironment. Therapeutic strategies that can eliminate Tregs in the tumor (i.e., therapies that do not run the risk of affecting normal tissues), are urgently needed for the development of cancer immunotherapies. Here we report our discovery of B-cell lymphoma extra-large (BCL-X) as a potential molecular target of tumor-infiltrating (TI) Tregs. We show that pharmacological degradation of BCL-X using a newly developed platelet-sparing BCL-X Proteolysis-targeting chimera (PROTAC) induces the apoptosis of TI-Tregs and the activation of TI-CD8 T cells. Moreover, these activities result in an effective suppression of syngeneic tumor growth in immunocompetent, but not in immunodeficient or CD8 T cell-depleted mice. Notably, treatment with BCL-X PROTAC does not cause detectable damage within several normal tissues or thrombocytopenia. These findings identify BCL-X as a target in the elimination of TI-Tregs as a component of cancer immunotherapies, and that the BCL-X-specific PROTAC has the potential to be developed as a therapeutic for cancer immunotherapy.
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http://dx.doi.org/10.1038/s41467-021-21573-xDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7904819PMC
February 2021

Understanding and Targeting Human Cancer Regulatory T Cells to Improve Therapy.

Adv Exp Med Biol 2021 ;1278:229-256

Department of Pathology, Immunology and Laboratory Medicine, University of Florida, Gainesville, FL, USA.

Regulatory T cells (Tregs) are critical in maintaining immune homeostasis under various pathophysiological conditions. A growing body of evidence demonstrates that Tregs play an important role in cancer progression and that they do so by suppressing cancer-directed immune responses. Tregs have been targeted for destruction by exploiting antibodies against and small-molecule inhibitors of several molecules that are highly expressed in Tregs-including immune checkpoint molecules, chemokine receptors, and metabolites. To date, these strategies have had only limited antitumor efficacy, yet they have also created significant risk of autoimmunity because most of them do not differentiate Tregs in tumors from those in normal tissues. Currently, immune checkpoint inhibitor (ICI)-based cancer immunotherapies have revolutionized cancer treatment, but the resistance to ICI is common and the elevation of Tregs is one of the most important mechanisms. Therapeutic strategies that can selectively eliminate Tregs in the tumor (i.e. therapies that do not run the risk of causing autoimmunity by affecting normal tissue), are urgently needed for the development of cancer immunotherapies. This chapter discusses specific properties of human Tregs under the context of cancer and the various ways to target Treg for cancer immunotherapy.
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http://dx.doi.org/10.1007/978-981-15-6407-9_12DOI Listing
February 2021

Mapping the immune environment in clear cell renal carcinoma by single-cell genomics.

Commun Biol 2021 01 27;4(1):122. Epub 2021 Jan 27.

Holden Comprehensive Cancer Center, University of Iowa, Iowa City, IA, USA.

Clear cell renal cell carcinoma (ccRCC) is one of the most immunologically distinct tumor types due to high response rate to immunotherapies, despite low tumor mutational burden. To characterize the tumor immune microenvironment of ccRCC, we applied single-cell-RNA sequencing (SCRS) along with T-cell-receptor (TCR) sequencing to map the transcriptomic heterogeneity of 25,688 individual CD45 lymphoid and myeloid cells in matched tumor and blood from three patients with ccRCC. We also included 11,367 immune cells from four other individuals derived from the kidney and peripheral blood to facilitate the identification and assessment of ccRCC-specific differences. There is an overall increase in CD8 T-cell and macrophage populations in tumor-infiltrated immune cells compared to normal renal tissue. We further demonstrate the divergent cell transcriptional states for tumor-infiltrating CD8 T cells and identify a MKI67 + proliferative subpopulation being a potential culprit for the progression of ccRCC. Using the SCRS gene expression, we found preferential prediction of clinical outcomes and pathological diseases by subcluster assignment. With further characterization and functional validation, our findings may reveal certain subpopulations of immune cells amenable to therapeutic intervention.
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http://dx.doi.org/10.1038/s42003-020-01625-6DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7840906PMC
January 2021

AP-2γ Is Required for Maintenance of Multipotent Mammary Stem Cells.

Stem Cell Reports 2021 01 30;16(1):106-119. Epub 2020 Dec 30.

Department of Surgery, University of Iowa, 200 Hawkins Drive, JCP 1509 Iowa City, IA 52242-1086, USA; Department of Molecular Physiology and Biophysics, University of Iowa, Iowa City, IA 52242, USA; Department of Biochemistry, University of Iowa, Iowa City, IA 52242, USA. Electronic address:

Mammary gland ductal morphogenesis depends on the differentiation of mammary stem cells (MaSCs) into basal and luminal lineages. The AP-2γ transcription factor, encoded by Tfap2c, has a central role in mammary gland development but its effect in mammary lineages and specifically MaSCs is largely unknown. Here, we utilized an inducible, conditional knockout of Tfap2c to elucidate the role of AP-2γ in maintenance and differentiation of MaSCs. Loss of AP-2γ in the basal epithelium profoundly altered the transcriptomes and decreased the number of cells within several clusters of mammary epithelial cells, including adult MaSCs and luminal progenitors. AP-2γ regulated the expression of genes known to be required for mammary development, including Cebpb, Nfkbia, and Rspo1. As a result, AP-2γ-deficient mice exhibited repressed mammary gland ductal outgrowth and inhibition of regenerative capacity. The findings demonstrate that AP-2γ can regulate development of mammary gland structures potentially regulating maintenance and differentiation of multipotent MaSCs.
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http://dx.doi.org/10.1016/j.stemcr.2020.12.002DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7897584PMC
January 2021

Body fatness and mTOR pathway activation of breast cancer in the Women's Circle of Health Study.

NPJ Breast Cancer 2020 21;6:45. Epub 2020 Sep 21.

Department of Cancer Prevention and Control, Roswell Park Comprehensive Cancer Center, Buffalo, NY USA.

Energy imbalance has an important role in breast cancer prognosis. Hyperactive mechanistic Target of Rapamycin (mTOR) pathway is associated with breast tumor growth, but the extent to which body fatness is associated with mTOR pathway activities in breast cancer is unclear. We performed immunostaining for mTOR, phosphorylated (p)-mTOR, p-AKT, and p-p70S6K in tumor tissue from 590 women (464 African Americans/Blacks and 126 Whites) with newly diagnosed invasive breast cancer in the Women's Circle of Health Study. Anthropometric measures were taken by study staff, and body composition was measured by bioelectrical impedance analysis. Linear regressions were used to estimate percent differences in protein expression between categories of body mass index (BMI), waist circumference, waist/hip ratio, fat mass, fat mass index, and percent body fat. We observed that BMI ≥ 35.0 vs. <25 kg/m was associated with 108.3% (95% CI = 16.9%-270.9%) and 101.8% (95% CI = 17.0%-248.8%) higher expression in p-mTOR and normalized p-mTOR, i.e., p-mTOR/mTOR, respectively. Quartiles 4 vs. 1 of waist/hip ratio was associated with 41.8% (95% CI = 5.81%-89.9%) higher mTOR expression. Similar associations were observed for the body fat measurements, particularly in patients with estrogen receptor-negative (ER-) tumors, but not in those with ER+ tumors, although the differences in associations were not significant. This tumor-based study found positive associations between body fatness and mTOR pathway activation, evident by a p-mTOR expression, in breast cancer. Our findings suggest that mTOR inhibition can be a treatment strategy to prevent the recurrence of these tumors in obese individuals.
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http://dx.doi.org/10.1038/s41523-020-00187-4DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7505987PMC
September 2020

Obesity and Breast Cancer: A Case of Inflamed Adipose Tissue.

Cancers (Basel) 2020 Jun 25;12(6). Epub 2020 Jun 25.

Department of Pathology, Immunology and Laboratory Medicine, Gainesville, FL 32610, USA.

Obesity is associated with an increased risk of estrogen receptor-positive breast cancer in postmenopausal women and a worse prognosis for all major breast cancer subtypes regardless of menopausal status. While the link between obesity and the pathogenesis of breast cancer is clear, the molecular mechanism of this association is not completely understood due to the complexity of both obesity and breast cancer. The aim of this review is to highlight the association between obesity and breast cancer and discuss the literature, which indicates that this association is due to chronic adipose tissue inflammation. We will discuss the epidemiological data for the association between breast cancer incidence and progression as well as the potential molecular mechanisms for this association. We will focus on the role of inflammation within the adipose tissue during the pathogenesis of breast cancer. A better understanding of how obesity and adipose tissue inflammation affects the pathogenesis of breast cancer will lead to new strategies to reduce breast cancer risk and improve patient outcomes for obese patients.
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http://dx.doi.org/10.3390/cancers12061686DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7352736PMC
June 2020

IL-1 Signaling in Tumor Microenvironment.

Adv Exp Med Biol 2020 ;1240:1-23

Department of Pathology, Immunology and Laboratory Medicine, UF Health Cancer Center, University of Florida, Gainesville, FL, USA.

Interleukin 1 (IL-1) has long been known for its pleiotropic effects on inflammation that plays a complex, and sometimes contrasting, role in different stages of cancer development. As a major proinflammatory cytokine, IL-1β is mainly expressed by innate immune cells. IL-1α, however, is expressed by various cell types under physiological and pathological conditions. IL-1R1 is the main receptor for both ligands and is expressed by various cell types, including innate and adaptive immune cell types, epithelial cells, endothelial cells, adipocytes, chondrocytes, fibroblasts, etc. IL-1 and IL-1R1 receptor interaction leads to a set of common signaling pathways, mainly the NF-kB and MAP kinase pathways, as a result of complex positive and negative regulations. The variety of cell types with IL-1R1 expression dictates the role of IL-1 signaling at different stages of cancer, which under certain circumstances leads to contrasting roles in tumor development. Recent availability of IL-1R1 conditional knockout mouse model has made it possible to dissect the role of IL-1/IL-1R1 signaling transduction in different cell types within the tumor microenvironment. This chapter will focus on the role of IL-1/IL-1R1 in different cell types within the tumor microenvironment and discuss the potential of targeting this pathway in cancer therapy.
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http://dx.doi.org/10.1007/978-3-030-38315-2_1DOI Listing
February 2020

Cancer cell-intrinsic function of CD177 in attenuating β-catenin signaling.

Oncogene 2020 04 10;39(14):2877-2889. Epub 2020 Feb 10.

Department of Pathology, Immunology and Laboratory Medicine, College of Medicine, University of Florida, Gainesville, FL, 32610, USA.

Aiming to identify immune molecules with a novel function in cancer pathogenesis, we found the cluster of differentiation 177 (CD177), a known neutrophil antigen, to be positively correlated with relapse-free, metastasis-free, or overall survival in breast cancer. In addition, CD177 expression is correlated with good prognosis in several other solid cancers including prostate, cervical, and lung. Focusing on breast cancer, we found that CD177 is expressed in normal breast epithelial cells and is significantly reduced in invasive cancers. Loss of CD177 leads to hyperproliferative mammary epithelium and contributes to breast cancer pathogenesis. Mechanistically, we found that CD177-deficiency is associated with an increase in β-catenin signaling. Here we identified CD177 as a novel regulator of mammary epithelial proliferation and breast cancer pathogenesis likely via the modulation of Wnt/β-catenin signaling pathway, a key signaling pathway involved in multiple cancer types.
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http://dx.doi.org/10.1038/s41388-020-1203-xDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7127950PMC
April 2020

TRAF2 Ser-11 Phosphorylation Promotes Cytosolic Translocation of the CD40 Complex To Regulate Downstream Signaling Pathways.

Mol Cell Biol 2020 04 13;40(9). Epub 2020 Apr 13.

Department of Pathology, University of Iowa Carver College of Medicine, Iowa City, Iowa, USA

CD40 plays an important role in immune responses by activating the c-Jun N-terminal protein kinase (JNK) and NF-κB pathways; however, the precise mechanisms governing the spatiotemporal activation of these two signaling pathways are not fully understood. Here, using four different TRAF2-deficient cell lines (A20.2J, CH12.LX, HAP1, and mouse embryonic fibroblasts [MEFs]) reconstituted with wild-type or phosphorylation mutant forms of TRAF2, along with immunoprecipitation, immunoblotting, gene expression, and immunofluorescence analyses, we report that CD40 ligation elicits TANK-binding kinase 1 (TBK1)-mediated phosphorylation of TRAF2 at Ser-11. This phosphorylation interfered with the interaction between TRAF2's RING domain and membrane phospholipids and enabled translocation of the TRAF2 complex from CD40 to the cytoplasm. We also observed that this cytoplasmic translocation is required for full activation of the JNK pathway and the secondary phase of the NF-κB pathway. Moreover, we found that in the absence of Ser-11 phosphorylation, the TRAF2 RING domain interacts with phospholipids, leading to the translocation of the TRAF2 complex to lipid rafts, resulting in its degradation and activation of the noncanonical NF-κB pathway. Thus, our results provide new insights into the CD40 signaling mechanisms whereby Ser-11 phosphorylation controls RING domain-dependent subcellular localization of TRAF2 to modulate the spatiotemporal activation of the JNK and NF-κB pathways.
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http://dx.doi.org/10.1128/MCB.00429-19DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7156217PMC
April 2020

Contribution of synergism between PHF8 and HER2 signalling to breast cancer development and drug resistance.

EBioMedicine 2020 Jan 7;51:102612. Epub 2020 Jan 7.

Department of Anatomy and Cell Biology, Carver College of Medicine, University of Iowa, Iowa City, IA, 52242, USA. Electronic address:

Background: HER2 plays a critical role in tumourigenesis and is associated with poor prognosis of patients with HER2-positive breast cancers. Although anti-HER2 drugs are beneficial for treating breast cancer, de novo, or acquired resistance often develops. Epigenetic factors are increasingly targeted for therapy; however, such mechanisms that interact with HER2 signalling are poorly understood.

Methods: RNA sequencing was performed to identify PHF8 targets downstream of HER2 signalling. CHIP-qPCR were used to investigate how PHF8 regulates HER2 transcription. ELISA determined cytokine secretion. Cell-based assay revealed a feed forward loop in HER2 signalling and then evaluated in vivo.

Findings: We report the synergistic interplay between histone demethylase PHF8 and HER2 signalling. Specifically, PHF8 levels were elevated in HER2-positive breast cancers and upregulated by HER2. PHF8 functioned as a coactivator that regulated the expression of HER2, markers of the HER2-driven epithelial-to-mesenchymal transition and cytokines. The HER2-PHF8-IL-6 regulatory axis was active in cell lines and in newly established MMTV-Her2/MMTV-Cre/Phf8°° mouse models, which revealed the oncogenic function of Phf8 in breast cancer for the first time. Further, the PHF8-IL-6 axis contributed to the resistance to trastuzumab in vitro and may play a critical role in the infiltration of T cells in HER2-driven breast cancers.

Interpretation: These findings provided informative mechanistic insight into the potential application of PHF8 inhibitors to overcome resistance to anti-HER2 therapies.

Funding: This work was supported by Carver Trust Young Investigator Award (01-224 to H.H.Q); and a Breast Cancer Research Award (to H.H.Q.).
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http://dx.doi.org/10.1016/j.ebiom.2019.102612DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7000350PMC
January 2020

A selective BCL-X PROTAC degrader achieves safe and potent antitumor activity.

Nat Med 2019 12 2;25(12):1938-1947. Epub 2019 Dec 2.

Department of Pharmacodynamics, University of Florida, Gainesville, FL, USA.

B-cell lymphoma extra large (BCL-X) is a well-validated cancer target. However, the on-target and dose-limiting thrombocytopenia limits the use of BCL-X inhibitors, such as ABT263, as safe and effective anticancer agents. To reduce the toxicity of ABT263, we converted it into DT2216, a BCL-X proteolysis-targeting chimera (PROTAC), that targets BCL-X to the Von Hippel-Lindau (VHL) E3 ligase for degradation. We found that DT2216 was more potent against various BCL-X-dependent leukemia and cancer cells but considerably less toxic to platelets than ABT263 in vitro because VHL is poorly expressed in platelets. In vivo, DT2216 effectively inhibits the growth of several xenograft tumors as a single agent or in combination with other chemotherapeutic agents, without causing appreciable thrombocytopenia. These findings demonstrate the potential to use PROTAC technology to reduce on-target drug toxicities and rescue the therapeutic potential of previously undruggable targets. Furthermore, DT2216 may be developed as a safe first-in-class anticancer agent targeting BCL-X.
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http://dx.doi.org/10.1038/s41591-019-0668-zDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6898785PMC
December 2019

Preparation and Characterization of Flame-Retarded Poly(butylene terephthalate)/Poly(ethylene terephthalate) Blends: Effect of Content and Type of Flame Retardant.

Polymers (Basel) 2019 Oct 31;11(11). Epub 2019 Oct 31.

Polymer Processing Lab, Shanghai Key Laboratory of Advanced Polymeric Materials, Key Laboratory for Ultrafine Materials of Ministry of Education, School of Materials Science and Engineering, East China University of Science and Technology, Shanghai 200237, China.

A flame retardant named TAD was synthesized by the reaction of 9,10-Dihydro-9-oxa-10-phosphaphenanthrene-10-oxide and triallyl isocyanurate at first. Then, novel flameretarded materials based on PBT and PET resin were formulated via melt blending with TAD, expandable graphite (EG), and a mixture of both. The effect of flame retardant type and TAD content on the flame behavior of PBT/PET blend was carefully investigated. TAD contributed towards higher LOI value and better UL-94 performance than EG. However, the best V-0 rating in the UL-94 test was achieved by the incorporation of TAD/EG mixture into the resin matrix. TAD/EG combination exhibited clear synergistic effect on both reducing the flaming intensity and increasing the residual char layer, as confirmed by cone calorimeter tests and TGA results. SEM images combined with XPS analysis revealed that expansion and migration of EG locked the P-containing radicals from decomposing TAD into the condensed phase, which led to the formation of compact and continuous char layers. All the results in our studies demonstrate that incorporation of TAD with a charring agent EG is an effective and promising technique to develop flame-retarded PBT/PET material, which has high potential for applications in the areas of electronic devices, household products, and automotive parts.
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http://dx.doi.org/10.3390/polym11111784DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6918192PMC
October 2019

Off-Target Deletion of Conditional Allele in the Mouse Line under Specific Setting.

Cells 2019 10 24;8(11). Epub 2019 Oct 24.

Department of Internal Medicine, Ohio State University College of Medicine and Wexner Medical Center, Columbus, OH 43210, USA.

The Cre-LoxP conditional knockout strategy has been used extensively to study gene function in a specific cell-type. In this study, the authors tried to engineer mice in which the gene is conditionally knocked out in Treg cells. Unexpectedly, the conditional allele was completely deleted with a low frequency in some mice harboring floxed allele under specific settings. It was found that the germline recombination of floxed allele, which caused knock out mice, occurred in the male mice harboring floxed allele. Even though the authors documented that is expressed in the testis, the germline recombination was not caused by the germline expression of Cre, which was driven by the promoter. The germline recombination may be caused by the unspecific expression of Cre recombinase in the fetus, in which the floxed allele of some stem cells with development potential to germ cells may be recombined. Additionally, this study found that the floxed allele was recombined in non-T cells of some mice, which need to be characterized. Our results also suggest that using male mice with a low frequency of recombined gene allele can reduce the risk of having full knock out mice.
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http://dx.doi.org/10.3390/cells8111309DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6912351PMC
October 2019

A Gene Signature Is Predictive of Outcome in HER2-Positive Breast Cancer.

Mol Cancer Res 2020 01 16;18(1):46-56. Epub 2019 Oct 16.

Department of Surgery, University of Iowa, Iowa City, Iowa.

The AP-2γ transcription factor, encoded by the gene, regulates the expression of estrogen receptor-alpha (ERα) and other genes associated with hormone response in luminal breast cancer. Little is known about the role of AP-2γ in other breast cancer subtypes. A subset of HER2 breast cancers with amplification of the gene locus becomes addicted to AP-2γ. Herein, we sought to define AP-2γ gene targets in HER2 breast cancer and identify genes accounting for physiologic effects of growth and invasiveness regulated by AP-2γ. Comparing HER2 cell lines that demonstrated differential response to growth and invasiveness with knockdown of , we identified a set of 68 differentially expressed target genes. and were among the genes differentially regulated by AP-2γ and that contributed to growth and invasiveness. Pathway analysis implicated the /p38δ and retinoic acid regulatory nodes, which were confirmed to display divergent responses in different HER2 cancer lines. To confirm the clinical relevance of the genes identified, the AP-2γ gene signature was found to be highly predictive of outcome in patients with HER2 breast cancer. We conclude that AP-2γ regulates a set of genes in HER2 breast cancer that drive cancer growth and invasiveness. The AP-2γ gene signature predicts outcome of patients with HER2 breast cancer and pathway analysis predicts that subsets of patients will respond to drugs that target the MAPK or retinoic acid pathways. IMPLICATIONS: A set of genes regulated by AP-2γ in HER2 breast cancer that drive proliferation and invasion were identified and provided a gene signature that is predictive of outcome in HER2 breast cancer.
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http://dx.doi.org/10.1158/1541-7786.MCR-19-0359DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6942205PMC
January 2020

Identification of novel TGF-β regulated genes with pro-migratory roles.

Biochim Biophys Acta Mol Basis Dis 2019 12 23;1865(12):165537. Epub 2019 Aug 23.

Department of Anatomy and Cell Biology, Carver College of Medicine, University of Iowa, Iowa City, IA 52242, USA. Electronic address:

Transforming growth factor-β (TGF-β) signaling plays fundamental roles in the development and homeostasis of somatic cells. Dysregulated TGF-β signaling contributes to cancer progression and relapse to therapies by inducing epithelial-to-mesenchymal transition (EMT), enriching cancer stem cells, and promoting immunosuppression. Although many TGF-β-regulated genes have been identified, only a few datasets were obtained by next-generation sequencing. In this study, we performed RNA-sequencing analysis of MCF10A cells and identified 1166 genes that were upregulated and 861 genes that were downregulated by TGF-β. Gene set enrichment analysis revealed that focal adhesion and metabolic pathways were the top enriched pathways of the up- and downregulated genes, respectively. Genes in these pathways also possess significant predictive value for renal cancers. Moreover, we confirmed that TGF-β induced expression of MICAL1 and 2, and the histone demethylase, KDM7A, and revealed their regulatory roles on TGF-β-induced cell migration. We also show a critical effect of KDM7A in regulating the acetylation of H3K27 on TGF-β-induced genes. In sum, this study identified novel effectors that mediate the pro-migratory role of TGF-β signaling, paving the way for future studies that investigate the function of MICAL family members in cancer and the novel epigenetic mechanisms downstream TGF-β signaling.
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http://dx.doi.org/10.1016/j.bbadis.2019.165537DOI Listing
December 2019

ROR1 Potentiates FGFR Signaling in Basal-Like Breast Cancer.

Cancers (Basel) 2019 May 24;11(5). Epub 2019 May 24.

Department of Pathology, Immunology, and Laboratory Medicine, University of Florida, Gainesville, FL 32610, USA.

Among all breast cancer types, basal-like breast cancer (BLBC) represents an aggressive subtype that lacks targeted therapy. We and others have found that receptor tyrosine kinase-like orphan receptor 1 (ROR1) is overexpressed in BLBC and other types of cancer and that ROR1 is significantly correlated with patient prognosis. In addition, using primary patient-derived xenografts (PDXs) and -knockout BLBC cells, we found that ROR1 cells form tumors in immunodeficient mice. We developed an anti-ROR1 immunotoxin and found that targeting ROR1 significantly kills ROR1 cancer cells and slows down tumor growth in ROR1 xenografts. Our bioinformatics analysis revealed that ROR1 expression is commonly associated with the activation of FGFR-mediated signaling pathway. Further biochemical analysis confirmed that ROR1 stabilized FGFR expression at the posttranslational level by preventing its degradation. CRISPR/Cas9-mediated knockout significantly reduced cancer cell invasion at cellular levels by lowering FGFR protein and consequent inactivation of AKT. Our results identified a novel signaling regulation from ROR1 to FGFR and further confirm that ROR1 is a potential therapeutic target for ROR1 BLBC cells.
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http://dx.doi.org/10.3390/cancers11050718DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6562526PMC
May 2019

Exceptional responses with sequential metronomic temozolomide after pembrolizumab failure in patients with metastatic melanoma.

Melanoma Res 2019 12;29(6):643-647

Departments of Hematology, Oncology, and Blood and Marrow Transplantation.

Pembrolizumab is an effective therapy for patients with metastatic melanoma. However, not all patients derive benefit. It is postulated that an increase in regulatory T cells in melanoma patients can impair the response to immunotherapies. Continuous low-dose temozolomide has shown to cause immunomodulatory effects resulting in CD4 + lymphopenia due to which Treg population can also decrease significantly. Herein, we present a case series of three patients with metastatic melanoma who after progression on pembrolizumab showed a radiological response after just one cycle of metronomic temozolomide (75 mg/m daily for 6 weeks on 8-week cycle). This suggests that temozolomide may be a useful alternative for patients with metastatic melanoma after disease progression on pembrolizumab. Further studies with biomarkers are warranted to elucidate which patients will derive benefit from this strategy.
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http://dx.doi.org/10.1097/CMR.0000000000000592DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6717692PMC
December 2019

Single-Cell Profiling of Cutaneous T-Cell Lymphoma Reveals Underlying Heterogeneity Associated with Disease Progression.

Clin Cancer Res 2019 05 4;25(10):2996-3005. Epub 2019 Feb 4.

Cancer Biology Graduate Program, University of Iowa, College of Medicine, Iowa City, Iowa.

Purpose: Cutaneous T-cell lymphomas (CTCL), encompassing a spectrum of T-cell lymphoproliferative disorders involving the skin, have collectively increased in incidence over the last 40 years. Sézary syndrome is an aggressive form of CTCL characterized by significant presence of malignant cells in both the blood and skin. The guarded prognosis for Sézary syndrome reflects a lack of reliably effective therapy, due, in part, to an incomplete understanding of disease pathogenesis.

Experimental Design: Using single-cell sequencing of RNA and the machine-learning reverse graph embedding approach in the Monocle package, we defined a model featuring distinct transcriptomic states within Sézary syndrome. Gene expression used to differentiate the unique transcriptional states were further used to develop a boosted tree classification for early versus late CTCL disease.

Results: Our analysis showed the involvement of malignant T cells during clonal evolution, transitioning from T cells to or (HELIOS) tumor cells. Transcriptomic diversities in a clonal tumor can be used to predict disease stage, and we were able to characterize a gene signature that predicts disease stage with close to 80% accuracy. was found to be the most important factor to predict early disease in CTCL, along with another 19 genes used to predict CTCL stage.

Conclusions: This work offers insight into the heterogeneity of Sézary syndrome, providing better understanding of the transcriptomic diversities within a clonal tumor. This transcriptional heterogeneity can predict tumor stage and thereby offer guidance for therapy.
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http://dx.doi.org/10.1158/1078-0432.CCR-18-3309DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6659117PMC
May 2019

The clinical promise of immunotherapy in triple-negative breast cancer.

Cancer Manag Res 2018 10;10:6823-6833. Epub 2018 Dec 10.

Holden Comprehensive Cancer Center, University of Iowa, Iowa City, IA, USA,

Triple-negative breast cancer (TNBC) is a heterogeneous disease with poorer outcomes compared to other breast cancer subtypes. Contributing to the worse prognosis in TNBC is the higher rates of relapse and rapid progression after relapse. Advances in targeted therapeutics and conventional chemotherapy for TNBC have been stymied due to the lack of specific targets. Moreover, the responses to chemotherapy in TNBC lack durability, partially accounting for the higher rates of relapse. Immunotherapy, notably immune-checkpoint blockade, has shown to improve survival and maintain robust antitumor responses in both hematologic and solid malignancies. Unlike lung cancer, melanoma, and bladder cancer, most breast cancers are not inherently immunogenic and typically have low T cell infiltration. However, among breast cancer subtypes, TNBC is characterized by greater tumor immune infiltrate and higher degree of stromal and intratumoral tumor-infiltrating lymphocytes (TILs), a predictive marker for responses to immunotherapy. Moreover, in TNBC, the high number of stromal TILs is predictive of more favorable survival outcomes and response to chemotherapy. Immunotherapy is being extensively explored in TNBC and clinical trials are showing some promising results. This article focuses on the rationale for immunotherapy in TNBC, to explore and discuss preclinical data, results from early clinical trials, and to summarize some ongoing trials. We will also discuss the potential application of immunotherapy in TNBC from a clinician's perspective.
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http://dx.doi.org/10.2147/CMAR.S185176DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6292225PMC
December 2018

Obesity-associated inflammation promotes angiogenesis and breast cancer via angiopoietin-like 4.

Oncogene 2019 03 5;38(13):2351-2363. Epub 2018 Dec 5.

Department of Pathology, University of Iowa Carver College of Medicine, Iowa City, IA, 52242, USA.

Obesity is a risk factor for breast cancer and also predicts poor clinical outcomes regardless of menopausal status. Contributing to the poor clinical outcomes is the suboptimal efficacy of standard therapies due to dose limiting toxicities and obesity-related complications, highlighting the need to develop novel therapeutic approaches for treating obese patients. We recently found that obesity leads to an increase in tumor-infiltrating macrophages with activated NLRC4 inflammasome and increased interleukin (IL)-1β production. IL-1β, in turn, leads to increased angiogenesis and cancer progression. Using Next Generation RNA sequencing, we identified an NLRC4/IL-1β-dependent upregulation of angiopoietin-like 4 (ANGPTL4), a known angiogenic factor in cancer, in tumors from obese mice. ANGPTL4-deficiency by genetic knockout or treatment with a neutralizing antibody led to a significant reduction in obesity-induced angiogenesis and tumor growth. At a mechanistic level, ANGPTL4 expression is induced by IL-1β from primary adipocytes in a manner dependent on NF-κB- and MAP kinase-activation, which is further enhanced by hypoxia. This report shows that adipocyte-derived ANGPTL4 drives disease progression under obese conditions and is a potential therapeutic target for treating obese breast cancer patients.
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http://dx.doi.org/10.1038/s41388-018-0592-6DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6440811PMC
March 2019

TRGAted: A web tool for survival analysis using protein data in the Cancer Genome Atlas.

F1000Res 2018 10;7:1235. Epub 2018 Aug 10.

Holden Comprehensive Cancer Center, University of Iowa, Iowa City, Iowa, 52245, USA.

Reverse-phase protein arrays (RPPAs) are a highthroughput approach to protein quantification utilizing antibody-based micro-to-nano scale dot blot. Within the Cancer Genome Atlas (TCGA), RPPAs were used to quantify over 200 proteins in 8,167 tumor and metastatic samples. Protein-level data has particular advantages in assessing putative prognostic or therapeutic targets in tumors. However, many of the available pipelines do not allow for the partitioning of clinical and RPPA information to make meaningful conclusions. We developed a cloud-based application, TRGAted to enable researchers to better examine patient survival based on single or multiple proteins across 31 cancer types in the TCGA. TRGAted contains up-to-date overall survival, disease-specific survival, disease-free interval and progression-free interval information. Furthermore, survival information for primary tumor samples can be stratified based on gender, age, tumor stage, histological type, and subtype, allowing for highly adaptive and intuitive user experience. The code and processed data are open sourced and available on github and contains a tutorial built into the application for assisting users.
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http://dx.doi.org/10.12688/f1000research.15789.2DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6173115PMC
November 2019

Re-Evaluating E-Cadherin and β-Catenin: A Pan-Cancer Proteomic Approach with an Emphasis on Breast Cancer.

Am J Pathol 2018 08 4;188(8):1910-1920. Epub 2018 Jun 4.

Department of Pathology, College of Medicine, University of Iowa, Iowa City, Iowa; Cancer Biology Graduate Program, College of Medicine, University of Iowa, Iowa City, Iowa; Medical Scientist Training Program, College of Medicine, University of Iowa, Iowa City, Iowa; Holden Comprehensive Cancer Center, College of Medicine, University of Iowa, Iowa City, Iowa; Free Radical and Radiation Biology Program, College of Medicine, University of Iowa, Iowa City, Iowa. Electronic address:

E-cadherin is conventionally considered to be a good prognostic marker in cancer. The loss of E-cadherin is one of the key hallmarks of epithelial-to-mesenchymal transition, a biological process that promotes cancer cell invasiveness and metastasis. Recent evidence has cast doubt on the importance of epithelial-to-mesenchymal transition in metastasis. The availability of protein-level data in the Cancer Genome Atlas allows for the quantitative analysis of protein and prognosis. The prognostic values of E-cadherin and β-catenin were revisited across 19 cancer types, and high E-cadherin was found to correlate with good prognosis in most cancers. Conversely, higher E-cadherin and β-catenin correlated with shorter survival in invasive breast carcinoma. Stratifying breast cancers by histologic subtype revealed that the poor prognosis of E-cadherin and β-catenin proteins was characteristic of infiltrating ductal, but not lobular, carcinomas. To further corroborate the protein findings and examine cellular localization, immunohistochemistry was used for E-cadherin and β-catenin in 163 breast patient samples from the Iowa cohort. Most previous studies showing that reduced or absent E-cadherin and β-catenin was inversely associated with tumor stages in ductal carcinomas were confirmed. Taken together, these results lead us to question the prognostic values of E-cadherin and β-catenin in ductal carcinomas and indicate a complicated role of E-cadherin and β-catenin in breast cancer progression.
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http://dx.doi.org/10.1016/j.ajpath.2018.05.003DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6119824PMC
August 2018

Keeping Tumors in Check: A Mechanistic Review of Clinical Response and Resistance to Immune Checkpoint Blockade in Cancer.

J Mol Biol 2018 07 22;430(14):2014-2029. Epub 2018 May 22.

Department of Pathology, University of Iowa, College of Medicine, Iowa City, IA 52242-11, USA; Cancer Biology Graduate Program, University of Iowa, College of Medicine, Iowa City, IA 52242-11, USA; Medical Scientist Training Program, University of Iowa, College of Medicine, Iowa City, IA 52242-11, USA; Holden Comprehensive Cancer Center, University of Iowa, College of Medicine, Iowa City, IA 52242-11, USA. Electronic address:

Immune checkpoints are a diverse set of inhibitory signals to the immune system that play a functional role in adaptive immune response and self-tolerance. Dysregulation of these pathways is a vital mechanism in the avoidance of immune destruction by tumor cells. Immune checkpoint blockade (ICB) refers to targeted strategies to disrupt the tumor co-opted immune suppression to enhance anti-tumor immunity. Cytotoxic T-lymphocyte-associated protein 4 (CTLA-4) and programmed cell death 1 (PD-1) are two immune checkpoints that have the widest range of antibody-based therapies. These therapies have gone from promising approaches to Food and Drug Administration-approved first- and second-line agents for a number of immunogenic cancers. The burgeoning investigations of ICB efficacy in blood and solid cancers have underscored the importance of identifying the predictors of response and resistance to ICB. Identification of response correlates is made complicated by the observations of mixed reactions, or different responses in multiple lesions from the same patient, and delayed responses that can occur over a year after the induction therapy. Factors that can influence response and resistance in ICB can illuminate underlying molecular mechanisms of immune activation and suppression. These same response predictors can guide the identification of patients who would benefit from ICB, reduce off-target immune-relate adverse events, and facilitate the use of combinatorial therapies to increase efficacy. Here we review the underlying principles of immune checkpoint therapy and results of single-agent ICB clinical trials, and summarize the predictors of response and resistance.
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http://dx.doi.org/10.1016/j.jmb.2018.05.030DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6071324PMC
July 2018

Stabilization of NF-κB-Inducing Kinase Suppresses MLL-AF9-Induced Acute Myeloid Leukemia.

Cell Rep 2018 01;22(2):350-358

Department of Pathology, Carver College of Medicine, University of Iowa, Iowa City, IA 52242, USA. Electronic address:

Canonical NF-κB signaling is constitutively activated in acute myeloid leukemia (AML) stem cells and is required for maintenance of the self-renewal of leukemia stem cells (LSCs). However, any potential role for NF-κB non-canonical signaling in AML has been largely overlooked. Here, we report that stabilization of NF-κB-inducing kinase (NIK) suppresses AML. Mechanistically, stabilization of NIK activates NF-κB non-canonical signaling and represses NF-κB canonical signaling. In addition, stabilization of NIK-induced activation of NF-κB non-canonical signaling upregulates Dnmt3a and downregulates Mef2c, which suppresses and promotes AML development, respectively. Importantly, by querying the connectivity MAP using up- and downregulated genes that are present exclusively in NIK-stabilized LSCs, we discovered that verteporfin has anti-AML effects, suggesting that repurposing verteporfin to target myeloid leukemia is worth testing clinically. Our data provide a scientific rationale for developing small molecules to stabilize NIK specifically in myeloid leukemias as an attractive therapeutic option.
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http://dx.doi.org/10.1016/j.celrep.2017.12.055DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5810947PMC
January 2018
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