Publications by authors named "Roderick T Bronson"

302 Publications

heterozygosity and replication stress drive esophageal cancer development in a mouse model.

Proc Natl Acad Sci U S A 2021 Oct;118(41)

Center for Personalized Cancer Therapy, University of Massachusetts Boston, Boston, MA 02125;

germline mutations are associated with an increased risk of breast and ovarian cancer. Recent findings of others suggest that mutation carriers also bear an increased risk of esophageal and gastric cancer. Here, we employ a mouse model to show that unresolved replication stress (RS) in heterozygous cells drives esophageal tumorigenesis in a model of the human equivalent. This model employs 4-nitroquinoline-1-oxide (4NQO) as an RS-inducing agent. Upon drinking 4NQO-containing water, heterozygous mice formed squamous cell carcinomas of the distal esophagus and forestomach at a much higher frequency and speed (∼90 to 120 d) than did wild-type (WT) mice, which remained largely tumor free. Their esophageal tissue, but not that of WT control mice, revealed evidence of overt RS as reflected by intracellular CHK1 phosphorylation and 53BP1 staining. These mutant tumors also revealed higher genome mutation rates than those of control animals; the mutational signature SBS4, which is associated with tobacco-induced tumorigenesis; and a loss of heterozygosity (LOH). This uniquely accelerated tumor model is also relevant to human esophageal squamous cell carcinoma, an often lethal tumor.
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http://dx.doi.org/10.1073/pnas.2108421118DOI Listing
October 2021

Combined Supplementation with Vitamin B-6 and Curcumin is Superior to Either Agent Alone in Suppressing Obesity-Promoted Colorectal Tumorigenesis in Mice.

J Nutr 2021 Sep 29. Epub 2021 Sep 29.

Vitamins & Carcinogenesis Laboratory, Jean Mayer USDA Human Nutrition Research Center on Aging at Tufts University, Boston, MA, USA.

Background: Obesity increases the colorectal cancer risk, in part by elevating colonic proinflammatory cytokines. Curcumin (CUR) and supplemental vitamin B-6 each suppress colonic inflammation.

Objectives: We examined whether the combination of CUR and vitamin B-6 amplifies each supplement's effects and thereby suppress obesity-promoted tumorigenesis.

Methods: Male Friend Virus B (FVB) mice (4-week-old; n = 110) received 6 weekly injections of azoxymethane beginning 1 week after arrival. Thereafter, they were randomized to receive a low-fat diet (10% energy from fat), a high-fat diet (HFD; 60% energy from fat), a HFD containing 0.2% CUR, a HFD containing supplemental vitamin B-6 (24 mg pyridoxine HCl/kg), or a HFD containing both CUR and supplemental vitamin B-6 (C + B) for 15 weeks. Colonic inflammation, assessed by fecal calprotectin, and tumor metrics were the primary endpoints. The anti-inflammatory efficacy of the combination was also determined in human colonic organoids.

Results: HFD-induced obesity produced a 2.6-fold increase in plasma IL-6 (P < 0.02), a 1.9-fold increase in fecal calprotectin (P < 0.05), and a 2.2-fold increase in tumor multiplicity (P < 0.05). Compared to the HFD group, the C + B combination, but not the individual agents, decreased fecal calprotectin (66%; P < 0.01) and reduced tumor multiplicity and the total tumor burden by 60%-80% (P < 0.03) in an additive fashion. The combination of C + B also significantly downregulated colonic phosphatidylinositol-4,5-bisphosphate 3-kinase, Wnt, and NF-κB signaling by 31%-47% (P < 0.05), effects largely absent with the single agents. Observations that may explain how the 2 agents work additively include a 2.8-fold increased colonic concentration of 3-hydroxyanthranillic acid (P < 0.05) and a 1.3-fold higher colonic concentration of the active coenzymatic form of vitamin B-6 (P < 0.05). In human colonic organoids, micromolar concentrations of CUR, vitamin B-6, and their combination suppressed secreted proinflammatory cytokines by 41%-93% (P < 0.03), demonstrating relevance to humans.

Conclusions: In this mouse model, C + B is superior to either agent alone in preventing obesity-promoted colorectal carcinogenesis. Augmented suppression of procancerous signaling pathways may be the means by which this augmentation occurs.
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http://dx.doi.org/10.1093/jn/nxab320DOI Listing
September 2021

SMARCA4 inactivation promotes lineage-specific transformation and early metastatic features in the lung.

Cancer Discov 2021 Sep 24. Epub 2021 Sep 24.

Koch Institute for Integrative Cancer Research, Massachusetts Institute of Technology

SMARCA4/BRG1 encodes for one of two mutually exclusive ATPases present in mammalian SWI/SNF chromatin remodeling complexes and is frequently mutated in human lung adenocarcinoma. However, the functional consequences of SMARCA4 mutation on tumor initiation, progression, and chromatin regulation in lung cancer remain poorly understood. Here, we demonstrate that loss of Smarca4 sensitizes CCSP+ cells within the lung in a cell-type dependent fashion to malignant transformation and tumor progression, resulting in highly advanced dedifferentiated tumors and increased metastatic incidence. Consistent with these phenotypes, Smarca4-deficient primary tumors lack lung lineage transcription factor activities and resemble a metastatic cell state. Mechanistically, we show that Smarca4 loss impairs the function of all three classes of SWI/SNF complexes, resulting in decreased chromatin accessibility at lung lineage motifs and ultimately accelerating tumor progression. Thus, we propose that the SWI/SNF complex - via Smarca4 - acts as a gatekeeper for lineage-specific cellular transformation and metastasis during lung cancer evolution.
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http://dx.doi.org/10.1158/2159-8290.CD-21-0248DOI Listing
September 2021

The CD155/TIGIT axis promotes and maintains immune evasion in neoantigen-expressing pancreatic cancer.

Cancer Cell 2021 Oct 5;39(10):1342-1360.e14. Epub 2021 Aug 5.

David H. Koch Institute for Integrative Cancer Research, Massachusetts Institute of Technology, Cambridge, MA 02139, USA; Department of Biology, Massachusetts Institute of Technology, Cambridge, MA 02139, USA. Electronic address:

The CD155/TIGIT axis can be co-opted during immune evasion in chronic viral infections and cancer. Pancreatic adenocarcinoma (PDAC) is a highly lethal malignancy, and immune-based strategies to combat this disease have been largely unsuccessful to date. We corroborate prior reports that a substantial portion of PDAC harbors predicted high-affinity MHC class I-restricted neoepitopes and extend these findings to advanced/metastatic disease. Using multiple preclinical models of neoantigen-expressing PDAC, we demonstrate that intratumoral neoantigen-specific CD8 T cells adopt multiple states of dysfunction, resembling those in tumor-infiltrating lymphocytes of PDAC patients. Mechanistically, genetic and/or pharmacologic modulation of the CD155/TIGIT axis was sufficient to promote immune evasion in autochthonous neoantigen-expressing PDAC. Finally, we demonstrate that the CD155/TIGIT axis is critical in maintaining immune evasion in PDAC and uncover a combination immunotherapy (TIGIT/PD-1 co-blockade plus CD40 agonism) that elicits profound anti-tumor responses in preclinical models, now poised for clinical evaluation.
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http://dx.doi.org/10.1016/j.ccell.2021.07.007DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8511341PMC
October 2021

Gene therapy for tuberous sclerosis complex type 2 in a mouse model by delivery of AAV9 encoding a condensed form of tuberin.

Sci Adv 2021 Jan 8;7(2). Epub 2021 Jan 8.

Molecular Neurogenetics Unit, Department of Neurology and Center for Molecular Imaging Research, Department of Radiology, Massachusetts General Hospital, and Program in Neuroscience, Harvard Medical School, Boston, MA, USA.

Tuberous sclerosis complex (TSC) results from loss of a tumor suppressor gene - 1 or 2, encoding hamartin and tuberin, respectively. These proteins formed a complex to inhibit mTORC1-mediated cell growth and proliferation. Loss of either protein leads to overgrowth lesions in many vital organs. Gene therapy was evaluated in a mouse model of TSC2 using an adeno-associated virus (AAV) vector carrying the complementary for a "condensed" form of human tuberin (cTuberin). Functionality of cTuberin was verified in culture. A mouse model of was generated by AAV-Cre recombinase disruption of -floxed alleles at birth, leading to a shortened lifespan (mean 58 days) and brain pathology consistent with TSC. When these mice were injected intravenously on day 21 with AAV9-cTuberin, the mean survival was extended to 462 days with reduction in brain pathology. This demonstrates the potential of treating life-threatening TSC2 lesions with a single intravenous injection of AAV9-cTuberin.
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http://dx.doi.org/10.1126/sciadv.abb1703DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7793581PMC
January 2021

A portable single-sided magnetic-resonance sensor for the grading of liver steatosis and fibrosis.

Nat Biomed Eng 2021 03 30;5(3):240-251. Epub 2020 Nov 30.

David H. Koch Institute for Integrative Cancer Research, Massachusetts Institute of Technology, Cambridge, MA, USA.

Low-cost non-invasive diagnostic tools for staging the progression of non-alcoholic chronic liver failure from fatty liver disease to steatohepatitis are unavailable. Here, we describe the development and performance of a portable single-sided magnetic-resonance sensor for grading liver steatosis and fibrosis using diffusion-weighted multicomponent T2 relaxometry. In a diet-induced mouse model of non-alcoholic fatty liver disease, the sensor achieved overall accuracies of 92% (Cohen's kappa, κ = 0.89) and 86% (κ = 0.78) in the ex vivo grading of steatosis and fibrosis, respectively. Localization of the measurements in living mice through frequency-dependent spatial encoding led to an overall accuracy of 87% (κ = 0.81) for the grading of steatosis. In human liver samples, the sensor graded steatosis with an overall accuracy of 93% (κ = 0.88). The use of T2 relaxometry as a sensitive measure in fully automated low-cost magnetic-resonance devices at the point of care would alleviate the accessibility and cost limits of magnetic-resonance imaging for diagnosing liver disease and assessing liver health before liver transplantation.
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http://dx.doi.org/10.1038/s41551-020-00638-0DOI Listing
March 2021

Navitoclax enhances the effectiveness of EGFR-targeted antibody-drug conjugates in PDX models of EGFR-expressing triple-negative breast cancer.

Breast Cancer Res 2020 11 30;22(1):132. Epub 2020 Nov 30.

Department of Cell Biology and Ludwig Center at Harvard, Harvard Medical School, 240 Longwood Avenue, Boston, MA, 02115, USA.

Background: Targeted therapies for triple-negative breast cancer (TNBC) are limited; however, the epidermal growth factor receptor (EGFR) represents a potential target, as the majority of TNBC express EGFR. The purpose of these studies was to evaluate the effectiveness of two EGFR-targeted antibody-drug conjugates (ADC: ABT-414; ABBV-321) in combination with navitoclax, an antagonist of the anti-apoptotic BCL-2 and BCL-X proteins, in order to assess the translational relevance of these combinations for TNBC.

Methods: The pre-clinical efficacy of combined treatments was evaluated in multiple patient-derived xenograft (PDX) models of TNBC. Microscopy-based dynamic BH3 profiling (DBP) was used to assess mitochondrial apoptotic signaling induced by navitoclax and/or ADC treatments, and the expression of EGFR and BCL-2/X was analyzed in 46 triple-negative patient tumors.

Results: Treatment with navitoclax plus ABT-414 caused a significant reduction in tumor growth in five of seven PDXs and significant tumor regression in the highest EGFR-expressing PDX. Navitoclax plus ABBV-321, an EGFR-targeted ADC that displays more effective wild-type EGFR-targeting, elicited more significant tumor growth inhibition and regressions in the two highest EGFR-expressing models evaluated. The level of mitochondrial apoptotic signaling induced by single or combined drug treatments, as measured by DBP, correlated with the treatment responses observed in vivo. Lastly, the majority of triple-negative patient tumors were found to express EGFR and co-express BCL-X and/or BCL-2.

Conclusions: The dramatic tumor regressions achieved using combined agents in pre-clinical TNBC models underscore the abilities of BCL-2/X antagonists to enhance the effectiveness of EGFR-targeted ADCs and highlight the clinical potential for usage of such targeted ADCs to alleviate toxicities associated with combinations of BCL-2/X inhibitors and systemic chemotherapies.
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http://dx.doi.org/10.1186/s13058-020-01374-8DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7708921PMC
November 2020

Control of Glucocorticoid Receptor Levels by PTEN Establishes a Failsafe Mechanism for Tumor Suppression.

Mol Cell 2020 10;80(2):279-295.e8

Cancer Program, Monash Biomedicine Discovery Institute and Department of Biochemistry and Molecular Biology, Monash University, Melbourne, VIC 3800, Australia. Electronic address:

The PTEN tumor suppressor controls cell death and survival by regulating functions of various molecular targets. While the role of PTEN lipid-phosphatase activity on PtdIns(3,4,5)P3 and inhibition of PI3K pathway is well characterized, the biological relevance of PTEN protein-phosphatase activity remains undefined. Here, using knockin (KI) mice harboring cancer-associated and functionally relevant missense mutations, we show that although loss of PTEN lipid-phosphatase function cooperates with oncogenic PI3K to promote rapid mammary tumorigenesis, the additional loss of PTEN protein-phosphatase activity triggered an extensive cell death response evident in early and advanced mammary tumors. Omics and drug-targeting studies revealed that PI3Ks act to reduce glucocorticoid receptor (GR) levels, which are rescued by loss of PTEN protein-phosphatase activity to restrain cell survival. Thus, we find that the dual regulation of GR by PI3K and PTEN functions as a rheostat that can be exploited for the treatment of PTEN loss-driven cancers.
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http://dx.doi.org/10.1016/j.molcel.2020.09.027DOI Listing
October 2020

Divergent Roles of PI3K Isoforms in PTEN-Deficient Glioblastomas.

Cell Rep 2020 09;32(13):108196

Department of Cancer Biology, Dana-Farber Cancer Institute, Boston, MA 02215, USA; Department of Biological Chemistry and Molecular Pharmacology, Harvard Medical School, Boston, MA 02215, USA; Broad Institute of Harvard and MIT, Cambridge, MA 02142, USA. Electronic address:

Loss of PTEN, the negative regulator of PI3K activity, is frequent in glioblastomas (GBMs). However, the role of the two major PI3K isoforms, p110α and p110β, in PTEN-deficient gliomagenesis remains unknown. We show that PTEN-deficient GBM largely depends on p110α for proliferation and p110β for migration. Genetic ablation of either isoform delays tumor progression in mice, but only ablating both isoforms completely blocks GBM driven by the concurrent ablation of Pten and p53. BKM120 (buparlisib) treatment only modestly prolongs survival in mice bearing intracranial Pten/p53 null tumors due to partial pathway inhibition. BKM120 extends the survival of mice bearing intracranial tumors in which p110β, but not p110α, has been genetically ablated in the Pten/p53 null glioma, indicating that BKM120 fails to inhibit p110β effectively. Our study suggests that the failure of PI3K inhibitors in GBM may be due to insufficient inhibition of p110β and indicates a need to develop brain-penetrant p110α/β inhibitors.
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http://dx.doi.org/10.1016/j.celrep.2020.108196DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7571617PMC
September 2020

Organoids Model Transcriptional Hallmarks of Oncogenic KRAS Activation in Lung Epithelial Progenitor Cells.

Cell Stem Cell 2020 10 4;27(4):663-678.e8. Epub 2020 Sep 4.

Stem Cell Program and Divisions of Hematology/Oncology and Pulmonary Medicine, Boston Children's Hospital, Boston, MA 02115, USA; Harvard Stem Cell Institute, Cambridge, MA 02138, USA; Department of Genetics, Harvard Medical School, Boston, MA 02115, USA. Electronic address:

Mutant KRAS is a common driver in epithelial cancers. Nevertheless, molecular changes occurring early after activation of oncogenic KRAS in epithelial cells remain poorly understood. We compared transcriptional changes at single-cell resolution after KRAS activation in four sample sets. In addition to patient samples and genetically engineered mouse models, we developed organoid systems from primary mouse and human induced pluripotent stem cell-derived lung epithelial cells to model early-stage lung adenocarcinoma. In all four settings, alveolar epithelial progenitor (AT2) cells expressing oncogenic KRAS had reduced expression of mature lineage identity genes. These findings demonstrate the utility of our in vitro organoid approaches for uncovering the early consequences of oncogenic KRAS expression. This resource provides an extensive collection of datasets and describes organoid tools to study the transcriptional and proteomic changes that distinguish normal epithelial progenitor cells from early-stage lung cancer, facilitating the search for targets for KRAS-driven tumors.
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http://dx.doi.org/10.1016/j.stem.2020.07.022DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7541765PMC
October 2020

BRG1 Loss Predisposes Lung Cancers to Replicative Stress and ATR Dependency.

Cancer Res 2020 09 20;80(18):3841-3854. Epub 2020 Jul 20.

Stem Cell Program, Division of Hematology/Oncology and Division of Pulmonary Medicine, Boston Children's Hospital, Boston, Massachusetts.

Inactivation of SMARCA4/BRG1, the core ATPase subunit of mammalian SWI/SNF complexes, occurs at very high frequencies in non-small cell lung cancers (NSCLC). There are no targeted therapies for this subset of lung cancers, nor is it known how mutations in contribute to lung cancer progression. Using a combination of gain- and loss-of-function approaches, we demonstrate that deletion of BRG1 in lung cancer leads to activation of replication stress responses. Single-molecule assessment of replication fork dynamics in BRG1-deficient cells revealed increased origin firing mediated by the prelicensing protein, CDC6. Quantitative mass spectrometry and coimmunoprecipitation assays showed that BRG1-containing SWI/SNF complexes interact with RPA complexes. Finally, BRG1-deficient lung cancers were sensitive to pharmacologic inhibition of ATR. These findings provide novel mechanistic insight into BRG1-mutant lung cancers and suggest that their dependency on ATR can be leveraged therapeutically and potentially expanded to BRG1-mutant cancers in other tissues. SIGNIFICANCE: These findings indicate that inhibition of ATR is a promising therapy for the 10% of non-small cell lung cancer patients harboring mutations in SMARCA4/BRG1. GRAPHICAL ABSTRACT: http://cancerres.aacrjournals.org/content/canres/80/18/3841/F1.large.jpg.
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http://dx.doi.org/10.1158/0008-5472.CAN-20-1744DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7501156PMC
September 2020

Keap1 mutation renders lung adenocarcinomas dependent on Slc33a1.

Nat Cancer 2020 Jun 8;1(6):589-602. Epub 2020 Jun 8.

Koch Institute for Integrative Cancer Research, Cambridge, MA, 02139, USA.

Approximately 20-30% of human lung adenocarcinomas (LUAD) harbor loss-of-function (LOF) mutations in Kelch-like ECH Associated-Protein 1 (), which lead to hyperactivation of the nuclear factor, erythroid 2-like 2 (NRF2) antioxidant pathway and correlate with poor prognosis. We previously showed that mutation accelerates KRAS-driven LUAD and produces a marked dependency on glutaminolysis. To extend the investigation of genetic dependencies in the context of mutation, we performed a druggable genome CRISPR-Cas9 screen in -mutant cells. This analysis uncovered a profound mutant-specific dependency on solute carrier family 33 member 1 (), an endomembrane-associated protein with roles in autophagy regulation, as well as a series of functionally-related genes implicated in the unfolded protein response. Targeted genetic and biochemical experiments using mouse and human -mutant tumor lines, as well as preclinical genetically-engineered mouse models (GEMMs) of LUAD, validate as a robust -mutant-specific dependency. Furthermore, unbiased genome-wide CRISPR screening identified additional genes related to dependency. Overall, our study provides a strong rationale for stratification of patients harboring -mutant or NRF2-hyperactivated tumors as likely responders to targeted SLC33A1 inhibition and underscores the value of integrating functional genetic approaches with GEMMs to identify and validate genotype-specific therapeutic targets.
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http://dx.doi.org/10.1038/s43018-020-0071-1DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8373048PMC
June 2020

Inhibition of sphingolipid synthesis improves outcomes and survival in GARP mutant mice, a model of motor neuron degeneration.

Proc Natl Acad Sci U S A 2020 05 28;117(19):10565-10574. Epub 2020 Apr 28.

Department of Molecular Metabolism, Harvard T. H. Chan School of Public Health, Harvard University, Boston, MA 02115;

Numerous mutations that impair retrograde membrane trafficking between endosomes and the Golgi apparatus lead to neurodegenerative diseases. For example, mutations in the endosomal retromer complex are implicated in Alzheimer's and Parkinson's diseases, and mutations of the Golgi-associated retrograde protein (GARP) complex cause progressive cerebello-cerebral atrophy type 2 (PCCA2). However, how these mutations cause neurodegeneration is unknown. GARP mutations in yeast, including one causing PCCA2, result in sphingolipid abnormalities and impaired cell growth that are corrected by treatment with myriocin, a sphingolipid synthesis inhibitor, suggesting that alterations in sphingolipid metabolism contribute to cell dysfunction and death. Here we tested this hypothesis in mice, a murine model with a homozygous partial loss-of-function mutation in (GARP protein) that causes motor neuron disease. Cytotoxic sphingoid long-chain bases accumulated in embryonic fibroblasts and spinal cords from mice. Remarkably, chronic treatment of mice with myriocin markedly improved their wellness scores, grip strength, neuropathology, and survival. Proteomic analyses of fibroblasts revealed extensive missorting of lysosomal proteins, including sphingolipid catabolism enzymes, to the Golgi compartment, which may contribute to the sphingolipid abnormalities. Our findings establish that altered sphingolipid metabolism due to GARP mutations contributes to neurodegeneration and suggest that inhibiting sphingolipid synthesis might provide a useful strategy for treating these disorders.
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http://dx.doi.org/10.1073/pnas.1913956117DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7229683PMC
May 2020

Generation of Genetically Engineered Mouse Lung Organoid Models for Squamous Cell Lung Cancers Allows for the Study of Combinatorial Immunotherapy.

Clin Cancer Res 2020 07 24;26(13):3431-3442. Epub 2020 Mar 24.

Department of Medical Oncology, Dana-Farber Cancer Institute, Boston, Massachusetts.

Purpose: Lung squamous cell carcinoma (LSCC) is a deadly disease for which only a subset of patients responds to immune checkpoint blockade (ICB) therapy. Therefore, preclinical mouse models that recapitulate the complex genetic profile found in patients are urgently needed.

Experimental Design: We used CRISPR genome editing to delete multiple tumor suppressors in lung organoids derived from Cre-dependent SOX2 knock-in mice. We investigated both the therapeutic efficacy and immunologic effects accompanying combination PD-1 blockade and WEE1 inhibition in both mouse models and LSCC patient-derived cell lines.

Results: We show that multiplex gene editing of mouse lung organoids using the CRISPR-Cas9 system allows for efficient and rapid means to generate LSCCs that closely mimic the human disease at the genomic and phenotypic level. Using this genetically defined mouse model and three-dimensional tumoroid culture system, we show that WEE1 inhibition induces DNA damage that primes the endogenous type I IFN and antigen presentation system in primary LSCC tumor cells. These events promote cytotoxic T-cell-mediated clearance of tumor cells and reduce the accumulation of tumor-infiltrating neutrophils. Beneficial immunologic features of WEE1 inhibition are further enhanced by the addition of anti-PD-1 therapy.

Conclusions: We developed a mouse model system to investigate a novel combinatory approach that illuminates a clinical path hypothesis for combining ICB with DNA damage-inducing therapies in the treatment of LSCC.
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http://dx.doi.org/10.1158/1078-0432.CCR-19-1627DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7334092PMC
July 2020

Targeting the cyclin-dependent kinase 5 in metastatic melanoma.

Proc Natl Acad Sci U S A 2020 04 19;117(14):8001-8012. Epub 2020 Mar 19.

Department of Cancer Biology, Dana-Farber Cancer Institute, Boston, MA 02215;

The cyclin-dependent kinase 5 (CDK5), originally described as a neuronal-specific kinase, is also frequently activated in human cancers. Using conditional CDK5 knockout mice and a mouse model of highly metastatic melanoma, we found that CDK5 is dispensable for the growth of primary tumors. However, we observed that ablation of CDK5 completely abrogated the metastasis, revealing that CDK5 is essential for the metastatic spread. In mouse and human melanoma cells CDK5 promotes cell invasiveness by directly phosphorylating an intermediate filament protein, vimentin, thereby inhibiting assembly of vimentin filaments. Chemical inhibition of CDK5 blocks the metastatic spread of patient-derived melanomas in patient-derived xenograft (PDX) mouse models. Hence, inhibition of CDK5 might represent a very potent therapeutic strategy to impede the metastatic dissemination of malignant cells.
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http://dx.doi.org/10.1073/pnas.1912617117DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7149478PMC
April 2020

Expression of Stromal Cell-Derived Factor-1 by Mesenchymal Stromal Cells Impacts Neutrophil Function During Sepsis.

Crit Care Med 2020 05;48(5):e409-e417

Division of Pulmonary and Critical Care Medicine, Department of Medicine, Brigham and Women's Hospital and Harvard Medical School, Boston, MA.

Objectives: Sepsis results in organ dysfunction caused by a dysregulated host response, in part related to the immune response of a severe infection. Mesenchymal stromal cells are known to modulate the immune response, and expression of stromal cell-derived factor-1 regulates mobilization of neutrophils from the bone marrow. We are investigating the importance of stromal cell-derived factor-1 in mesenchymal stromal cells and its role in promoting neutrophil function after the onset of cecal ligation and puncture-induced sepsis. Stromal cell-derived factor-1 expression was silenced in mesenchymal stromal cells, compared with the control scrambled construct mesenchymal stromal cells.

Design: Animal study and cell culture.

Setting: Laboratory investigation.

Subjects: BALB/c mice.

Interventions: Polymicrobial sepsis was induced by cecal ligation and puncture. shSCR mesenchymal stromal cells and shSDF-1 mesenchymal stromal cells were delivered by tail vein injections to septic mice. The mice were assessed for survival, bacterial clearance, and the inflammatory response during sepsis in each of the groups. Mesenchymal stromal cells were also assessed for their ability to promote bacterial phagocytosis by neutrophils.

Measurements And Main Results: Injection of shSCR mesenchymal stromal cells after the onset of sepsis led to an increase in mouse survival (70%) at 7 days, whereas survival of mice receiving shSDF-1 mesenchymal stromal cells was significantly diminished (33%). The loss of survival benefit in mice receiving shSDF-1 mesenchymal stromal cells was associated with less efficient bacterial clearance compared with shSCR mesenchymal stromal cells. Although shSCR mesenchymal stromal cells, or their conditioned medium, were able to increase neutrophil phagocytosis of bacteria, this effect was significantly blunted with shSDF-1 mesenchymal stromal cells. Assessment of peritoneal inflammation revealed that neutrophils were significantly increased and more immature in septic mice receiving shSDF-1 mesenchymal stromal cells. This response was associated with hypocellularity and increased neutrophil death in the bone marrow of mice receiving shSDF-1 mesenchymal stromal cells.

Conclusions: Expression of stromal cell-derived factor-1 in mesenchymal stromal cells enhances neutrophil function with increased phagocytosis, more efficient clearance of bacteria, and bone marrow protection from depletion of cellular reserves during sepsis.
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http://dx.doi.org/10.1097/CCM.0000000000004244DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7556326PMC
May 2020

CRISPR-mediated modeling and functional validation of candidate tumor suppressor genes in small cell lung cancer.

Proc Natl Acad Sci U S A 2020 01 23;117(1):513-521. Epub 2019 Dec 23.

David H. Koch Institute for Integrative Cancer Research, Massachusetts Institute of Technology, Cambridge, MA 02139;

Small cell lung cancer (SCLC) is a highly aggressive subtype of lung cancer that remains among the most lethal of solid tumor malignancies. Recent genomic sequencing studies have identified many recurrently mutated genes in human SCLC tumors. However, the functional roles of most of these genes remain to be validated. Here, we have adapted the CRISPR-Cas9 system to a well-established murine model of SCLC to rapidly model loss-of-function mutations in candidate genes identified from SCLC sequencing studies. We show that loss of the gene significantly accelerates tumor progression. Notably, compared with loss of the closely related gene , loss of results in fewer but larger tumors as well as earlier metastatic spread. In addition, we observe differences in proliferation and apoptosis as well as altered distribution of initiated tumors in the lung, resulting from loss of or Collectively, these data demonstrate the feasibility of using the CRISPR-Cas9 system to model loss of candidate tumor suppressor genes in SCLC, and we anticipate that this approach will facilitate efforts to investigate mechanisms driving tumor progression in this deadly disease.
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http://dx.doi.org/10.1073/pnas.1821893117DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6955235PMC
January 2020

The KDM5A/RBP2 histone demethylase represses NOTCH signaling to sustain neuroendocrine differentiation and promote small cell lung cancer tumorigenesis.

Genes Dev 2019 12 14;33(23-24):1718-1738. Epub 2019 Nov 14.

Department of Medical Oncology, Dana-Farber Cancer Institute and Brigham and Women's Hospital, Harvard Medical School, Boston, Massachusetts 02215, USA.

More than 90% of small cell lung cancers (SCLCs) harbor loss-of-function mutations in the tumor suppressor gene The canonical function of the gene product, pRB, is to repress the E2F transcription factor family, but pRB also functions to regulate cellular differentiation in part through its binding to the histone demethylase KDM5A (also known as RBP2 or JARID1A). We show that KDM5A promotes SCLC proliferation and SCLC's neuroendocrine differentiation phenotype in part by sustaining expression of the neuroendocrine transcription factor ASCL1. Mechanistically, we found that KDM5A sustains ASCL1 levels and neuroendocrine differentiation by repressing NOTCH2 and NOTCH target genes. To test the role of KDM5A in SCLC tumorigenesis in vivo, we developed a CRISPR/Cas9-based mouse model of SCLC by delivering an adenovirus (or an adeno-associated virus [AAV]) that expresses Cre recombinase and sgRNAs targeting , and into the lungs of Lox-Stop-Lox Cas9 mice. Coinclusion of a KDM5A sgRNA decreased SCLC tumorigenesis and metastasis, and the SCLCs that formed despite the absence of KDM5A had higher NOTCH activity compared to SCLCs. This work establishes a role for KDM5A in SCLC tumorigenesis and suggests that KDM5 inhibitors should be explored as treatments for SCLC.
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http://dx.doi.org/10.1101/gad.328336.119DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6942053PMC
December 2019

Long-Term Therapeutic Efficacy of Intravenous AAV-Mediated Hamartin Replacement in Mouse Model of Tuberous Sclerosis Type 1.

Mol Ther Methods Clin Dev 2019 Dec 16;15:18-26. Epub 2019 Aug 16.

Molecular Neurogenetics Unit, Department of Neurology and Center for Molecular Imaging Research, Department of Radiology, Massachusetts General Hospital, and Neurodiscovery Center, Harvard Medical School, Charlestown, MA, USA.

Tuberous sclerosis complex (TSC) is a tumor suppressor syndrome caused by mutations in or encoding hamartin and tuberin, respectively. These proteins act as a complex that inhibits mammalian target of rapamycin (mTOR)-mediated cell growth and proliferation. Loss of either protein leads to overgrowth in many organs, including subependymal nodules, subependymal giant cell astrocytomas, and cortical tubers in the human brain. Neurological manifestations in TSC include intellectual disability, autism, hydrocephalus, and epilepsy. In a stochastic mouse model of TSC1 brain lesions, complete loss of is achieved in homozygous floxed mice in a subpopulation of neural cells in the brain by intracerebroventricular (i.c.v.) injection at birth of an adeno-associated virus (AAV) vector encoding Cre recombinase. This results in median survival of 38 days and brain pathology, including subependymal lesions and enlargement of neuronal cells. Remarkably, when these mice were injected intravenously on day 21 with an AAV9 vector encoding hamartin, most survived at least up to 429 days in apparently healthy condition with marked reduction in brain pathology. Thus, a single intravenous administration of an AAV vector encoding hamartin restored protein function in enough cells in the brain to extend lifespan in this TSC1 mouse model.
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http://dx.doi.org/10.1016/j.omtm.2019.08.003DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6745533PMC
December 2019

BRAF V600E and Pten deletion in mice produces a histiocytic disorder with features of Langerhans cell histiocytosis.

PLoS One 2019 17;14(9):e0222400. Epub 2019 Sep 17.

Department of Medical Oncology, Dana-Farber Cancer Institute, Harvard Medical School, Boston, MA, United States of America.

Langerhans cell histiocytosis (LCH) is characterized by the accumulation of Langerin (CD207)-expressing histiocytes. Mutational activation of mitogen-activated protein kinase pathway genes, in particular BRAF, drives most cases. To test whether activated BRAF is sufficient for the development of LCH, we engineered mice to express BRAF V600E under the control of the human Langerin promoter. These mice have shortened survivals, smaller lymphoid organs, absent Leydig cells, and fewer epidermal LCs than controls, but do not accumulate histiocytes. To test whether the absence of histiocyte proliferation could be due to oncogene-induced senescence, we engineered homozygous Pten loss in the same cells that expressed BRAF V600E. Like mice with intact Pten, these mice have shortened survivals, smaller thymi, and absent Leydig cells. However, loss of Pten also leads to the accumulation of CD207+ histiocytes in spleen, thymus, and some lymph nodes. While many CD207+ histiocytes in the thymus are CD8-, reminiscent of LCH cells, the CD207+ histiocytes in the spleen and lymph nodes are CD8+. These mice also accumulate large numbers of CD207- cells in the lamina propria (LP) of the small intestine. Both the lymphoid and LP phenotypes are likely due to human Langerin promoter-driven BRAF V600E expression in resident CD8+ dendritic cells in the former and LP dendritic cells in the latter and confirm that Pten loss is required to overcome inhibitory pathways induced by BRAF V600E expression. The complex phenotype of these mice is a consequence of the multiple murine cell types in which the human Langerin promoter is active.
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http://journals.plos.org/plosone/article?id=10.1371/journal.pone.0222400PLOS
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6748438PMC
March 2020

The crucial role of DNA-dependent protein kinase and myelin transcription factor 1-like protein in the miR-141 tumor suppressor network.

Cell Cycle 2019 Nov 16;18(21):2876-2892. Epub 2019 Sep 16.

Department of Biological Sciences, University of Lethbridge , Lethbridge , Canada.

Glioblastoma is the most aggressive brain tumor. Although miR-141 has been demonstrated to primarily function as a tumor suppressor in numerous malignancies, including glioblastoma, the mechanisms involved remain poorly understood. Here, it is shown that miR-141 is downregulated in glioblastoma cell lines and tissues and may exert its biological function via directly targeting (). Using two glioblastoma cell lines that differ from each other by the functionality of DNA-dependent protein kinase (DNAPK), a functional involvement of DNAPK in the miR-141 tumor suppression network was observed. In M059K cells with a normal function of DNAPK, the enforced expression of miR-141 attenuated MYT1L expression and suppressed cell proliferation. Conversely, the inhibition of miR-141 expression promoted cell proliferation; however, in M059J cells with a loss-of-function DNAPK, miR-141 constitutively inhibited cell proliferation upon ectopic overexpression or inhibition. An overexpression of miR-141 suppressed M059J cell migration, while it had no effect on M059K. Furthermore, the ectopic expression of miR-141 induced an S-phase arrest in both cell lines, whereas the inhibition of miR-141 caused a G1 arrest in M059J and accelerated the S phase in M059K. An overexpression and suppression of miR-141 resulted in an aberrant expression of cell-cycle proteins, including p21. Moreover, MYT1L may be a transcription factor of p21 in p53-mutant cells, whereas DNAPK may function as a repressor of MYT1L. The findings revealed the crucial role of DNAPK in miR-141-mediated suppression of gliomagenesis and demonstrated that it may be a target molecule in miR-141-associated therapeutic interventions for glioblastoma.
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http://dx.doi.org/10.1080/15384101.2019.1652033DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6791708PMC
November 2019

Increased PHGDH expression promotes aberrant melanin accumulation.

BMC Cancer 2019 Jul 22;19(1):723. Epub 2019 Jul 22.

Koch Institute for Integrative Cancer Research, Cambridge, 02139, MA, USA.

Background: Copy number gain of the D-3-phosphoglycerate dehydrogenase (PHGDH) gene, which encodes the first enzyme in serine biosynthesis, is found in some human cancers including a subset of melanomas.

Methods: In order to study the effect of increased PHGDH expression in tissues in vivo, we generated mice harboring a PHGDH allele that allows tissue-specific, doxycycline-inducible PHGDH expression, and we analyzed the phenotype of mice with a ubiquitous increase in PHGDH expression.

Results: Tissues and cells derived from PHGDH mice exhibit increased serine biosynthesis. Histological examination of skin tissue from PHGDH mice reveals the presence of melanin granules in early anagen hair follicles, despite the fact that melanin synthesis is closely coupled to the hair follicle cycle and does not normally begin until later in the cycle. This phenotype occurs in the absence of any global change in hair follicle cycle timing. The aberrant presence of melanin early in the hair follicle cycle following PHGDH expression is also accompanied by increased melanocyte abundance in early anagen skin.

Conclusions: These data suggest increased PHGDH expression impacts normal melanocyte biology, but PHGDH expression alone is not sufficient to cause cancer.
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http://dx.doi.org/10.1186/s12885-019-5933-5DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6647269PMC
July 2019

Therapeutic benefit of combining calorie-restricted ketogenic diet and glutamine targeting in late-stage experimental glioblastoma.

Commun Biol 2019 29;2:200. Epub 2019 May 29.

1Department of Biology, Boston College, Chestnut Hill, MA 02467 USA.

Glioblastoma (GBM) is an aggressive primary human brain tumour that has resisted effective therapy for decades. Although glucose and glutamine are the major fuels that drive GBM growth and invasion, few studies have targeted these fuels for therapeutic management. The glutamine antagonist, 6-diazo-5-oxo-L-norleucine (DON), was administered together with a calorically restricted ketogenic diet (KD-R) to treat late-stage orthotopic growth in two syngeneic GBM mouse models: VM-M3 and CT-2A. DON targets glutaminolysis, while the KD-R reduces glucose and, simultaneously, elevates neuroprotective and non-fermentable ketone bodies. The diet/drug therapeutic strategy killed tumour cells while reversing disease symptoms, and improving overall mouse survival. The therapeutic strategy also reduces edema, hemorrhage, and inflammation. Moreover, the KD-R diet facilitated DON delivery to the brain and allowed a lower dosage to achieve therapeutic effect. The findings support the importance of glucose and glutamine in driving GBM growth and provide a therapeutic strategy for non-toxic metabolic management.
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http://dx.doi.org/10.1038/s42003-019-0455-xDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6541653PMC
May 2020

Hepatocyte Deletion of Triglyceride-Synthesis Enzyme Acyl CoA: Diacylglycerol Acyltransferase 2 Reduces Steatosis Without Increasing Inflammation or Fibrosis in Mice.

Hepatology 2019 12 26;70(6):1972-1985. Epub 2019 Jun 26.

Department of Genetics and Complex Diseases, Harvard T.H. Chan School of Public Health, Boston, MA.

Nonalcoholic fatty liver disease (NAFLD) is characterized by excess lipid accumulation in hepatocytes and represents a huge public health problem owing to its propensity to progress to nonalcoholic steatohepatitis, fibrosis, and liver failure. The lipids stored in hepatic steatosis (HS) are primarily triglycerides (TGs) synthesized by two acyl-CoA:diacylglycerol acyltransferase (DGAT) enzymes. Either DGAT1 or DGAT2 catalyzes this reaction, and these enzymes have been suggested to differentially utilize exogenous or endogenously synthesized fatty acids, respectively. DGAT2 has been linked to storage of fatty acids from de novo lipogenesis, a process increased in NAFLD. However, whether DGAT2 is more responsible for lipid accumulation in NAFLD and progression to fibrosis is currently unknown. Also, it is unresolved whether DGAT2 can be safely inhibited as a therapy for NAFLD. Here, we induced NAFLD-like disease in mice by feeding a diet rich in fructose, saturated fat, and cholesterol and found that hepatocyte-specific Dgat2 deficiency reduced expression of de novo lipogenesis genes and lowered liver TGs by ~70%. Importantly, the reduction in steatosis was not accompanied by increased inflammation or fibrosis, and insulin and glucose metabolism were unchanged. Conclusion: This study suggests that hepatic DGAT2 deficiency successfully reduces diet-induced HS and supports development of DGAT2 inhibitors as a therapeutic strategy for treating NAFLD and preventing downstream consequences.
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http://dx.doi.org/10.1002/hep.30765DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6893913PMC
December 2019

Intergenerational epigenetic inheritance of cancer susceptibility in mammals.

Elife 2019 04 9;8. Epub 2019 Apr 9.

Whitehead Institute, Cambridge, United States.

Susceptibility to cancer is heritable, but much of this heritability remains unexplained. Some 'missing' heritability may be mediated by epigenetic changes in the parental germ line that do not involve transmission of genetic variants from parent to offspring. We report that deletion of the chromatin regulator () in the paternal germ line results in elevated tumor incidence in genetically wild type mice. This effect increases following passage through two successive generations of male germline deletion, but is lost following passage through a wild type germ line. The H3K27me3 mark is redistributed in sperm of mutants, and we define approximately 200 H3K27me3-marked regions that exhibit increased DNA methylation, both in sperm of mutants and in somatic tissue of progeny. Hypermethylated regions in enhancers may alter regulation of genes involved in cancer initiation or progression. Epigenetic changes in male gametes may therefore impact cancer susceptibility in adult offspring.
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http://dx.doi.org/10.7554/eLife.39380DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6456297PMC
April 2019

Neutralization of BCL-2/X Enhances the Cytotoxicity of T-DM1 .

Mol Cancer Ther 2019 06 8;18(6):1115-1126. Epub 2019 Apr 8.

Department of Cell Biology and Ludwig Center at Harvard, Harvard Medical School, Boston, Massachusetts.

One of the most recent advances in the treatment of HER2 breast cancer is the development of the antibody-drug conjugate, T-DM1. T-DM1 has proven clinical benefits for patients with advanced and/or metastatic breast cancer who have progressed on prior HER2-targeted therapies. However, T-DM1 resistance ultimately occurs and represents a major obstacle in the effective treatment of this disease. Because anti-apoptotic BCL-2 family proteins can affect the threshold for induction of apoptosis and thus limit the effectiveness of the chemotherapeutic payload, we examined whether inhibition of BCL-2/X would enhance the efficacy of T-DM1 in five HER2-expressing patient-derived breast cancer xenograft models. Inhibition of BCL-2/X via navitoclax/ABT-263 significantly enhanced the cytotoxicity of T-DM1 in two of three models derived from advanced and treatment-exposed metastatic breast tumors. No additive effects of combined treatment were observed in the third metastatic tumor model, which was highly sensitive to T-DM1, as well as a primary treatment-exposed tumor, which was refractory to T-DM1. A fifth model, derived from a treatment naïve primary breast tumor, was sensitive to T-DM1 but markedly benefited from combination treatment. Notably, both PDXs that were highly responsive to the combination therapy expressed low HER2 protein levels and lacked amplification, suggesting that BCL-2/X inhibition can enhance sensitivity of tumors with low HER2 expression. Toxicities associated with combined treatments were significantly ameliorated with intermittent ABT-263 dosing. Taken together, these studies provide evidence that T-DM1 cytotoxicity could be significantly enhanced via BCL-2/X blockade and support clinical investigation of this combination beyond -amplified and/or HER2-overexpressed tumors.
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http://dx.doi.org/10.1158/1535-7163.MCT-18-0743DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6758547PMC
June 2019

The Combination of Curcumin and Salsalate is Superior to Either Agent Alone in Suppressing Pro-Cancerous Molecular Pathways and Colorectal Tumorigenesis in Obese Mice.

Mol Nutr Food Res 2019 04 4;63(8):e1801097. Epub 2019 Feb 4.

Vitamins & Carcinogenesis Laboratory, Jean Mayer USDA Human Nutrition Research Center on Aging at Tufts University, Boston, MA, 02111.

Scope: High-fat diets (HFDs) and adiposity increase colorectal cancer risk, in part by elevating pro-inflammatory cytokines that activate pro-cancerous signaling pathways. Curcumin (CUR), a dietary polyphenol and salsalate (SAL), an non-steroidal anti-inflammatory drug (NSAID) lacking the gastrotoxicity of aspirin, each suppress inflammatory signaling, but via different cellular pathways.

Methods And Results: A/J mice (n = 110) are fed a low-fat diet (LFD, 10% kcal), a HFD (60% kcal), a HFD containing 0.4% CUR, a HFD containing 0.3% SAL, or a HFD containing both agents (CUR/SAL). All mice receive six injections of azoxymethane. Compared to LFD-fed mice, HFD-fed mice display elevated colonic cytokines, crypt cell proliferation, and increased tumorigenesis (p < 0.05). CUR/SAL significantly reduces colonic cytokines (p < 0.01), suppresses activation of the PI3K/Akt/mTOR/NF-κB/Wnt pathways (p < 0.01), activates AMPK (p < 0.01), attenuates abnormal proliferation of the colonic mucosa (p < 0.05), and reduces tumor multiplicity and burden (p < 0.05), in comparison to the HFD control. In contrast, CUR or SAL alone does not suppress abnormal crypt cell proliferation or tumor multiplicity, and is largely ineffective in modifying activation of these signaling pathways.

Conclusion: These observations demonstrate the superiority of the CUR/SAL over the individual agents and provide a scientific basis for future translational studies in obese subjects and/or those habitually consuming HFDs.
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http://dx.doi.org/10.1002/mnfr.201801097DOI Listing
April 2019

Single-Cell Analysis Identifies LY6D as a Marker Linking Castration-Resistant Prostate Luminal Cells to Prostate Progenitors and Cancer.

Cell Rep 2018 12;25(12):3504-3518.e6

Prostate Oncobiology, Cancer Research UK Manchester Institute, The University of Manchester, Alderley Park SK10 4TG, UK; Belfast-Manchester Movember Centre of Excellence, Cancer Research UK Manchester Institute, The University of Manchester, Alderley Park SK10 4TG, UK. Electronic address:

The exact identity of castrate-resistant (CR) cells and their relation to CR prostate cancer (CRPC) is unresolved. We use single-cell gene profiling to analyze the molecular heterogeneity in basal and luminal compartments. Within the luminal compartment, we identify a subset of cells intrinsically resistant to castration with a bi-lineage gene expression pattern. We discover LY6D as a marker of CR prostate progenitors with multipotent differentiation and enriched organoid-forming capacity. Lineage tracing further reveals that LY6D CR luminal cells can produce LY6D luminal cells. In contrast, in luminal cells lacking PTEN, LY6D cells predominantly give rise to LY6D tumor cells, contributing to high-grade PIN lesions. Gene expression analyses in patients' biopsies indicate that LY6D expression correlates with early disease progression, including progression to CRPC. Our studies thus identify a subpopulation of luminal progenitors characterized by LY6D expression and intrinsic castration resistance. LY6D may serve as a prognostic maker for advanced prostate cancer.
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http://dx.doi.org/10.1016/j.celrep.2018.11.069DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6315111PMC
December 2018

PARP Inhibition Elicits STING-Dependent Antitumor Immunity in Brca1-Deficient Ovarian Cancer.

Cell Rep 2018 12;25(11):2972-2980.e5

Department of Cancer Biology, Dana-Farber Cancer Institute, Boston, MA 02215, USA; Department of Biological Chemistry and Molecular Pharmacology, Harvard Medical School, Boston, MA 02115, USA; Broad Institute of Harvard and MIT, Cambridge, MA 02142, USA. Electronic address:

PARP inhibitors have shown promising clinical activities for patients with BRCA mutations and are changing the landscape of ovarian cancer treatment. However, the therapeutic mechanisms of action for PARP inhibition in the interaction of tumors with the tumor microenvironment and the host immune system remain unclear. We find that PARP inhibition by olaparib triggers robust local and systemic antitumor immunity involving both adaptive and innate immune responses through a STING-dependent antitumor immune response in mice bearing Brca1-deficient ovarian tumors. This effect is further augmented when olaparib is combined with PD-1 blockade. Our findings thus provide a molecular mechanism underlying antitumor activity by PARP inhibition and lay a foundation to improve therapeutic outcome for cancer patients.
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http://dx.doi.org/10.1016/j.celrep.2018.11.054DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6366450PMC
December 2018

Compound haploinsufficiency of Dok2 and Dusp4 promotes lung tumorigenesis.

J Clin Invest 2019 01 26;129(1):215-222. Epub 2018 Nov 26.

Cancer Research Institute, Beth Israel Deaconess Cancer Center, Department of Medicine and Pathology, Beth Israel Deaconess Medical Center (BIDMC), Harvard Medical School, Boston, Massachusetts, USA.

Recurrent broad-scale heterozygous deletions are frequently observed in human cancer. Here we tested the hypothesis that compound haploinsufficiency of neighboring genes at chromosome 8p promotes tumorigenesis. By targeting the mouse orthologs of human DOK2 and DUSP4 genes, which were co-deleted in approximately half of human lung adenocarcinomas, we found that compound-heterozygous deletion of Dok2 and Dusp4 in mice resulted in lung tumorigenesis with short latency and high incidence, and that their co-deletion synergistically activated MAPK signaling and promoted cell proliferation. Conversely, restoration of DOK2 and DUSP4 in lung cancer cells suppressed MAPK activation and cell proliferation. Importantly, in contrast to downregulation of DOK2 or DUSP4 alone, concomitant downregulation of DOK2 and DUSP4 was associated with poor survival in human lung adenocarcinoma. Therefore, our findings lend in vivo experimental support to the notion that compound haploinsufficiency, due to broad-scale chromosome deletions, constitutes a driving force in tumorigenesis.
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http://dx.doi.org/10.1172/JCI99699DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6307955PMC
January 2019
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