Publications by authors named "Meaghan M Broman"

8 Publications

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Folate Receptor Beta Designates Immunosuppressive Tumor-Associated Myeloid Cells That Can Be Reprogrammed with Folate-Targeted Drugs.

Cancer Res 2021 02 17;81(3):671-684. Epub 2020 Nov 17.

Department of Chemistry, Purdue University, West Lafayette, Indiana.

Although immunotherapies of tumors have demonstrated promise for altering the progression of malignancies, immunotherapies have been limited by an immunosuppressive tumor microenvironment (TME) that prevents infiltrating immune cells from performing their anticancer functions. Prominent among immunosuppressive cells are myeloid-derived suppressor cells (MDSC) and tumor-associated macrophages (TAM) that inhibit T cells via release of immunosuppressive cytokines and engagement of checkpoint receptors. Here, we explore the properties of MDSCs and TAMs from freshly isolated mouse and human tumors and find that an immunosuppressive subset of these cells can be distinguished from the nonimmunosuppressive population by its upregulation of folate receptor beta (FRβ) within the TME and its restriction to the TME. This FRβ subpopulation could be selectively targeted with folate-linked drugs. Delivery of a folate-targeted TLR7 agonist to these cells (i) reduced their immunosuppressive function, (ii) increased CD8 T-cell infiltration, (iii) enhanced M1/M2 macrophage ratios, (iv) inhibited tumor growth, (v) blocked tumor metastasis, and (vi) improved overall survival without demonstrable toxicity. These data reveal a broadly applicable strategy across tumor types for reprogramming MDSCs and TAMs into antitumorigenic immune cells using a drug that would otherwise be too toxic to administer systemically. The data also establish FRβ as the first marker that distinguishes immunosuppressive from nonimmunosuppressive subsets of MDSCs and TAMs. Because all solid tumors accumulate MDSCs and TAMs, a general strategy to both identify and reprogram these cells should be broadly applied in the characterization and treatment of multiple tumors. SIGNIFICANCE: FRβ serves as both a means to identify and target MDSCs and TAMs within the tumor, allowing for delivery of immunomodulatory compounds to tumor myeloid cells in a variety of cancers.
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http://dx.doi.org/10.1158/0008-5472.CAN-20-1414DOI Listing
February 2021

Heterogeneity of human prostate carcinoma-associated fibroblasts implicates a role for subpopulations in myeloid cell recruitment.

Prostate 2020 02 25;80(2):173-185. Epub 2019 Nov 25.

Department of Surgery, NorthShore University HealthSystem, Evanston, Illinois.

Background: Carcinoma-associated fibroblasts (CAF) are a heterogeneous group of cells within the tumor microenvironment (TME) that can promote tumorigenesis in the prostate. By understanding the mechanism(s) by which CAF contributes to tumor growth, new therapeutic targets for the management of this disease may be identified. These studies determined whether unique sub-populations of human prostate CAF can be identified and functionally characterized.

Methods: Single-cell RNA-seq of primary human prostate CAF followed by unsupervised clustering was utilized to generate cell clusters based on differentially expressed (DE) gene profiles. Potential communication between CAF and immune cells was analyzed using in vivo tissue recombination by combining CAF or normal prostate fibroblasts (NPF) with non-tumorigenic, initiated prostate epithelial BPH-1 cells. Resultant grafts were assessed for inflammatory cell recruitment.

Results: Clustering of 3321 CAF allows for visualization of six subpopulations, demonstrating heterogeneity within CAF. Sub-renal capsule recombination assays show that the presence of CAF significantly increases myeloid cell recruitment to resultant tumors. This is supported by significantly increased expression of chemotactic chemokines CCL2 and CXCL12 in large clusters compared to other subpopulations. Bayesian analysis topologies also support differential communication signals between chemokine-related genes of individual clusters. Migration of THP-1 monocyte cells in vitro is stimulated in the presence of CAF conditioned medium (CM) compared with NPF CM. Further in vitro analyses suggest that CAF-derived chemokine CCL2 may be responsible for CAF-stimulated migration of THP-1 cells, since neutralization of this chemokine abrogates migration capacity.

Conclusions: CAF clustering based on DE gene expression supports the concept that clusters have unique functions within the TME, including a role in immune/inflammatory cell recruitment. These data suggest that CCL2 produced by CAF may be involved in the recruitment of inflammatory cells, but may also directly regulate the growth of the tumor. Further studies aimed at characterizing the subpopulation(s) of CAF which promote immune cell recruitment to the TME and/or stimulate prostate cancer growth and progression will be pursued.
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http://dx.doi.org/10.1002/pros.23929DOI Listing
February 2020

Distinct expression patterns of SULT2B1b in human prostate epithelium.

Prostate 2019 08 18;79(11):1256-1266. Epub 2019 Jun 18.

Department of Comparative Pathobiology, College of Veterinary Medicine, Purdue University, West Lafayette, Indiana.

Background: SULT2B1b (sulfotransferase family cytosolic 2B member 1b) catalyzes the sulfate conjugation of substrates such as cholesterol and oxysterols. Our laboratory has previously shown that SULT2B1b inhibition modulates androgen receptor signaling and induces apoptosis in prostate cancer cells. However, the functions of SULT2B1b in the prostate remain poorly understood.

Methods: We characterized the expression pattern of SULT2B1b in human benign prostate hyperplasia (BPH) as well as prostate cancer to determine the relationship between SULT2B1b and prostate diseases, using immunohistochemistry, immunofluorescence staining, immunoblot, and real-time polymerase chain reaction.

Results: SULT2B1b was strongly detected in the prostate epithelium but was absent in the stroma. Significantly lower SULT2B1b was found in primary cancer cells compared with adjacent normal epithelial cells. SULT2B1b further decreased in metastatic cancer cells. Most interestingly, we found, for the first time, that SULT2B1b was much more concentrated in the luminal layer than in the basal layer in both normal prostate and BPH samples. The stronger presence of SULT2B1b in luminal epithelial cells was confirmed by costaining with luminal and basal markers and in sorted paired luminal and basal cells. SULT2B1b expression was induced with prostate organoid differentiation.

Conclusions: SULT2B1b inversely correlates with prostate cancer status, with the highest level in the normal epithelium and lowest in the advanced metastatic prostate cancer. Furthermore, SULT2B1b is mostly located within the luminal layer of the prostate epithelium, suggesting that it may be implicated in luminal differentiation.
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http://dx.doi.org/10.1002/pros.23829DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7064034PMC
August 2019

Identification of LIMK2 as a therapeutic target in castration resistant prostate cancer.

Cancer Lett 2019 04 1;448:182-196. Epub 2019 Feb 1.

Department of Chemistry and Purdue University Center for Cancer Research, 560 Oval Drive, West Lafayette, IN, 47907, USA. Electronic address:

This study identified LIMK2 kinase as a disease-specific target in castration resistant prostate cancer (CRPC) pathogenesis, which is upregulated in response to androgen deprivation therapy, the current standard of treatment for prostate cancer. Surgical castration increases LIMK2 expression in mouse prostates due to increased hypoxia. Similarly, human clinical specimens showed highest LIMK2 levels in CRPC tissues compared to other stages, while minimal LIMK2 was observed in normal prostates. Most notably, inducible knockdown of LIMK2 fully reverses CRPC tumorigenesis in castrated mice, underscoring its potential as a clinical target for CRPC. We also identified TWIST1 as a direct substrate of LIMK2, which uncovered the molecular mechanism of LIMK2-induced malignancy. TWIST1 is strongly associated with CRPC initiation, progression and poor prognosis. LIMK2 increases TWIST1 mRNA levels upon hypoxia; and stabilizes TWIST1 by direct phosphorylation. TWIST1 also stabilizes LIMK2 by inhibiting its ubiquitylation. Phosphorylation-dead TWIST1 acts as dominant negative and fully prevents EMT and tumor formation in vivo, thereby highlighting the significance of LIMK2-TWIST1 signaling axis in CRPC. As LIMK2 null mice are viable, targeting LIMK2 should have minimal collateral toxicity, thereby improving the overall survival of CRPC patients.
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http://dx.doi.org/10.1016/j.canlet.2019.01.035DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7079209PMC
April 2019

Targeting Plk1 to Enhance Efficacy of Olaparib in Castration-Resistant Prostate Cancer.

Mol Cancer Ther 2017 03 9;16(3):469-479. Epub 2017 Jan 9.

Department of Biochemistry, Purdue University, West Lafayette, Indiana.

Olaparib is an FDA-approved PARP inhibitor (PARPi) that has shown promise as a synthetic lethal treatment approach for BRCA-mutant castration-resistant prostate cancer (CRPC) in clinical use. However, emerging data have also shown that even BRCA-mutant cells may be resistant to PARPi. The mechanistic basis for these drug resistances is poorly understood. Polo-like kinase 1 (Plk1), a critical regulator of many cell-cycle events, is significantly elevated upon castration of mice carrying xenograft prostate tumors. Herein, by combination with Plk1 inhibitor BI2536, we show a robust sensitization of olaparib in 22RV1, a BRCA1-deficient CRPC cell line, as well as in CRPC xenograft tumors. Mechanistically, monotherapy with olaparib results in an override of the G-S checkpoint, leading to high expression of Plk1, which attenuates olaparib's overall efficacy. In BRCA1 wild-type C4-2 cells, Plk1 inhibition also significantly increases the efficacy of olaparib in the presence of p53 inhibitor. Collectively, our findings not only implicate the critical role of Plk1 in PARPi resistance in BRCA-mutant CRPC cells, but also shed new light on the treatment of non-BRCA-mutant patient subgroups who might also respond favorably to PARPi. .
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http://dx.doi.org/10.1158/1535-7163.MCT-16-0361DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5337144PMC
March 2017

Pathology in Practice.

J Am Vet Med Assoc 2016 Jun;248(11):1253-5

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http://dx.doi.org/10.2460/javma.248.11.1253DOI Listing
June 2016

PREVALENCE AND SIGNIFICANCE OF AN ULTRASONOGRAPHIC COLONIC MUSCULARIS HYPERECHOIC BAND PARALLELING THE SEROSAL LAYER IN DOGS.

Vet Radiol Ultrasound 2015 Nov-Dec;56(6):666-9. Epub 2015 Jul 15.

Department of Comparative Pathobiology, Purdue University, West Lafayette, IN, 47907.

The muscularis layer of the canine colon has been reported to appear homogeneously hypoechoic on ultrasonography. A hyperechoic band in the muscularis layer paralleling the serosal surface has been observed by authors in routine canine abdominal ultrasound examinations. The purpose of this prospective and retrospective cross-sectional study was to determine the prevalence of this lesion, characterize its ultrasonographic and postmortem histologic features, and correlate its presence with clinical signs of gastrointestinal disease. In the prospective study, all dogs that underwent routine abdominal ultrasonography by one of two observers during a 4-week period were included without any exclusion criteria. One observer reviewed ultrasound images and recorded the presence or absence of this lesion and its distribution, e.g. focal (< 2 cm long) or diffuse (> 2 cm long). In the retrospective study, all dogs that had both abdominal ultrasonography and necropsy from January 2011 to December 2013 were included without any exclusion criteria. Histologic examinations were performed by two observers and Masson's trichrome stain was used to identify fibrous collagen. Prevalence for the hyperechoic band was 32% in the prospective and 4.8% in the retrospective sample populations, respectively. The hyperechoic band appeared as diffuse, focal, or a combination of both. Histologic sections were available for six dogs. In a few cases, the lesion corresponded to the presence of fibrous tissue in the myenteric plexus or in the tunica muscularis. None of the dogs had a history of diarrhea. Findings supported the hypothesis that a colonic muscularis hyperechoic band paralleling the serosal layer in dogs could be a normal variant rather than a marker of disease.
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http://dx.doi.org/10.1111/vru.12275DOI Listing
August 2016