Biology subjects

Feigin, M. E.

Publications and source records attributed to Feigin, M. E..

5 recordsLinked to original sources

bioRxiv2026

A targetable opioid/cancer associated fibroblast axis drives extracellular matrix remodeling and tumor aggressiveness in pancreatic cancer

Pancreatic ductal adenocarcinoma (PDAC) is an intractable disease with few effective treatment options. PDAC is characterized by a dense, fibro-inflammatory tumor microenvironment (TME) consisting mainly of cancer-associated fibroblasts (CAFs) and a CAF-generated collagen-rich extracellular matrix (ECM). As the ECM has profound impacts on tumor progression and therapy response, it is critical that we understand the mechanisms underlying ECM deposition and remodeling. In addition to a highly fibrotic and reactive TME, a hallmark of PDAC is pain. 93% of PDAC patients experience pain, and [~]70% are prescribed opioids for pain management during the course of their cancer treatment. Despite epidemiological evidence linking opioid use with diminished patient survival, how opioids impact tumor biology remains largely unknown. We now provide evidence that both endogenous and exogenous opioids drive ECM remodeling in the PDAC TME. We find that the commonly prescribed opioid morphine promotes the development of poorly differentiated tumors and increases collagen bundling and maturation in a mouse model of PDAC. Accordingly, RNA sequencing reveals that morphine induces significant upregulation of ECM genes and collagen modifying enzymes. We developed a morphine-induced gene signature which correlates significantly with the basal/mesenchymal subtypes of human PDAC and predicts worse overall survival in PDAC and other tumor types. Mechanistically, pharmacological inhibition and genetic knockdown of the mu opioid receptor (OPRM1) in CAFs attenuates expression of type 1a and type 3a collagens, and the myofibroblastic CAF marker alpha-SMA, demonstrating that opioid signaling is a direct regulator of CAF biology. Additionally, we provide the first evidence that CAFs produce endogenous opioids capable of activating OPRM1 and driving collagen expression. Finally, treatment with the FDA-approved peripherally restricted OPRM1 antagonist methylnaltrexone (MNTX) reduces desmoplasia, tumor weight, and ascites burden in a mouse model of PDAC. Therefore, we have identified a novel opioid-mediated signaling axis driving PDAC desmoplasia and reveal MNTX as a potential therapeutic to inhibit both exogenous and endogenous opioid-induced ECM remodeling and tumor aggressiveness.

cancer biology↗

bioRxiv2025

Targeting FGFR4 Abrogates HNF1A-driven Metastasis in Pancreatic Ductal Adenocarcinoma

PurposeWe previously identified an oncogenic role for the transcription factor HNF1A in pancreatic ductal adenocarcinoma (PDAC). However, the role of HNF1A in the metastatic progression of PDAC remains unknown and targeting modalities for HNF1A -dependent phenotypes have yet to be identified. Experimental DesignTranswell chambers were used to assess the effects of HNF1A and FGFR4 modulation on the migration and invasion of ATCC and patient-derived PDAC cells in vitro. An intrasplenic injection xenograft model was used to evaluate the impact of HNF1A knockdown and overexpression on metastatic tumor burden. Single-cell RNA sequencing, tissue microarray (TMA) data, and UMAP spatial profiling were used to identify FGFR4 as an HNF1A target gene upregulated in metastatic cells. RNAi and two FGFR4 inhibiting modalities (H3B-6527 and U3- 1784) were utilized to demonstrate the efficacy of FGFR4 inhibiting agents at reducing HNF1A- driven metastasis. ResultsKnockdown of HNF1A significantly decreases and HNF1A overexpression significantly increases PDAC cell migration and invasion. In vivo studies show that HNF1A knockdown significantly abrogates metastasis, while overexpression significantly promotes metastasis. Single-cell RNAseq shows that FGFR4 is upregulated in metastatic PDAC cells and staining for HNF1A and FGFR4 in a PDAC TMA reveals significant correlation between HNF1A and FGFR4 in PDAC patients. Further, knockdown and inhibition of FGFR4 significantly decreases HNF1A- mediated cell migration and invasion, and blocks HNF1A-driven metastasis in vivo. ConclusionsThese findings demonstrate that HNF1A drives PDAC metastasis via upregulation of FGFR4, and FGFR4 inhibition is a potential mechanism to target metastasis in PDAC patients. Translational RelevancePancreatic ductal adenocarcinoma (PDAC) is one of the most lethal malignancies, made even more devastating when metastases overwhelm major organs. The vast majority of PDAC patients either present with metastases or will relapse with recurrent metastatic PDAC after primary tumor resection. Unfortunately, toxic and largely ineffective chemotherapies are currently the only approved treatment options for these patients and therefore there exists a critical and unmet clinical need for targeted therapies against pro-metastatic pathways in PDAC. In the current study, we identify HNF1A as an oncogenic transcription factor that drives metastasis in PDAC, and it does so through upregulation of the receptor tyrosine kinase FGFR4. Importantly, FGFR4 is a targetable vulnerability and treatment with an FGFR4 blocking antibody reduces HNF1A-driven metastasis. These findings suggest that FGFR4 inhibitors could be an efficacious treatment for PDAC patients for the prevention or delay of metastatic tumor development.

cancer biology↗

bioRxiv2022

CPSF3 inhibition blocks pancreatic cancer cell proliferation through disruption of core histone processing

Pancreatic ductal adenocarcinoma (PDAC) is a lethal disease with limited effective treatment options. This potentiates the importance of uncovering novel drug targets. We have discovered global dysregulation of the gene regulatory process alternative polyadenylation (APA) in PDAC. APA is a pre-mRNA processing mechanism that generates mRNAs with distinct 3 ends, impacting gene expression and protein function. We revealed that APA dysregulation in PDAC drives oncogenic signatures and predicts poor patient outcome. As APA directs widespread gene expression dysregulation across the PDAC patient population, we hypothesized that inhibition of APA has therapeutic potential. APA is controlled by a complex of proteins, including cleavage and polyadenylation specificity factor 3 (CPSF3). CPSF3 is the endonuclease catalyzing mRNA cleavage, and a potentially druggable target. We now find that CPSF3 is highly expressed and associated with poor prognosis in PDAC patients. CPSF3 knockdown decreases PDAC proliferation and clonogenicity in vitro and tumor growth in vivo. We demonstrate that CPSF3 knockdown induces widespread APA alterations of oncogenes and tumor suppressors, and determine the contribution of one of these events to CPSF3-induced cell proliferation phenotype. Furthermore, we find that PDAC, but not non-transformed pancreatic cells, are sensitive to the CPSF3 small molecule inhibitor JTE-607. Mechanistically, JTE-607 impairs replication-dependent histone processing, disrupting nucleosome assembly and destabilizing chromatin structure. Finally, we determine that JTE-607 attenuates cell proliferation by arresting cells in early S-phase of the cell cycle. Altogether, we identify CPSF3 as a druggable target in PDAC and reveal novel mechanisms by which CPSF3 controls cancer cell growth. SignificanceThis work identifies CPSF3 as a potential drug target in pancreatic ductal adenocarcinoma and reveals new mechanisms by which CPSF3 inhibition attenuates PDAC cell proliferation through modulating alternative polyadenylation and histone processing.

cancer biology↗

bioRxiv2021

Alternative polyadenylation characterizes epithelial and fibroblast phenotypic heterogeneity in pancreatic ductal adenocarcinoma

Human tumors are characterized by extensive intratumoral transcriptional variability within the cancer cell and stromal compartments. This variation drives phenotypic heterogeneity, producing cell states with differential pro- and anti-tumorigenic properties. While bulk RNA sequencing cannot achieve cell type specific transcriptional granularity, single cell sequencing has permitted an unprecedented view of these cell states. Despite this knowledge, we lack an understanding of the mechanistic drivers of this transcriptional and phenotypic heterogeneity. 3 untranslated region alternative polyadenylation (3 UTR-APA) drives gene expression alterations through regulation of 3 UTR length. These 3 UTR alterations modulate mRNA stability, protein expression and protein localization, resulting in cellular phenotypes including differentiation, cell proliferation, and migration. Therefore, we sought to determine whether 3 UTR-APA events could characterize phenotypic heterogeneity of tumor cell states. Here we analyze the largest single cell human pancreatic ductal adenocarcinoma (PDAC) dataset and resolve 3 UTR-APA patterns across PDAC cell states. We find that increased proximal 3 UTR-APA is associated with PDAC progression and characterizes a metastatic ductal epithelial subpopulation and an inflammatory fibroblast population. Furthermore, we find significant 3 UTR shortening events in cell state-specific marker genes associated with increased expression. Therefore, we propose that 3 UTR-APA drives phenotypic heterogeneity in cancer.

cancer biology↗

bioRxiv2019

Alternative polyadenylation drives oncogenic gene expression in pancreatic ductal adenocarcinoma

Alternative polyadenylation (APA) is a gene regulatory process that dictates mRNA 3-UTR length, resulting in changes in mRNA stability and localization. APA is frequently disrupted in cancer and promotes tumorigenesis through altered expression of oncogenes and tumor suppressors. Pan-cancer analyses have revealed common APA events across the tumor landscape; however, little is known about tumor type-specific alterations that may uncover novel events and vulnerabilities. Here we integrate RNA-sequencing data from the Genotype-Tissue Expression (GTEx) project and The Cancer Genome Atlas (TCGA) to comprehensively analyze APA events in 148 pancreatic ductal adenocarcinomas (PDAs). We report widespread, recurrent and functionally relevant 3-UTR alterations associated with gene expression changes of known and newly identified PDA growth-promoting genes and experimentally validate the effects of these APA events on expression. We find enrichment for APA events in genes associated with known PDA pathways, loss of tumor-suppressive miRNA binding sites, and increased heterogeneity in 3-UTR forms of metabolic genes. Survival analyses reveal a subset of 3-UTR alterations that independently characterize a poor prognostic cohort among PDA patients. Finally, we identify and validate the casein kinase CK1 as an APA-regulated therapeutic target in PDA. Knockdown or pharmacological inhibition of CK1 attenuates PDA cell proliferation and clonogenic growth. Our single-cancer analysis reveals APA as an underappreciated driver of pro-tumorigenic gene expression in PDA via the loss of miRNA regulation.

cancer biology↗