Biology subjects

Tisdale, A. A.

Publications and source records attributed to Tisdale, A. A..

3 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↗

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↗

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↗