our science
Our lab seeks to understand the molecular causes of cancer in order to develop better therapies and improve patient outcome. Through a combination of computational and experimental methods, we study how genes are regulated in cancer, and how changes in gene regulation and cell signaling networks drive tumor progression.
Everyday medications and the tumor microenvironment
Patients with pancreatic cancer routinely receive opioids for pain and benzodiazepines for anxiety and nausea. These drugs act on receptors expressed by tumor and stromal cells, so they may be changing the disease as well as treating its symptoms. We found that the benzodiazepine lorazepam stimulates IL-6 production by cancer-associated fibroblasts through the proton-sensing GPCR GPR68, promotes fibrosis in mouse tumors, and is associated with shorter survival in patients, whereas the closely related drug alprazolam is associated with longer survival (Cornwell et al., Clinical Cancer Research, 2023). Following up, we showed that alprazolam does the opposite of lorazepam in fibroblasts. It shuts down production of IL-6, IL-8, CCL2 and CXCL12 by blocking Toll-like receptor 4 signaling, and it lowers IL-6 inside pancreatic tumors in mice (Reavis et al., Cancer Research Communications, 2026). Small differences in drug structure can therefore push the tumor microenvironment in opposite directions. We have also shown that morphine drives collagen deposition and stromal stiffening through the mu opioid receptor on fibroblasts, and that methylnaltrexone, an FDA-approved peripheral opioid blocker, reverses these effects in mice (Maraszek et al., bioRxiv, 2026).
Gene regulation and alternative polyadenylation
Cancer is driven not only by mutations in genes but by changes in how they are regulated. We showed that noncoding mutations alter cancer gene expression in pancreatic cancer (Feigin, Garvin et al., Nature Genetics, 2017). We also performed the first large-scale analysis of alternative polyadenylation (APA) in a single tumor type, which revealed APA signatures linked to poor outcome and identified CK1α as a therapeutic target (Venkat et al., Genome Research, 2020). APA changes the 3′ end of messenger RNAs, which alters how stable and active they are. We have since mapped APA at single-cell resolution in tumor and fibroblast cells (Venkat & Feigin, Cancers, 2024) and shown that inhibiting the 3′ end processing enzyme CPSF3 blocks pancreatic cancer cell growth by disrupting histone mRNA processing (Alahmari et al., RNA, 2024).