The Sherman Lab aims to understand the transcriptional and epigenetic gene-regulatory networks that underlie tumor-stroma interactions in pancreatic cancer, and to target these networks for therapeutic benefit. Our research focuses on the tumor-permissive molecular mechanisms underlying cancer-associated fibroblast function, and how these stromal mechanisms affect cell fate and function in the pancreatic epithelium with respect to gene expression, metabolism, and growth. Our laboratory uses a multidisciplinary approach to investigate the mechanistic underpinnings of the pancreatic tumor microenvironment, including mouse models of pancreatic cancer, three-dimensional cell culture systems such as patient-derived organoids, and diverse molecular- and cell-biological techniques focused on gene regulation.
Developing new mouse models to interrogate the PDAC stromal reaction
The pancreatic tumor microenvironment includes a substantial population of cancer-associated fibroblasts. Previous work suggests both tumor-supportive and tumor-suppressive or homeostatic roles for these cells, and recent literature highlights substantial transcriptional heterogeneity among PDAC CAFs. However, due to a lack of available models, the functional significance of CAF heterogeneity and the roles of specific subtypes remain unclear. In the Sherman lab, we are developing new mouse models to track and manipulate specific CAF subpopulations in vivo, to understand the ontologies and functions of these diverse cells and to identify relevant routes for therapeutic intervention in the stroma.
Understanding bioenergetic coupling of stromal and epithelial cellular metabolism
Increasing evidence suggests that the non-malignant cells of the tumor microenvironment support tumor growth by modulating cancer cell metabolism, either by providing growth factors which stimulate anabolic pathways in a paracrine manner, or by providing secreted nutrients or metabolites which contribute to epithelial cell biomass. With our collaborators at the Beatson Institute for Cancer Research, we are using metabolomics approaches combined with co-culture systems and mouse models to identify mechanisms and therapeutic targets involved in microenvironmental regulation of pancreatic cancer metabolism.
Identification of novel chromatin-interacting therapeutic targets
The cancer epigenome is dynamic, and can be regulated both by cell-autonomous oncogenic signaling pathways and by signals from the tumor microenvironment. Chromatin-interacting proteins which sense or regulate the cancer epigenome have emerged as exciting potential therapeutic targets, as cancer cells of multiple tumor types have been shown to be remarkably sensitive to inhibition of gene-regulatory mechanisms at the epigenome level. We are taking an unbiased approach using CRISPR-Cas9 genome editing to identify chromatin-interacting factors which regulate pancreatic tumor growth in the context of relevant signals from the microenvironment.