The candidate's short-term goal is to obtain a faculty position at an academic research institute; her long-term goal is to better understand the nature and molecular underpinnings of tumor-stroma crosstalk in pancreatic cancer, and to harness this improved understanding to treat the human disease. She intends to focus on pancreatic stellate cells, myofibroblast-like cells of the tumor microenvironment, and study how these unique lipid-storing cells interact with tumor cells to effect gene expression, metabolism, and growth. The candidate's background in cancer biology and gene expression analysis will be supplemented by the expertise in high-throughput sequencing and metabolic physiology in the lab and at the present institution to help her realize her goals. Further, the extensive mentorship experience of the advisor and the contributions of a well-balanced mentorship committee will enhance the candidate's scientific and professional development as she transitions to independence. The studies proposed here will evaluate novel mechanisms underlying PDAC tumor-stroma interactions with the following specific aims.
Aim 1 : Examine the role of stromal VDR/NF-kB crosstalk in PDAC desmoplasia and tumor growth. Recent data suggest that the vitamin D receptor (VDR) negatively regulates PSC activation, leading to reduced expression of pro-inflammatory genes in PSCs and decreased paracrine induction of factors that support tumor growth, by inhibiting NF-kB chromatin occupancy and target gene expression. The role of stromal VDR/NF-kB crosstalk will be examined in patient-derived PSC lines and in a new allograft model of PDAC featuring prominent desmoplasia. These experiments will determine the significance of these factors in the activation of key pathways known to regulate pancreatic cancer cell growth and metabolism.
Aim 2 : Understand the effect of PSC secreted factors on cancer cell lipid metabolism. Using recently developed systems for analysis of tumor-stroma crosstalk, the candidate will interrogate the link between lipid metabolism and gene expression, in the context of PSC secreted factors. Preliminary data suggest that PSCs secrete factors that foster the recently established fatty acid scavenging phenotype of Kras- transformed cells while providing signaling modulators that impact the availability of acetyl-CoA as a substrate for histone acetylation. The results from these studies will be useful in understanding the unique metabolic properties of PDAC cells.
Aim 3 : Evaluate paracrine regulation of redox homeostasis by PDAC stromal cues. The contribution of structural and diffusible features of the tumor stroma will be assessed in tumor cells faced with cellular stress relevant to the tumor microenvironment. These studies will help to define the nature of paracrine pro-survival pathways that contribute to redox balance in the neoplastic compartment, and that may serve as new therapeutic targets. Together, the proposed experiments will probe previously unexplored aspects of PDAC biology, with the potential to uncover novel vulnerabilities for therapeutic intervention.
Pancreatic cancer is characterized by a prominent stromal reaction, which has been shown to promote tumor initiation, progression, evasion of antitumor immunity, and resistance to chemotherapy. The research proposed here aims to better understand how pancreatic stellate cells, key drivers of the stromal reaction in pancreatic cancer, interact with and influence pancreatic epithelial cells to promote growth-permissive changes in metabolism and gene expression. Careful dissection of pancreatic tumor-stroma crosstalk will shed light on the biology of these tumors and, hopefully, will highlight new therapeutic avenues to combat pancreatic cancer.
|Sherman, Mara H; Yu, Ruth T; Tseng, Tiffany W et al. (2017) Stromal cues regulate the pancreatic cancer epigenome and metabolome. Proc Natl Acad Sci U S A 114:1129-1134|
|Sousa, Cristovão M; Biancur, Douglas E; Wang, Xiaoxu et al. (2016) Pancreatic stellate cells support tumour metabolism through autophagic alanine secretion. Nature 536:479-83|