How do pancreatic cancers remodel the tumor microenvironment to facilitate lethal metastatic outgrowth?

Abstract public domain (NIH RePORTER)

PROJECT SUMMARY Pancreatic ductal adenocarcinoma (PDAC) will become the second leading cause of US cancer-related deaths by the year 2030. Primary PDACs are encased within a densely fibrotic, nutrient poor (“desmoplastic”) stroma enriched with extracellular matrix, fibroblasts, and immune cells. In contrast, distant metastatic PDACs grow rapidly within a nutrient replete, loosely fibrotic stroma. The project objective is to define those fundamental TME differences and the fibroinflammatory signaling networks that govern them. The hypothesis is that PDACs remodel metastatic TMEs into a loosely fibrotic, immunodeficient stroma by suppressing pathways that yield fibroinflammatory cytokines. This hypothesis will be tested by two specific aims. Aim 1: Define key differences between primary and metastatic TMEs. Primary versus metastatic TMEs will be interrogated in humans and mice by (1) scoring key histopathological TME parameters across hundreds of primary and metastatic PDAC patient tissue samples; (2) quantifying tumor: stroma cell lineage abundances and communication networks using single cell RNA-seq datasets from PDAC patients; (3) flow cytometric sorting of cell lineages that comprise primary and metastatic TMEs in gold standard PDAC mouse models. The goal of Aim 1 is to discover TME determinants of divergent clinical behaviors and biological properties between primary tumors and distant metastases. Aim 2: Evaluate mechanisms that remodel metastatic TMEs. Genetic and pharmacological gain- and loss-of-function approaches will determine if (1) suppressing inflammatory signals depletes primary tumor fibroinflammatory cytokines from metastatic secretomes; (2) (re)- introducing those cytokines back into metastatic secretomes triggers a desmoplastic stromal response that restrains distant metastatic outgrowth; (3) depleting those cytokines from primary tumor secretomes remodels the desmoplastic stroma to facilitate distant metastatic spread. The goal of Aim 2 is to identify and functionally characterize primary tumor fibroinflammatory signals that are reprogrammed to facilitate distant metastasis. These studies will positively impact cancer research by concretely demonstrating how primary and metastatic TMEs diverge from one another and illustrating precise mechanisms that drive such divergences. The findings are expected to conceptually advance our understanding of cancer progression and rationally inform therapeutic strategies against primary and metastatic tumors, even within the same individual patient(s). This research will be conducted as part of an MD-PhD dual degree fellowship training plan at the University of Miami Miller School of Medicine Medical Scientist Training Program (UMMSM MSTP). The UMMSM MSTP training environment includes access to theoretical and technical instruction, physician scientist mentors, and state-of-the-art facilities for these studies. This proposal seeks to prepare for a training goal of becoming a physician scientist in the field of oncology.

Public health relevance public domain (NIH RePORTER)

PROJECT NARRATIVE Understanding how pancreatic ductal adenocarcinoma (PDAC) remodels its tumor microenvironment (TME) to rapidly advance its metastatic outgrowth is of great importance to public health because there is critical need for new therapeutic strategies to target this lethal disease. Deciphering how fibroinflammatory changes contribute to the loss of primary PDAC’s hallmark fibrous, immune cell-rich “desmoplastic” stroma upon metastatic progression is of vital importance because it may uncover how metastatic PDACs compose its poorly fibrotic, immune-cell deplete stroma to support disease progression. This is significantly relevant to the NCI’s mission because understanding mechanisms that govern primary versus metastatic PDAC TME will inform new treatment methods to better serve PDAC patients.