Profiling pancreatic intraepithelial neoplasia using single cell RNA-seq

The tumor microenvironment evolves to include diverse cell types that adopt a variety of fates, which can dramatically influence disease progression. This heterogeneity in the cellular milieu of both tumor and its microenvironment poses an urgent need in defining their precise composition in order to understand the roles of such different components in tumor disease and progression. Here we study the compositional evolution of pancreatic adenocarcinoma (PDAC), among the deadliest tumor types, for which there are no current effective therapies. The disease can initiate from duct or acinar pancreatic cells, most often through Kras activation, and progresses to malignancy through premalignant lesions of several types, including pancreatic intraepithelial neoplasias (PanINs). Inflammation is an important determinant of PDAC formation and progression, and tumors have a rich stroma involving multiple immune and other cell types, whose functions are poorly understood.

In this project we focus on exploring the early events that give raise to cellular environment that support PDAC. We have used single cell RNA-seq to profile mouse PanINs in several time points after the induction of constitutively active Kras.

We are currently investigating: (i) Which cells infiltrate PanINs, (ii) Which genes differentially expressed between cells that infiltrate PanINs and cells in control samples, (iii) How neoplasia form after Kras activation, (iv) The interactions between different cell types in the PanINs microenvironment.

The results expect to shed light on the early events that support the construction of the tumor microenvironment in pancreatic cancer.