Fibroblast Heterogeneity In Pancreatic Cancer Immunity

Author

Josephine Darpolor, The University of Texas MD Anderson Cancer Center UTHealth Graduate School of Biomedical SciencesFollow

Author ORCID Identifier

0000-0003-1606-8600

Date of Graduation

12-2020

Document Type

Dissertation (PhD)

Program Affiliation

Cancer Biology

Degree Name

Doctor of Philosophy (PhD)

Advisor/Committee Chair

Raghu Kalluri, M.D, Ph.D

Committee Member

Timothy McDonnell, M.D., Ph.D

Committee Member

Ronald DePinho, M.D

Committee Member

Pawel Mazur, Ph.D

Committee Member

Samuel Mok, Ph.D

Committee Member

Cullen Taniguchi, M.D., Ph.D.

Committee Member

Stephanie Watowich, Ph.D

Abstract

Fibroblasts are a unique cell type defined by their mesenchymal phenotype and exclusion from epithelial, immune, and endothelial cell subsets. Although well studied in wound healing, cancer associated fibroblasts (CAFs) are incredibly heterogeneous, leading to contradictions as to the roles CAFs play in the tumor microenvironment (TME). CAFs were thought to be a barrier to treatment of pancreatic ductal adenocarcinoma (PDAC). However, general stromal targeting strategies have largely failed in the clinic likely due to the heterogeneity of CAFs in the TME. Therefore, our groups and others have worked to unravel the heterogeneity of CAFs in PDAC. In the works presented herein, we seek to identify the functions of two commonly studied CAF subsets defined by expression of aSMA and FAP.

We employed single cell RNA sequencing, mass cytometry, and multiplex immunohistochemistry to assess genetically engineered mouse models (GEMMs) in which we could deplete aSMA⁺ and FAP⁺ CAFs. We found the aSMA⁺ and FAP⁺ CAFs were distinct subsets with tumor restraining and tumor supporting roles, respectively. aSMA⁺ CAFs were immune stimulatory and associated with prolonged survival in GEMMs. Meanwhile, FAP⁺ CAFs were immunosuppressive and correlated with shortened survival in GEMMs. Altogether, we discovered that aSMA⁺ and FAP⁺ CAFs are distinct CAF populations with opposing roles in PDAC progression and immunity.

Keywords

fibroblast, pdac, tumor microenvironment