39: Mechanoresponsive Pancreatic Ductal Adenocarcinoma Cancer Associated Fibroblasts Shows an FAK-Dependent Subtype Divergent from Canonical Fibrotic TGFB-Pathway Dependence

Thursday, March 23, 2023

10:36 AM – 10:46 AM

Location: Ballroom B

Abstract Presenter(s)

Deshka Foster, MD, PhD

Resident
Stanford University, United States

Disclosure(s): No financial relationships to disclose

First Author(s)

Deshka Foster, MD, PhD

Resident
Stanford University, United States

Disclosure(s): No financial relationships to disclose

Author(s)

DD

Daniel Delitto, Assistant Professor

Surgeon
Stanford University, United States

Disclosure information not submitted.
MJ

Michael Januszyk, MD, PhD

Post-doctoral research fellow
Stanford University, United States

Disclosure information not submitted.
KY

Kathryn Yost, PhD

Post-doctoral research fellow
Stanford University, United States

Disclosure information not submitted.
MG

Michelle Griffin, MD PhD

Post-doctoral fellow
Stanford University, United States

Disclosure information not submitted.
JG

Jason Guo, PhD

Post-doctoral research fellow
Stanford University, United States

Disclosure information not submitted.
NG

Nicholas Guardino, n/a

undergraduate student
Stanford University, United States

Disclosure information not submitted.
AD

Andrea Delitto, PhD

Technician
Stanford University, United States

Disclosure information not submitted.
MC

Malini Chinta, MD

Medical student researcher
Stanford University, United States

Disclosure information not submitted.
AB

Austin Burcham, BS

Undergraduate researcher
Stanford University, United States

Disclosure information not submitted.
AN

Alan Nguyen, BS

Undergraduate researcher
Stanford University, United States

Disclosure information not submitted.
KB

Khristian Bauer-Rowe, BS

MD/PhD Student Researcher
Stanford University, United States

Disclosure information not submitted.
HL

Hunter Lindsay, n/a

Undergraduate student
BYU, United States

Disclosure information not submitted.
CB

Charlotte Berry, BS

Medical student researcher
Stanford University, United States

Disclosure information not submitted.
AK

Alexia Kim, BS

Life Sciences Research Professional
Stanford University, United States

Disclosure information not submitted.
FN

Fatemeh Nosrati, BS

Life Sciences Research Professional
Stanford University, United States

Disclosure information not submitted.
Irene Wapnir, MD

Professor of Surgery
Standford University School of Medicine
Stanford, CA, United States

Disclosure information not submitted.
HC

Howard Chang, MD, PhD

Professor
Stanford University, United States

Disclosure information not submitted.
JN

Jeffrey A. Norton, n/a

Professor of Surgery
Stanford Unoversity
Palo Alto, California, United States

Disclosure information not submitted.
ML

Michael Longaker, MD PhD

Professor of Surgery
Stanford University, United States

Disclosure information not submitted.

Disclosure(s):

Deshka Foster, MD, PhD: No financial relationships to disclose

Introduction: Cancer associated fibroblasts (CAFs) are abundant in the desmoplastic stroma of solid tumors such as pancreatic ductal adenocarcinoma (PDAC) (Fig 1A). However, CAFs have yet to become a standard treatment target because their heterogeneity remains incompletely understood. Using single cell transcriptomics, chromatin accessibility, spatial, and proteomic analysis, our group recently identified three CAF superclusters – steady state-like (SSL), immunomodulatory (IM), and mechanoresponsive (MR) – which are conserved across multiple solid tumor types and species. Within the MR CAF supercluster there are distinct subtypes. Our aim here was to interrogate PDAC MR CAFs towards identifying potential therapeutic CAF targets.

Methods: We applied single cell gene expression and phenotypic (as well as chromatin accessibility and proteomic) analysis level to CAFs isolated from primary human PDAC tumor specimens. Integrated enrichment analysis was used to characterize MR CAF subtypes in terms of pathway drivers and functional significance.

Results: PDAC CAFs represent a heterogeneous cell population with distinct subtypes (Fig. 1B). We have recently shown that CAF subpopulations can be categorized into three superclusters – SSL, IM, and MR – which are highly conserved across species and solid tumor types, including PDAC (Fig 1C). Interrogating MR CAF subtypes across an analytically integrated dataset including PDAC and breast cancer CAFs (Fig 1D), we identify a majority of mechanoresponsive CAFs that show prominent TGFB-pathway (p_adj=5.51*10^-5) and extracellular matrix (ECM) protein expression (Fig 1E-F); however, a distinct subpopulation shows elevated focal adhesion kinase (FAK, p<sub>adj=0.15) and integrin expression supporting a primary role in directing and responding to the ECM rather than directly producing it.

Conclusions: These data interrogate PDAC MR CAF subtype gene expression (informed by chromatin accessibility, spatial transcriptomics, and proteomic analysis). Using an integrated CAF dataset, we identified a distinct FAK-driven MR CAF subpopulation with distinct potential for selective therapeutic targeting. Our ongoing functional work aims to understand how the “push-pull” between CAF subtypes determines tumor growth dynamics. Overall, these data support translational efforts to target CAF subtypes as a component of multi-modal therapy and demonstrate a multimodal-omics framework for understanding the PDAC microenvironment.

Learning Objectives:

Upon completion, participants will have a better understanding of the various cell types within PDAC tumors
Upon completion, participants will understand cancer associated fibroblast heterogeneity in the PDAC microenvironment
Upon completion, participants will be aware of potential novel pathways being explored for PDAC therapies