45: Tumor Stroma Crosstalk in Pancreatic Ductal Adenocarcinoma Is Molecular Subtype Dependent

Thursday, March 10, 2022

4:11 PM – 4:19 PM CST

Location: Chantilly East

Abstract Presenter(s)

Joseph Kearney, MD

Surgical Resident
University of North Carolina
Durham, North Carolina, United States

Disclosure: I do not have any relevant financial / non-financial relationships with any proprietary interests.

Participants should be aware of the following financial/non-financial relationships:

Joseph Kearney, MD: I do not have any relevant financial / non-financial relationships with any proprietary interests.

Introduction:

Introduction: The interaction between Pancreatic Ductal Adenocarcinoma (PDAC) and its tumor microenvironment (TME) is complex. Efforts to target the TME have been disappointing to date. We have used computational deconvolution to identify tumor- and stroma-specific interactions. We found two tumor-intrinsic (basal/classical) and two stroma-intrinsic subtypes (normal/activated). We have shown that cancer associated fibroblasts (CAFs) are the contributory cell to activated stroma. Interactions between tumor and stroma subtypes are seen in patients, with normal stroma/classical subtype tumor combinations having the best outcome. Thus, we hypothesized that CAF effects on PDAC cells are subtype dependent.

Methods:

Methods: CAF and PDAC cell lines were RNA sequenced and subtyped. Conditioned media (CM) was harvested from myofibroblastic CAF (myCAF), inflammatory CAF (iCAF), and normal associated fibroblast (NAF) lines. Co-stimulated CM (CoCM) was harvested from PDAC lines in co-culture with CAFs/NAFs. PDAC migration, growth and invasion was evaluated.

Results:

Results: myCAF CM decreased growth and migration of a classical PDAC line compared to control and iCAF CM (p < 0.01), but myCAF CM had no effect on basal PDAC. CoCM from co-culturing a NAF with a classical PDAC line increased invasion compared to CM from the NAF alone (p = 0.048). However, the same CoCM decreased invasion of the basal PDAC line (p = 0.034). CoCM from a CAF line cultured with a classical PDAC line had no effect on either classical or basal PDAC invasion.

Conclusions:

Conclusions: CAFs are heterogenous and exhibit a subtype-dependent effect on tumor cells, supporting context specific crosstalk. Furthermore, the juxtacrine interaction of CAF/NAFs with tumor cells alters paracrine signaling, which affects the behavior of basal and classical subtype PDAC differently. Altogether, our results support the importance of understanding the heterogeneity of CAF and tumor cells, CAF-tumor interactions in the context of different subtypes, and suggest caution in imprecise attempts to target tumor and stroma.

Learning Objectives:

Upon completion, the participant will be able to describe the tumor subtypes of pancreatic adenocarcinoma.
Upon completion, the participant will be able to describe the stroma subtypes of pancreatic adenocarcinoma.
Upon completion, the participant will be able to understand how tumor and stroma compartment subtypes may be interacting, and how that may affect the outcomes of stroma-targeting chemotherapy.