Cancer Associated Fibroblasts Drive Epithelial to Mesenchymal Transition and Classical to Basal Change in Pancreatic Ductal Adenocarcinoma Cells with Loss of IL-8 Expression

Overview

Journal bioRxiv

Date 2025 Jan 20

PMID 39829906

Authors

Samantha Guinn

Brayan Perez

Joseph A Tandurella

Mili Ramani

Jae W Lee

Daniel J Zabransky

Emma Kartalia

Jignasha Patel

Haley Zlomke

Norman Nicolson

Sarah Shin

Benjamin Barrett

Nicholas Sun

Alexei Hernandez

Erin Coyne

Courtney Cannon

Nicole E Gross

Soren Charmsaz

Yeonju Cho

James Leatherman

Melissa Lyman

Jacob Mitchell

Luciane T Kagohara

Michael G Goggins

Kelly J Lafaro

Jin He

Christopher Shubert

William Burns

Lei Zheng

Elana J Fertig

Elizabeth M Jaffee

Richard A Burkhart

Won Jin Ho

Jacquelyn W Zimmerman

Affiliations

Soon will be listed here.

Abstract

Pancreatic ductal adenocarcinoma (PDAC) carries an extremely poor prognosis, in part resulting from cellular heterogeneity that supports overall tumorigenicity. Cancer associated fibroblasts (CAF) are key determinants of PDAC biology and response to systemic therapy. While CAF subtypes have been defined, the effects of patient-specific CAF heterogeneity and plasticity on tumor cell behavior remain unclear. Here, multi-omics was used to characterize the tumor microenvironment (TME) in tumors from patients undergoing curative-intent surgery for PDAC. In these same patients, matched tumor organoid and CAF lines were established to functionally validate the impact of CAFs on the tumor cells. CAFs were found to drive epithelial-mesenchymal transition (EMT) and a switch in tumor cell classificiaton from classical to basal subtype. Furthermore, we identified CAF-specific interleukin 8 (IL-8) as an important modulator of tumor cell subtype. Finally, we defined neighborhood relationships between tumor cell and T cell subsets.

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