Adipose Stromal Cell-Derived Cancer-Associated Fibroblasts Promote Pancreatic Adenocarcinoma Progression Through SFRP4 Signaling

Authors

Joseph Rupert
Lingyi Cai
Alexes C Daquinag
Dimitris Anastassiou
Mikhail G Kolonin

Language

English

Publication Date

1-12-2026

Journal

Cancers

DOI

10.3390/cancers18020233

PMID

41595155

PMCID

PMC12838676

PubMedCentral® Posted Date

1-12-2026

PubMedCentral® Full Text Version

Post-print

Abstract

Background/objectives: Progression of pancreatic ductal adenocarcinoma (PDAC) and other carcinomas relies on cancer-associated fibroblasts (CAFs). A subset of CAFs is derived from adipose stromal cells (ASCs) recruited by tumors and the ASC-CAF conversion has been associated with invasiveness and poor prognosis.

Methods: To explore the underlying molecular mechanisms, we used a model based on primary ASCs derived from human visceral adipose tissue co-cultured with human PDAC cell line Capan-1. To investigate cancer progression in vivo, we also used mice orthotopically grafted with mouse KPC cells.

Results: Genomic analysis revealed that Capan-1 co-culture induces Wnt and TGFβ signaling and extracellular matrix (ECM) gene expression in ASC. We investigated the function of two markers of the fibroblastic transition highly induced by cancer cells: a long non-coding RNA LINC01614 and a Wnt signaling modulator SFRP4. By using ASCs with either SFRP4 or LINC01614 knocked out (ko), we showed that both genes are required for Wnt/TGFβ signaling and ECM induction in ASCs by Capan-1. Analysis of changes in Capan-1 genes that rely on LINC01614 and SFRP4 expression in ASCs also identified the Wnt and TGF pathways. SFRP4 ko in ASCs suppressed both migration and invasion of Capan-1 cells. We show that tumors in SFRP4 ko mice have less desmoplasia, less epithelial dedifferentiation, reduced growth rate, and reduced progression to metastasis.

Conclusions: We conclude that SFRP4 promotes cancer progression in pancreatic cancer and is a promising therapeutic target.

Keywords

cancer, tumor microenvironment, metastasis, pancreas, fibroblast, stromal, adipose, LINC01614, SFRP4, Wnt, TGF, SMAD

Published Open-Access

yes

Recommended Citation

Rupert, Joseph; Cai, Lingyi; Daquinag, Alexes C; et al., "Adipose Stromal Cell-Derived Cancer-Associated Fibroblasts Promote Pancreatic Adenocarcinoma Progression Through SFRP4 Signaling" (2026). Faculty, Staff and Student Publications. 6003.
https://digitalcommons.library.tmc.edu/uthgsbs_docs/6003