# Adipose‐derived mesenchymal stem cells differentiate into pancreatic cancer‐associated fibroblasts in vitro

## TL;DR

This study shows that fat-derived stem cells can become different types of cancer-related fibroblasts in the lab, depending on how they're cultured.

## Contribution

The study demonstrates that adipose-derived MSCs can differentiate into distinct CAF subtypes in vitro under different co-culture conditions.

## Key findings

- AD-MSCs differentiate into myCAFs and iCAFs when in direct contact with PDAC cells.
- Indirect co-culture results in differentiation into only iCAFs.
- Novel CAF markers were identified that may help understand their role in the tumor microenvironment.

## Abstract

Here, we report that adipose‐derived MSC can differentiate into distinct CAF subtypes in vitro depending on the co‐culture conditions used; in addition, we have identified potential CAF markers that may aid in investigating the mechanisms underlying the role of CAFs in the tumor microenvironment.

Cancer‐associated fibroblasts (CAFs) are key components of the dense, proliferating stroma observed in pancreatic ductal adenocarcinoma (PDAC), and CAF subpopulations drive tumor heterogeneity and play a major role in PDAC progression and drug resistance. CAFs consist of heterogenous subpopulations such as myoblastic CAF (myCAF) and inflammatory CAF (iCAF), and each has distinct essential roles. However, it is not clear how CAF subpopulations are formed in PDAC. Adipose‐derived MSCs (AD‐MSCs), which possess a high multilineage potential and self‐renewal capacity, are reported to be one of the in vivo CAF sources. Here, we aimed to investigate whether AD‐MSCs can act as precursors for CAFs in vitro. We recorded morphological features and collected omics data from two in vitro co‐culture models for recapitulating clinical PDAC. Additionally, we tested the advantages of the co‐culture model in terms of accurately modeling morphology and CAF heterogeneity. We showed that AD‐MSCs differentiate into two distinct CAF subpopulations: Direct contact co‐culture with PDAC cell line Capan‐1 induced differentiation into myCAFs and iCAFs, while indirect co‐culture induced differentiation into only iCAFs. Using these co‐culture systems, we also identified novel CAF markers that may be helpful for elucidating the mechanisms of CAFs in the tumor microenvironment (TME). In conclusion, AD‐MSCs can differentiate into distinct CAF subtypes depending on the different co‐culture conditions in vitro, and the identification of potential CAF markers may aid in future investigations of the mechanisms underlying the role of CAFs in the TME.