Mesenchymal Lineage Heterogeneity Underlies Non-Redundant Functions of Pancreatic Cancer-Associated Fibroblasts

Abstract

Cancer-associated fibroblast (CAF) heterogeneity is increasingly appreciated, but the origins and functions of distinct CAF subtypes remain poorly understood. The abundant and transcriptionally diverse CAF population in pancreatic ductal adenocarcinoma (PDAC) is thought to arise from a common cell of origin, pancreatic stellate cells (PSCs), with diversification resulting from cytokine and growth factor gradients within the tumor microenvironment. Here we analyzed the differentiation and function of PSCs during tumor progression in vivo. Contrary to expectations, we found that PSCs give rise to a numerically minor subset of PDAC CAFs. Targeted ablation of PSC-derived CAFs within their host tissue revealed non-redundant functions for this defined CAF population in shaping the PDAC microenvironment, including production of specific components of the extracellular matrix. Together, these findings link stromal evolution from distinct cells of origin to transcriptional heterogeneity among PDAC CAFs, and demonstrate unique functions for CAFs of a defined cellular origin.Statement of significanceBy tracking and ablating a specific CAF population, we find that a numerically minor CAF subtype from a defined cell of origin plays unique roles in establishing the pancreatic tumor microenvironment. Together with prior studies, this work suggests that mesenchymal lineage heterogeneity as well as signaling gradients diversify PDAC CAFs.

Extrinsic KRAS Signaling Shapes the Pancreatic Microenvironment Through Fibroblast Reprogramming

“… 68 Accordingly, a lineage tracing study following pancreatic stellate cells in pancreatic cancer showed that they only contribute to a small subset of CAFs. 69 In vitro characterization and, more recently, scRNAseq studies have identified CAF subsets with specific transcriptional signatures and functional roles. 70 , 71 , 72 …”

CAFs Interacting With TAMs in Tumor Microenvironment to Enhance Tumorigenesis and Immune Evasion

“…Toullec et al reported that stromal derived factor 1 (SDF-1) is an effective factor for the activation of resident fibroblasts in tumors (47). In a very recent study, Helms et al investigated the differentiation of pancreatic stellate cells during tumor progression in vivo and reported that pancreatic stellate cells could give rise to a minor subset of pancreatic ductal adenocarcinoma CAFs (48). It was also suggested that miRNAs have regulatory roles in the transformation of normal fibroblasts to CAFs (49).…”

What is the Potential Interplay between Microbiome and Tumor Microenvironment in Oral Squamous Cell Carcinomas?

“…( Radisky et al, 2007;Potenta et al, 2008;Spaeth et al, 2009;Wikström et al, 2009;Bochet et al, 2013;Shiga et al, 2015;Kalluri, 2016;Bartoschek et al, 2018;Helms et al, 2021)…”

“…Nevertheless, CAF different subtypes with heterogeneous biological properties make distinct functional contributions (Tab. 3) (Chang et al, 2002;Orimo and Weinberg, 2007;Radisky et al, 2007;Zeisberg et al, 2007;Potenta et al, 2008;Council and Hameed, 2009;Kalluri and Weinberg, 2009;Spaeth et al, 2009;Wikström et al, 2009;Toullec et al, 2010;Bochet et al, 2013;Jia et al, 2013;Kim et al, 2015;Shiga et al, 2015;Kalluri, 2016;Öhlund et al, 2017;Bartoschek et al, 2018;Gunaydin, 2021;Helms et al, 2021). CAFs secrete a considerable variety of autocrine and paracrine cytokines and other tumor-promoting factors so as to modulate the TME primarily embodied in the aspects of cancer-elicited inflammation, angiogenesis, cancer cell proliferation, invasion, migration, metastasis, therapeutic resistance, etc.…”