The Cellular Origins of Cancer-Associated Fibroblasts and Their Opposing Contributions to Pancreatic Cancer Growth

Abstract

Pancreatic tumors are known to harbor an abundant and highly desmoplastic stroma. Among the various cell types that reside within tumor stroma, cancer-associated fibroblasts (CAFs) have gained a lot of attention in the cancer field due to their contributions to carcinogenesis and tumor architecture. These cells are not a homogeneous population, but have been shown to have different origins, phenotypes, and contributions. In pancreatic tumors, CAFs generally emerge through the activation and/or recruitment of various cell types, most notably resident fibroblasts, pancreatic stellate cells (PSCs), and tumor-infiltrating mesenchymal stem cells (MSCs). In recent years, single cell transcriptomic studies allowed the identification of distinct CAF populations in pancreatic tumors. Nonetheless, the exact sources and functions of those different CAF phenotypes remain to be fully understood. Considering the importance of stromal cells in pancreatic cancer, many novel approaches have aimed at targeting the stroma but current stroma-targeting therapies have yielded subpar results, which may be attributed to heterogeneity in the fibroblast population. Thus, fully understanding the roles of different subsets of CAFs within the stroma, and the cellular dynamics at play that contribute to heterogeneity in CAF subsets may be essential for the design of novel therapies and improving clinical outcomes. Fortunately, recent advances in technologies such as microfluidics and bio-printing have made it possible to establish more advanced ex vivo models that will likely prove useful. In this review, we will present the different roles of stromal cells in pancreatic cancer, focusing on CAF origin as a source of heterogeneity, and the role this may play in therapy failure. We will discuss preclinical models that could be of benefit to the field and that may contribute to further clinical development.

Editorial: Mechanisms of Inflammation and Fibrosis Interplays in the Digestive Diseases

“…Origin of these cancer-promoting stromal cells has been extensively studied. In addition to the activation of resident fibroblast, PSCs and MSCs, cells from non-fibroblastic lineage such as epithelial cells, endothelial cells, adipocytes, pericytes and smooth muscle cells undergo transdifferentiation to support pancreatic cancer progression ( Manoukian et al, 2021 ). Among these wide variety of cellular origins, PSCs remain numerically minor population of cancer-associated fibroblasts, whereas play nonredundant role such as specific ECM production ( Helms et al, 2022 ).…”

Ym1+ macrophages orchestrate fibrosis, lesion growth, and progression during development of murine pancreatic cancer

“…This desmoplastic reaction is regulated via the three major cell types in lesion/tumor areas: lesion cells, macrophages, and fibroblasts ( Storz and Crawford, 2020 ). PDA cancer-associated fibroblasts (CAFs) can have different origins ( Manoukian et al., 2021 ), but one major source is pancreas-resident quiescent stellate cells (qPSCs) ( Apte et al., 2004 ; Bachem et al., 2005 ; Ohlund et al., 2017 ). Recent in vivo lineage tracing using Fabp4-driven Cre indicated that only a portion of CAFs arise from PSCs, but that myCAFs with PSC origins have a tumor-promoting role ( Helms et al., 2021 ).…”

Cancer-Associated Fibroblasts Influence the Biological Properties of Malignant Tumours via Paracrine Secretion and Exosome Production

“…Other candidate cell types hypothesised as precursors of CAFs and factors stimulating their formation [59][60][61][62][63][64][65] are included in Table 1. Members of the TGF-β family seem to be the most frequently discussed in this context as inducers of the transition of precursor cells to myofibroblasts [66].…”