Cancer-Associated Fibroblasts in Pancreatic Ductal Adenocarcinoma: An Update on Heterogeneity and Therapeutic Targeting

Abstract

Pancreatic ductal adenocarcinoma (PDAC) is a leading cause of cancer-related morbidity and mortality in the western world, with limited therapeutic strategies and dismal long-term survival. Cancer-associated fibroblasts (CAFs) are key components of the pancreatic tumor microenvironment, maintaining the extracellular matrix, while also being involved in intricate crosstalk with cancer cells and infiltrating immunocytes. Therefore, they are potential targets for developing therapeutic strategies against PDAC. However, recent studies have demonstrated significant heterogeneity in CAFs with respect to their origins, spatial distribution, and functional phenotypes within the PDAC tumor microenvironment. Therefore, it is imperative to understand and delineate this heterogeneity prior to targeting CAFs for PDAC therapy.

Keywords: CAF heterogeneity; apCAF; cancer-associated fibroblasts; iCAF; myCAF; pancreatic cancer; pancreatic ductal adenocarcinoma.

Figure 1

Origin of CAFs. Illustration of the potential cells of origin of CAFs, including resident fibroblasts, endothelial cells, epithelial cells, mesothelial cells, mesenchymal stem cells, and adipocytes with probable mechanisms.

Figure 2

CAF Heterogeneity. Illustration of CAF heterogeneity, showing differentiation of precursor cells, such as resident fibroblast or mesothelial cells, or BM-derived MSCs, etc., into myCAF, iCAF, and apCAF, with reported probable mechanisms.

Figure 3

Functions of CAFs. Schematic representation of the functions of CAFs in the tumor microenvironment, such as ECM deposition, immunosuppression, tumor promotion, neoangiogenesis, metastasis, etc.