Transcription factors in fibroblast plasticity and CAF heterogeneity

Abstract

In recent years, research focused on the multifaceted landscape and functions of cancer-associated fibroblasts (CAFs) aimed to reveal their heterogeneity and identify commonalities across diverse tumors for more effective therapeutic targeting of pro-tumoral stromal microenvironment. However, a unified functional categorization of CAF subsets remains elusive, posing challenges for the development of targeted CAF therapies in clinical settings.The CAF phenotype arises from a complex interplay of signals within the tumor microenvironment, where transcription factors serve as central mediators of various cellular pathways. Recent advances in single-cell RNA sequencing technology have emphasized the role of transcription factors in the conversion of normal fibroblasts to distinct CAF subtypes across various cancer types.This review provides a comprehensive overview of the specific roles of transcription factor networks in shaping CAF heterogeneity, plasticity, and functionality. Beginning with their influence on fibroblast homeostasis and reprogramming during wound healing and fibrosis, it delves into the emerging insights into transcription factor regulatory networks. Understanding these mechanisms not only enables a more precise characterization of CAF subsets but also sheds light on the early regulatory processes governing CAF heterogeneity and functionality. Ultimately, this knowledge may unveil novel therapeutic targets for cancer treatment, addressing the existing challenges of stromal-targeted therapies.

Keywords: CAF activation; CAF subtypes; Cancer Associated fibroblasts (CAFs); Fibrosis; Transcription factors (TFs).

Fig. 1

Schematic representation of the main transcription factors involved in normal fibroblasts conversion into myofibroblasts during wound healing, fibrosis and cancer. EN1-positive dermal fibroblasts are major contributors toward wound repair. The major TFs upregulated or downregulated during fibroblast activation due to wound healing, fibrosis or cancer are reported. RUNX2 identifies both wound fibroblasts and the “early wound CAF” subtype. CSL complex with p53, ATF3 or AR to act as transcriptional repressor control of early CAF activation. Created with BioRender.com

Fig. 2

Transcription factors specifying CAF Subtypes. Three main CAF populations have been described: inflammatory, iCAF characterized by cytokine/chemokine secretion; myofibroblasts, myCAF providing ECM modulation, collagen deposition; antigen-presenting CAF, apCAF expressing major histocompatibility complex (MHC) class II genes. TFs associated with each of the CAF subtype are reported. Additional subtypes were defined by scRNA-seq. From 3 tumor histotypes, melanoma, head and neck squamous cell carcinoma, and lung cancer, 6 different subtypes including pan-myCAF, pan-dCAF, pan-iCAF, have been identified and associated with specific transcription factors (3 Tumor types) [8]. From scRNA-seq data of 9 studies of pan-cancer CAF atlas, four different CAF subtypes, namely progenitor CAF (proCAF), inflammatory CAF (iCAF), myofibroblastic CAF (myCAF), and matrix-producing CAF (matCAF) emerged as associated with core regulatory network of transcription factors (TFs), that are highly activated in CAF subtypes with similar functionality (9 tumor types) [92]. Finally, transcriptomic profiles of fibroblasts from multiple tumor types (10 tumor types) different clusters have been identified, with three major components, including cancer-associated myofibroblasts (CAFmyo), inflammatory CAFs (CAFinfla), and adipogenic CAFs (CAFadi), along with minor components, such as endothelial-to-mesenchymal transition CAF (CAFEndMT), peripheral nerve-like CAF (CAFPN), and antigen-presenting CAF (CAFap) [9]. Created with BioRender.com

Fig. 3

STAT3 signaling targeting modulates the stroma by affecting CAF activation/functions and cancer cell/CAF crosstalk in PDAC and NSCLC. Effects of the JAK/STAT axis targeting by JAK inhibitor AZD1480 on: (A) reprogramming inflammatory CAFs (iCAFs) in a mouse model of PDAC; (B) affecting in vivo drug delivery and therapeutic response in PDAC, in combination with gemcitabine [119, 120]. C Hampering CAF activity and the crosstalk between NSCLC cells and CAFs through STAT3 silencing by an aptamer-based strategy [121]; (D) Reprogramming of the CAF population and the immune microenvironment to overcome resistance to immune checkpoint blockade in PDAC by the combination of MEKi (trametinib) and STAT3i (ruxolitinib) [122]