Cancer‐associated fibroblasts: activin A adds another string to their bow

Abstract

Non‐melanoma skin cancer (NMSC) is characterized by a strong desmoplastic reaction, largely responsible for cancer aggressiveness. Within the tumour microenvironment, cancer‐associated fibroblasts (CAFs) play a key role in tumour progression, secretion of extracellular matrix proteins and recruitment of immunosuppressive cells. However, pathways involved in acquisition of CAF phenotype remain unclear. In this issue of EMBO Molecular Medicine, Cangkrama et al describe a new mechanism of fibroblast activation in squamous cell carcinoma. Cancer cell‐secreted activin A induces a tumour‐promoting phenotype in the fibroblast compartment, with distinct properties compared to TGF‐β‐activated fibroblasts. Activin A reprograms fibroblasts through transcriptional regulation of mDia2 and reduction of nuclear p53, which favours CAF marker expression, and increases tumour growth and migration. Inhibition of this pathway shows promising results in different models and could offer a new therapeutic strategy in NMSC.

The Role of Cancer-Associated Fibroblasts in Tumor Progression

“…In a novel study looking at non-melanoma skin cancer (NMSC), Cangkrama et al identified cancer cell secretion of activin A, rather than TGF-β as a major activation factor for CAF cell differentiation into a protumoral phenotype through activation of a Smad2–mDia2–p53 signaling axis [ 19 , 93 ]. Their study demonstrated in PDX in vivo models and 3D organotypic models that cancer cells with high expression of activin A formed larger tumors and also had significantly higher invasion of the basement membrane layers, in addition to significantly increased stromal fibroblast proliferation rates.…”

“…Notably, CAFs have been identified in numerous systemic cancers in which they embody unique roles, illustrating their heterogeneity [ 9 ]. Cancers where CAFs have definitively been characterized span solid tumors and carcinomas across almost every physiologic system, including head and neck [ 8 , 10 , 11 ], breast [ 12 , 13 , 14 ], lung [ 15 , 16 , 17 , 18 ], skin [ 19 , 20 , 21 ], gastrointestinal (GI) and biliary tract [ 22 , 23 , 24 ], and genitourinary (GU) cancers [ 25 , 26 ]. To date, there has not been any indication that CAFs are implicated in lymphoid and hematopoietic cancers, and there is sparse, but growing evidence alluding to the presence of CAFs in central nervous system (CNS) cancers such as glioblastoma multiforme (GBM) [ 27 , 28 , 29 ].…”

Fibroblasts in Scar Formation: Biology and Clinical Translation

“…It has been reported to reprogram fibroblasts into protumorigenic CAFs via a Smad2-mediated transcriptional regulation of the formin mDia2, promoting filopodia formation and cell migration. Blockade of this paracrine activin A-mDia2 axis suppresses cancer cell malignancy and squamous carcinogenesis in vitro and in vivo [ 86 , 87 ]. As for facilitated invasiveness, keloid tissue-derived fibroblasts (KF) with upregulated LARP6 expression demonstrates enhanced cell proliferation and invasive behavior in cell culture system, while knockdown of LARP reverses this effect, with reduced deposition of type I collagen and inhibition of proliferation and invasion ability [ 88 ].…”

Data-driven analysis to identify prognostic immune-related biomarkers in BRAF mutated cutaneous melanoma microenvironment

“…Monocyte-lymphocyte ratio (MLR) is considered to be an important indicator of tumor prognosis ( Garcia et al, 2022 ). It has been reported that cancer-associated Macrophage play a key role in tumor progression, angiogenesis, invasion and recruitment of immunosuppressive cells ( Samain and Sanz-Moreno, 2020 ). Persistent immune-related gene expression and T-cell penetration were associated with clinical benefit in SKCM patients ( Shoushtari et al, 2022 ).…”