Bad Neighborhood: Fibrotic Stroma as a New Player in Melanoma Resistance to Targeted Therapies

Abstract

Current treatments for metastatic cutaneous melanoma include immunotherapies and drugs targeting key molecules of the mitogen-activated protein kinase (MAPK) pathway, which is often activated by BRAF driver mutations. Overall responses from patients with metastatic BRAF mutant melanoma are better with therapies combining BRAF and mitogen-activated protein kinase kinase (MEK) inhibitors. However, most patients that initially respond to therapies develop drug resistance within months. Acquired resistance to targeted therapies can be due to additional genetic alterations in melanoma cells and to non-genetic events frequently associated with transcriptional reprogramming and a dedifferentiated cell state. In this second scenario, it is possible to identify pro-fibrotic responses induced by targeted therapies that contribute to the alteration of the melanoma tumor microenvironment. A close interrelationship between chronic fibrosis and cancer has been established for several malignancies including breast and pancreatic cancers. In this context, the contribution of fibrosis to drug adaptation and therapy resistance in melanoma is rapidly emerging. In this review, we summarize recent evidence underlining the hallmarks of fibrotic diseases in drug-exposed and resistant melanoma, including increased remodeling of the extracellular matrix, enhanced actin cytoskeleton plasticity, high sensitivity to mechanical cues, and the establishment of an inflammatory microenvironment. We also discuss several potential therapeutic options for manipulating this fibrotic-like response to combat drug-resistant and invasive melanoma.

A Framework of Major Tumor-Promoting Signal Transduction Pathways Implicated in Melanoma-Fibroblast Dialogue

“…Unfortunately, patients frequently develop mutation-independent resistance to this therapy. Acquired resistance is mostly driven by the secretory activity of TAMs and MAFs [ 225 , 226 , 227 ].…”

“…In fibroblasts, the expression of mitogen-activated protein kinase kinase 1 (MAPKK1) is strongly induced by melanoma cells secretome [ 75 ]. Several studies underlined the key role of fibroblast-derived cytokines in MAPK inhibitor tolerance [ 225 , 226 , 227 , 228 , 229 ]. This effect is mostly due to the non-negligible direct effect of this class of compound on BRAF wild type surrounding non-melanoma cells.…”

Échappement thérapeutique du mélanome : la piste biomécanique

“…Comme YAP, MRTF, en réponse à une augmentation de rigidité de la matrice extracellulaire, est transloqué dans le noyau, où il active l'expression de ses gènes cibles, impliqués dans la contraction du cytosquelette [10]. Comme les CAF, les cellules de mélanome ont la capacité de sécréter leur propre matrice extracellulaire, en particulier après la transition phénotypique mésenchymateuse qui a lieu en réponse aux traitements ciblés [11].…”

Invasive dedifferentiated melanoma cells inhibit JAK1-STAT3-driven actomyosin contractility of human fibroblastic reticular cells of the lymph node

“…In other tissues, like the skin, quiescent fibroblasts are not spontaneously contractile but can be converted into contractile myofibroblasts by factors secreted during wound healing or tumor progression, such as TGF-β or IL-6 family cytokines (24). Factors secreted by tumor cells transform fibroblasts in the tumor vicinity into cancer associated fibroblasts (CAF) (25).…”