Mesenchymal Cancer Cell-Stroma Crosstalk Promotes Niche Activation, Epithelial Reversion, and Metastatic Colonization

Abstract

SummaryDuring metastatic colonization, tumor cells must establish a favorable microenvironment or niche that will sustain their growth. However, both the temporal and molecular details of this process remain poorly understood. Here, we found that metastatic initiating cells (MICs) exhibit a high capacity for lung fibroblast activation as a result of Thrombospondin 2 (THBS2) expression. Importantly, inhibiting the mesenchymal phenotype of MICs by blocking the epithelial-to-mesenchymal transition (EMT)-associated kinase AXL reduces THBS2 secretion, niche-activating ability, and, consequently, metastatic competence. Subsequently, disseminated metastatic cells revert to an AXL-negative, more epithelial phenotype to proliferate and decrease the phosphorylation levels of TGF-β-dependent SMAD2-3 in favor of BMP/SMAD1-5 signaling. Remarkably, newly activated fibroblasts promote this transition. In summary, our data reveal a crosstalk between cancer cells and their microenvironment whereby the EMT status initially triggers and then is regulated by niche activation during metastatic colonization.

The Multiple Roles of Exosomes in Metastasis

“…Myeloid-derived suppressor cells (MDSCs) derived from HPC have been shown to accumulate in metastatic niches and to suppress cytotoxic CD8 + T-cells through production of reactive oxygen species (ROS) as well as NK cell cytotoxicity and maturity (63). Cancer-associated fibroflasts (CAFs), derived from MSCs contribute to niche formation by excessive deposition of constituents of the ECM, by secretion of MMPs that mediate degradation and remodeling of the ECM as well as by promoting proliferation, invasion and motility of niche-related tumor cells (64). In the course of the maturation of the premetastatic niche, DTCs are recruited to the pre-metastatic niche (PMN) for example by interaction between nichederived SDF-1 and CXCR4 on tumor cells (48)(49)(50).…”

Peking University - Juntendo University Joint Symposium on Cancer Research and Treatment

“…In distant organs, the recruited CAFs support metastatic colonization of carcinoma cells via the formation of a metastatic niche producing periostin (POSTN) and tenascin C (TNC), as well as by promoting MET which confers the epithelial phenotype on cancer cells ) that CAFs have the ability to induce EMT phenotypes in apposed human carcinomas, thereby facilitating both invasion and metastatic dissemination. In contrast, when these fibroblasts were recruited to metastatic sites, mesenchymal to epithelial transition (MET) was induced in mesenchymal breast carcinoma cells, such that the fibroblasts facilitated their metastatic colonization 34) (Figure-3). The mesenchymal cancer cells, when cultured with CAFs for 24 hours under adherence conditions, showed increased E-cadherin expression and decreased AXL and vimentin expressions, findings indicative of the induction of MET 34) .…”

“…In contrast, when these fibroblasts were recruited to metastatic sites, mesenchymal to epithelial transition (MET) was induced in mesenchymal breast carcinoma cells, such that the fibroblasts facilitated their metastatic colonization 34) (Figure-3). The mesenchymal cancer cells, when cultured with CAFs for 24 hours under adherence conditions, showed increased E-cadherin expression and decreased AXL and vimentin expressions, findings indicative of the induction of MET 34) . BMP-induced Smad1/5 signaling was also revealed to mediate CAF-induced MET, indicating that CAFs play novel MET-inducing roles in sites of distant metastasis (Figure-3).…”

Mesenchymal traits at the convergence of tumor-intrinsic and -extrinsic mechanisms of resistance to immune checkpoint blockers

“…In NSCLC, the dynamic crosstalk between tumor cells and CAFs, by secreting IL-6, forces tumor cells toward a mesenchymal phenotype correlated to chemoresistance [148]. Incipient data are showing the role of the AXL in the paracrine feedback loop between cancer and fibroblastic cells with significant effects on resistance to conventional therapies, and likely, immunotherapy [149], paving the way for the design of new therapeutic strategies combining AXL targeting with ICBs. Growing evidence shows that FAP, selectively expressed on CAF subtypes and associated with ECM remodeling, induces tumor-promoting inflammation [150][151][152].…”