Gas6 derived from cancer-associated fibroblasts promotes migration of Axl-expressing lung cancer cells during chemotherapy

Abstract

Alterations to the tumor stromal microenvironment induced by chemotherapy could influence the behavior of cancer cells. In the tumor stromal microenvironment, cancer-associated fibroblasts (CAFs) play an important role. Because the receptor tyrosine kinase Axl and its ligand Gas6 could be involved in promoting non-small cell lung cancer (NSCLC), we investigated the role of Gas6 secreted by CAFs during chemotherapy in NSCLC. In a murine model, we found that Gas6 expression by CAFs was upregulated following cisplatin treatment. Gas6 expression might be influenced by intratumoral hypoperfusion during chemotherapy, and it increased after serum starvation in a human lung CAF line, LCAFhTERT. Gas6 is associated with LCAFhTERT cell growth. Recombinant Gas6 promoted H1299 migration, and conditioned medium (CM) from LCAFhTERT cells activated Axl in H1299 cells and promoted migration. Silencing Gas6 in LCAFhTERT reduced the Axl activation and H1299 cell migration induced by CM from LCAFhTERT. In clinical samples, stromal Gas6 expression increased after chemotherapy. Five-year disease-free survival rates for patients with tumor Axl- and stromal Gas6-positive tumors (n = 37) was significantly worse than for the double negative group (n = 12) (21.9% vs 51.3%, p = 0.04). Based on these findings, it is presumed that Gas6 derived from CAFs promotes migration of Axl-expressing lung cancer cells during chemotherapy and is involved in poor clinical outcome.

AXL Controls Directed Migration of Mesenchymal Triple-Negative Breast Cancer Cells

“…The authors further show that AXL inhibition decreases the activity of these activated macrophages reducing cancer cell invasiveness and restoring drug sensitivity of cancer cells [66]. Cancer-associated fibroblasts can also produce Gas6 following therapy leading to the migration of AXL-positive lung cancer cells [77]. Collectively, the contact with extracellular matrix may lead to AXL overexpression in cancer cells and Gas6, secreted by some stromal cells, could induce the polarization of the Golgi toward the microenvironment allowing the escape of tumor cells.…”

Cellular heterogeneity during mouse pancreatic ductal adenocarcinoma progression at single-cell resolution

“…FB2 specifically expressed Nov , a member of the CCN family of secreted matricellular proteins [16] as well as Pi16 , which has been shown to be expressed in fibroblast populations in various tissue types [17], in addition to Ly6a and Ly6c1 . FB3 showed distinct expression of mesothelial markers such as Lrrn4, Gpm6a, Nkain4, Lgals7 , and Msln [18] in addition to other genes previously shown to be expressed in fibroblasts such as Cav1, Cdh11 , and Gas6 [19–21].…”

Patient-derived explants (PDEs) as a powerful preclinical platform for anti-cancer drug and biomarker discovery

“…There is now strong evidence for extensive inter-and intra-tumour heterogeneity both within and between human cancer samples 10,11 and for a critical role of the tumour microenvironment (TME) in driving cancer hallmarks and in influencing drug responses. 12,13 Indeed, the previous lack of appreciation for the diversity and complexity of human tumours might well have accounted for the attrition of many anti-cancer agents. An ideal 'modern' preclinical cancer model is one that can recapitulate both human tumour heterogeneity as well as the TME, and in the past 10 years or so, improvements have been made in available models to take into account this complexity.…”