IGF-binding proteins secreted by cancer-associated fibroblasts induce context-dependent drug sensitization of lung cancer cells
Menée à l'aide de lignées cellulaires de cancer du poumon et de xénogreffes sur un modèle murin, cette étude démontre que les fibroblastes associés au cancer peuvent, en fonction du contexte de signalisation, sensibiliser ou non les cellules cancéreuses aux anticancéreux
Cancer-associated fibroblasts (CAFs) in the tumor microenvironment are often linked to drug resistance. Here, we found that coculture with CAFs or culture in CAF-conditioned medium unexpectedly induced drug sensitivity in certain lung cancer cell lines. Gene expression and secretome analyses of CAFs and normal lung?associated fibroblasts (NAFs) revealed differential abundance of insulin-like growth factors (IGFs) and IGF-binding proteins (IGFBPs), which promoted or inhibited, respectively, signaling by the receptor IGF1R and the kinase FAK. Similar drug sensitization was seen in gefitinib-resistant, EGFR-mutant PC9GR lung cancer cells treated with recombinant IGFBPs. Conversely, drug sensitivity was decreased by recombinant IGFs or conditioned medium from CAFs in which IGFBP5 or IGFBP6 was silenced. Phosphoproteomics and receptor tyrosine kinase (RTK) array analyses indicated that exposure of PC9GR cells to CAF-conditioned medium also inhibited compensatory IGF1R and FAK signaling induced by the EGFR inhibitor osimertinib. Combined small-molecule inhibition of IGF1R and FAK phenocopied the CAF-mediated effects in culture and increased the antitumor effect of osimertinib in mice. Cells that were osimertinib resistant and had MET amplification or showed epithelial-to-mesenchymal transition also displayed residual sensitivity to IGFBPs. Thus, CAFs promote or reduce drug resistance in a context-dependent manner, and deciphering the relationship between the differential content of CAF secretomes and the signaling dependencies of the tumor may reveal effective combination treatment strategies. Specific CAFs can signal to suppress or enhance drug resistance depending on the tumor. Cancer-associated fibroblasts (CAFs) are often implicated in drug resistance and tumor progression. However, CAFs are phenotypically and functionally heterogeneous, and those with a specific proteomic profile are associated with tumor suppression. Remsing Rix et al. found another twist in the role of CAFs in drug efficacy. They found that the same CAFs that induced drug resistance in some lung cancer cell lines promoted drug sensitivity in others. In EGFR-mutant tumors, drug-induced compensatory signaling was attenuated by IGF-binding proteins (IGFBPs) secreted by CAFs, thus enhancing or restoring drug efficacy in treatment-naïve and drug-resistant cells. Thus, rather than being binary, the function of CAFs in drug resistance depends on the signaling context of the cancer cells with which they interact.
Science Signaling 2022