{"database":"biostudies-literature","file_versions":[],"scores":null,"additional":{"submitter":["Remsing Rix LL"],"funding":["NCI NIH HHS"],"pagination":["eabj5879"],"full_dataset_link":["https://www.ebi.ac.uk/biostudies/studies/S-EPMC9528501"],"repository":["biostudies-literature"],"omics_type":["Unknown"],"volume":["15(747)"],"pubmed_abstract":["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, <i>EGFR</i>-mutant PC9GR lung cancer cells treated with recombinant IGFBPs. Conversely, drug sensitivity was decreased by recombinant IGFs or conditioned medium from CAFs in which <i>IGFBP5</i> or <i>IGFBP6</i> 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 <i>MET</i> 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."],"journal":["Science signaling"],"pubmed_title":["IGF-binding proteins secreted by cancer-associated fibroblasts induce context-dependent drug sensitization of lung cancer cells."],"pmcid":["PMC9528501"],"funding_grant_id":["F99 CA212456","P30 CA076292","R01 CA219347"],"pubmed_authors":["Chen YA","Sumi NJ","Welsh EA","Rix U","Fang B","Antonia SJ","Kuenzi BM","Marusyk A","Li X","Bryant AT","Lovly CM","Remsing Rix LL","Haura EB","Kinose F","Hu Q","Koomen JM","Desai B"],"additional_accession":[]},"is_claimable":false,"name":"IGF-binding proteins secreted by cancer-associated fibroblasts induce context-dependent drug sensitization of lung cancer cells.","description":"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, <i>EGFR</i>-mutant PC9GR lung cancer cells treated with recombinant IGFBPs. Conversely, drug sensitivity was decreased by recombinant IGFs or conditioned medium from CAFs in which <i>IGFBP5</i> or <i>IGFBP6</i> 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 <i>MET</i> 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.","dates":{"release":"2022-01-01T00:00:00Z","publication":"2022 Aug","modification":"2026-05-10T06:57:48.196Z","creation":"2025-02-18T23:44:53.527Z"},"accession":"S-EPMC9528501","cross_references":{"pubmed":["35973030"],"doi":["10.1126/scisignal.abj5879"]}}