CD47 regulates pro-metastatic phenotypes through an ERK-dependent epithelial-to-mesenchymal transition program in non-small cell lung cancer

CD47 is best known for its role in tumor immune evasion; however, studies in diverse cell models indicate that it also has cell-autonomous, tumor-promoting functions which are cell type- and context-specific. Motivated by CD47's prognostic and therapeutic significance and the limited knowledge regarding its roles beyond immune evasion in non-small cell lung cancer (NSCLC), we sought to define the cellular and molecular processes driven by intrinsic CD47 signaling in NSCLC. Transcriptome profiling of CD47 wildtype and knockout NSCLC models implicated its regulation of genes enriched for signatures of epithelial-to-mesenchymal transition (EMT) and MAPK signaling. Functional studies indicated that CD47 does not regulate cell proliferation in NSCLC cells as it does in other cancer types. Instead, we found that CD47 regulates cell adhesion and migration through an ERK-dependent mechanism, validating our transcriptomic findings. Our discoveries reveal a novel role for CD47 in relaying signals through ERK to promote EMT expression programs and pro-metastatic phenotypes in NSCLC. These findings reinforce CD47's therapeutic potential, rationalizing further research to develop CD47 blockade as a multimodal therapy for NSCLC.