<scp>CD47</scp> promotes mitogen‐activated protein kinase and epithelial‐to‐mesenchymal transition molecular programs to drive prometastatic phenotypes 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 the prognostic and therapeutic significance of CD47 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 wild-type and knockout NSCLC cells implicated its regulation of genes enriched for signatures of mitogen-activated protein kinase (MAPK) signaling and epithelial-to-mesenchymal transition (EMT). A significant positive association between CD47 and MAPK/EMT expression signatures was also evident in large cohorts of NSCLC cell lines and tumor tissues. Functional studies indicated that CD47 does not regulate cell proliferation in NSCLC cells like it does in other cancer types. Instead, CD47 regulates cell adhesion and migration through an ERK and EMT axis, validating our transcriptomic findings. Moreover, CD47 loss-of-function significantly diminished the ability of NSCLC cells to metastasize in vivo, demonstrating the physiological relevance of cell-intrinsic CD47 signaling in lung cancer cells. Our data reveal a novel role for CD47 in relaying signals through ERK to promote EMT expression programs and prometastatic phenotypes in NSCLC. Although additional mechanistic studies are needed to further decipher the CD47-ERK-EMT signaling pathway, our findings reinforce the therapeutic potential of CD47, rationalizing further research to develop CD47 blockade as a multimodal therapy for NSCLC.