Abstract
Oncogenic KRAS has been previously identified to act in a cell-intrinsic manner to modulate multiple biological functions of colorectal cancer (CRC). Here, we demonstrate a cell-extrinsic role of KRAS, where KRAS engages with the tumor microenvironment by functional reprogramming of tumor-associated macrophages (TAMs). In human CRC specimens, mutant KRAS positively correlates with the presence of TAMs. Mutationally activated KRAS in tumor cells reprograms macrophages to a TAM-like phenotype via a combination effect of tumor-derived CSF2 and lactate. In turn, KRAS-reprogrammed macrophages were shown to not only promote tumor progression but also induce the resistance of tumor cells to cetuximab therapy. Mechanistically, KRAS drives the production of CSF2 and lactate in tumor cells by stabilizing hypoxia-inducible factor-1α (HIF-1α), a transcription factor that controls the expression of CSF2 and glycolytic genes. Mutant KRAS increased the production of reactive oxygen species, an inhibitor of prolyl hydroxylase activity which decreases HIF-1α hydroxylation, leading to enhanced HIF-1α stabilization. This cell-extrinsic mechanism awards KRAS a critical role in engineering a permissive microenvironment to promote tumor malignancy, and may present new insights on potential therapeutic defense strategies against mutant KRAS tumors.
Highlights
Colorectal cancer (CRC) remains a frequently encountered fatal disease worldwide
KRAS mutation positively correlates with tumor-associated macrophages (TAMs) in CRC To probe the potential link between KRAS and TAMs in CRC, we examined the presence of TAMs in 338 CRC samples, including 104 KRAS mutant and 234 KRAS wild-type cases
Mutant KRAS triggers functional reprogramming of tumor-associated
Summary
Colorectal cancer (CRC) remains a frequently encountered fatal disease worldwide. Approximately 20% of CRC patients exhibit distant metastasis at the time of diagnosis.[1]. KRAS mutation, which is typically associated with tumor progression and poor prognosis, was reported to occur in 35–50% of CRC patients.[5,6] The roles of KRAS in CRC pathogenesis were faithfully indicated by genetically engineered CRC mouse models, in which the conditional expression of the mutant allele of KRAS promoted tumor invasion and metastases.[7] mutationally activated KRAS was found to elicit intrinsic resistance to epidermal growth factor receptor inhibitors.[8] These insights imply that KRAS exerts complex effects in tumors. This study sought to investigate the cell-extrinsic role of KRAS in tumor crosstalk with TAMs and the mechanism by which this occurs
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