期刊
SIGNAL TRANSDUCTION AND TARGETED THERAPY
卷 6, 期 1, 页码 -出版社
SPRINGERNATURE
DOI: 10.1038/s41392-021-00534-2
关键词
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资金
- National Natural Science Foundation of China [81870383]
- Clinical Innovation Research Program of Guangzhou Regenerative Medicine and Health Guangdong Laboratory [2018GZR0201005]
- Science and Technology Planning Project of Guangzhou City [201804010014]
- National Key R&D Program of China [2017YFC1308800]
This study reveals a cell-extrinsic role of KRAS in modulating the tumor microenvironment by reprogramming tumor-associated macrophages, promoting tumor progression and inducing resistance to cetuximab therapy. Mechanistically, mutant KRAS stabilizes HIF-1 alpha to drive the production of CSF2 and lactate in tumor cells, enhancing HIF-1 alpha stabilization and contributing to a permissive microenvironment for tumor malignancy.
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-1 alpha (HIF-1 alpha), 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-1 alpha hydroxylation, leading to enhanced HIF-1 alpha 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.
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