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 ...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-la(HIF-1a),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-1a hydroxylation,leading to enhanced HIF-1a 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.展开更多
基金This work was supported by the National Natural Science Foundation of China(81870383)Clinical Innovation Research Program of Guangzhou Regenerative Medicine and Health Guangdong Laboratory(2018GZR0201005)+1 种基金Science and Technology Planning Project of Guangzhou City(201804010014)the National Key R&D Program of China(2017YFC1308800).
文摘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-la(HIF-1a),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-1a hydroxylation,leading to enhanced HIF-1a 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.
