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Mutant KRAS triggers functional reprogramming of tumor-associated macrophages in colorectal cancer
Huashan Liu1,2,3, Zhenxing Liang1,2, Chi Zhou4,5
1Department of Colorectal Surgery, The Sixth Affiliated Hospital, Sun Yat-sen University, Guangzhou, Guangdong, China.
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.
Insights
Mutant KRAS reprograms tumor-associated macrophages (TAMs) in colorectal cancer (CRC) through CSF2 and lactate, promoting tumor growth and therapy resistance. This highlights a novel cell-extrinsic role for KRAS in cancer progression.
Area of Science:
- Oncology
- Cancer Biology
- Tumor Microenvironment
Background:
- Oncogenic KRAS mutations are key drivers in colorectal cancer (CRC).
- KRAS typically functions intrinsically, affecting tumor cell biology.
- A cell-extrinsic role for KRAS in modulating the tumor microenvironment is less understood.
Purpose of the Study:
- To investigate the cell-extrinsic function of oncogenic KRAS in colorectal cancer.
- To elucidate the mechanism by which KRAS interacts with tumor-associated macrophages (TAMs).
- To determine the impact of KRAS-mediated TAM reprogramming on tumor progression and therapy resistance.
Main Methods:
- Analysis of human CRC specimens to correlate KRAS mutation status with TAM presence.
- Investigating the reprogramming of macrophages by tumor cells with activated KRAS.
- Assessing the role of tumor-derived CSF2 and lactate in macrophage phenotype.
- Examining the stabilization of hypoxia-inducible factor-1α (HIF-1α) by mutant KRAS.
- Evaluating the effect of KRAS-reprogrammed TAMs on tumor cell response to cetuximab therapy.
Main Results:
- Mutant KRAS positively correlates with TAM infiltration in human CRC.
- Tumor cell-derived CSF2 and lactate reprogram macrophages to a TAM-like phenotype.
- KRAS stabilizes HIF-1α by increasing reactive oxygen species, enhancing CSF2 and glycolytic gene expression.
- KRAS-reprogrammed TAMs promote tumor progression and cetuximab resistance.
Conclusions:
- Oncogenic KRAS plays a critical cell-extrinsic role in shaping the tumor microenvironment.
- KRAS reprograms TAMs via CSF2 and lactate, promoting CRC malignancy and therapeutic resistance.
- This mechanism offers potential new therapeutic targets for mutant KRAS colorectal cancer.
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