Mutant KRAS triggers functional reprogramming of tumor-associated macrophages in colorectal cancer

Liu, Huashan; Liang, Zhenxing; Zhou, Chi; Zeng, Ziwei; Wang, Fengwei; Hu, Tuo; He, Xiaowen; Wu, Xiaojian; Wu, Xianrui; Lan, Ping

doi:10.1038/s41392-021-00534-2

Cited by 51 publications

(49 citation statements)

References 48 publications

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“…Cetuximab, an EGFR-targeting agent, is a standard treatment for KRAS wild-type mCRC [ 27 ]. KRAS mutant CRC cells have been reported that it could promote tumour progression and induce resistance to cetuximab therapy [ 28 ]; however, there is no effective treatment to specifically treat cancers expressing KRAS mutations [ 29 , 30 ].…”

Section: Discussionmentioning

confidence: 99%

Cetuximab promotes RSL3-induced ferroptosis by suppressing the Nrf2/HO-1 signalling pathway in KRAS mutant colorectal cancer

et al. 2021

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Cetuximab is approved for the treatment of metastatic colorectal cancer (mCRC) with RAS wild-type. Nevertheless, the prognosis remains poor and the effectiveness of cetuximab is limited in KRAS mutant mCRC. Recently, emerging evidence has shown that ferroptosis, a newly discovered form of nonapoptotic cell death, is closely related to KRAS mutant cells. Here, we further investigated whether cetuximab-mediated regulation of p38/Nrf2/HO-1 promotes RSL3-induced ferroptosis and plays a pivotal role in overcoming drug resistance in KRAS mutant colorectal cancer (CRC). In our research, we used two KRAS mutant CRC cell lines, HCT116 and DLD-1, as models of intrinsic resistance to cetuximab. The viability of cells treated with the combination of RSL3 and cetuximab was assessed by the CCK-8 and colony formation assays. The effective of cetuximab to promote RSL3-induced ferroptosis was investigated by evaluating lipid reactive oxygen species accumulation and the expression of the malondialdehyde and the intracellular iron assay. Cetuximab therapy contributed to regulating the p38/Nrf2/HO-1 axis, as determined by western blotting and transfection with small interfering RNAs. Cetuximab promoted RSL3-induced ferroptosis by inhibiting the Nrf2/HO-1 in KRAS mutant CRC cells, and this was further demonstrated in a xenograft nude mouse model. Our work reveals that cetuximab enhances the cytotoxic effect of RSL3 on KRAS mutant CRC cells and that cetuximab enhances RSL3-induced ferroptosis by inhibiting the Nrf2/HO-1 axis through the activation of p38 MAPK.

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Section: Discussionmentioning

confidence: 99%

Cetuximab promotes RSL3-induced ferroptosis by suppressing the Nrf2/HO-1 signalling pathway in KRAS mutant colorectal cancer

et al. 2021

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“…HE staining demonstrating the histology of tumors formed in the livers was observed using the ImageScope software as described. 54 …”

Section: Methodsmentioning

confidence: 99%

XBP1 regulates the protumoral function of tumor-associated macrophages in human colorectal cancer

Zhao

Zhang

Huo

et al. 2021

Sig Transduct Target Ther

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Macrophages are among the most abundant immune cells in colorectal cancer (CRC). Re-educating tumor-associated macrophages (TAMs) to switch from protumoral to anti-tumoral activity is an attractive treatment strategy that warrants further investigation. However, little is known about the key pathway that is activated in TAMs. In this study, infitrating CD206+ TAMs in CRC were sorted and subjected to RNA-seq analysis. Differentially expressed genes were found to be enriched in unfolded protein response/endoplasmic reticulum stress response processes, and XBP1 splicing/activation was specifically observed in TAMs. XBP1 activation in TAMs promoted the growth and metastasis of CRC. Ablation of XBP1 inhibited the expression of the pro-tumor cytokine signature of TAMs, including IL-6, VEGFA, and IL-4. Simultaneously, XBP1 depletion could directly inhibit the expression of SIRPα and THBS1, thereby blocking “don’t eat me” recognition signals and enhancing phagocytosis. Therapeutic XBP1 gene editing using AAV2-sgXBP1 enhanced the anti-tumor activity. Together, XBP1 activation in TAMs drives CRC progression by elevating pro-tumor cytokine expression and secretion, as well as inhibiting macrophage phagocytosis. Targeting XBP1 signaling in TAMs may be a potential strategy for CRC therapy.

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“…Patients with mutant KRAS tumors had a significantly shorter time to CRPM development and CRPM-free survival compared to those wild-type KRAS status [ 84 ]. Concordantly, Liu et al [ 85 ] demonstrated that mutant KRAS reprograms macrophages to a M2 TAM-like phenotype through colony-stimulating factor 2 and lactate production, which promoted tumor progression and conferred EGFR inhibitor resistance.…”

Section: The Tumor Microenvironment In Crcmentioning

confidence: 96%

The Colorectal Cancer Tumor Microenvironment and Its Impact on Liver and Lung Metastasis

Chandra

Karalis

Liu

et al. 2021

Cancers

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Colorectal cancer (CRC) is the third most common malignancy and the second most common cause of cancer-related mortality worldwide. A total of 20% of CRC patients present with distant metastases, most frequently to the liver and lung. In the primary tumor, as well as at each metastatic site, the cellular components of the tumor microenvironment (TME) contribute to tumor engraftment and metastasis. These include immune cells (macrophages, neutrophils, T lymphocytes, and dendritic cells) and stromal cells (cancer-associated fibroblasts and endothelial cells). In this review, we highlight how the TME influences tumor progression and invasion at the primary site and its function in fostering metastatic niches in the liver and lungs. We also discuss emerging clinical strategies to target the CRC TME.

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Mutant KRAS triggers functional reprogramming of tumor-associated macrophages in colorectal cancer

Cited by 51 publications

References 48 publications

Cetuximab promotes RSL3-induced ferroptosis by suppressing the Nrf2/HO-1 signalling pathway in KRAS mutant colorectal cancer

Cetuximab promotes RSL3-induced ferroptosis by suppressing the Nrf2/HO-1 signalling pathway in KRAS mutant colorectal cancer

XBP1 regulates the protumoral function of tumor-associated macrophages in human colorectal cancer

The Colorectal Cancer Tumor Microenvironment and Its Impact on Liver and Lung Metastasis

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