Tumor-Associated Macrophages Promote Oxaliplatin Resistance via METTL3-Mediated m⁶A of TRAF5 and Necroptosis in Colorectal Cancer

Abstract

As a third-generation platinum drug, oxaliplatin (OX) is widely used as the first-line chemotherapeutic agent in the treatment of colorectal cancer (CRC). CRC cells acquire resistance to chemotherapy and develop resistance, which is a major challenge for the treatment of advanced CRC. Recent studies have suggested that the therapeutic resistance of tumors is affected by the tumor microenvironment (TME). As a critical role among TME, tumor-associated macrophages (TAMs) play an important role. However, their regulatory mechanism underlying the drug resistance in CRC remains largely unknown. In the present study, we found that the density of macrophages infiltrated into the CRC tissues from OX-resistant patients was significantly higher compared with the OX-sensitive patients. Interestingly, both the total N 6 -methyladenosine (m 6 A) RNA content and the expression of its critical methyltransferase METTL3 were increased in the CRC tissues from OX-resistant patients compared with the OX-sensitive patients. Furthermore, we demonstrated that the M2-polarized TAMs enabled the OX resistance via the elevation of METTL3-mediated m 6 A modification in cells. Through whole-genome CRISPR screening and further validation, we found that TRAF5 contributes to the METTL3-triggered OX resistance in CRC cells. This study unveiled that M2-TAMs were important mediators for the acquisition of OX resistance. Furthermore, we provided evidence that targeting of M2-TAMs and METTL3-mediated m 6 A modification might be a promising adjuvant therapeutic strategy for CRC patients, especially for OX-resistant CRC patients.

Quantification of m6A RNA methylation modulators pattern was a potential biomarker for prognosis and associated with tumor immune microenvironment of pancreatic adenocarcinoma

“…However, therapies targeting signaling pathways in pancreatic cancer lack efficacy due to the heterogeneity of tumor microenvironment (TME) in patients, TME prevents antitumor drug resistance, immune escape and tumor cell’s infiltration during cancer progression. Increasing evidence demonstrated that m6A modification is associated with TME of cancer, and the polarization of tumor-associated macrophages-M2 enabled the oxaliplatin resistance via the elevation of METTL3-mediated m6A modification [ 34 ]. Dali et al found a risen level of CD8+ cytotoxic T cells and natural killer (NK) cells while a reduced infiltration of myeloid-derived suppressor cells (MDSC) from Ythdf1−/− tumor mice compared to WT mice, besides, the therapeutic efficacy of PD-L1 checkpoint blockade is enhanced in Ythdf1−/− mice [ 35 ].…”

RNA m6A methyltransferase METTL3 promotes colorectal cancer cell proliferation and invasion by regulating Snail expression

“…METTL3, as the most important writer of m 6 A, is upregulated in numerous malignancies and can epigenetically increase gene expression by specifically editing m 6 A sites modification, thus eliciting a potential malignant function ( 39 ). Previous studies have demonstrated that METTL3 is frequently upregulated in CRC, where it maintains high m 6 A modification levels ( 40 – 42 ). Consistently, the present data showed that METTL3 is elevated in five paired CRC tissues and CRC cell lines.…”

Identification and Validation of a Novel 2-LncRNAs Signature Associated with m6A Regulation in Colorectal Cancer

“…M2-polarized tumor-associated macrophages can elevate the level of m6A modification mediated by METTL3 and induce oxaliplatin (OX) resistance. Modulation of METTL3-mediated m6A modification may be a potential treatment strategy and molecular target for patients with OX resistance [32].…”