Cancer-associated fibroblasts promote osimertinib resistance in non-small cell lung cancer cells via METTL1-mediated NET1 m7G modification

TL;DR

Cancer-associated fibroblasts help lung cancer cells resist treatment by modifying RNA, offering new insights into drug resistance.

Contribution

A novel mechanism linking CAFs, METTL1, and m7G modification to osimertinib resistance in NSCLC is revealed.

Findings

CAFs promote osimertinib resistance in NSCLC cells via METTL1-mediated m7G modification.

HMGB1 secreted by CAFs upregulates METTL1 in NSCLC cells.

Reducing m7G modification via METTL1 knockdown decreases CAF-induced resistance in NSCLC.

Abstract

Osimertinib resistance remains a major challenge in the treatment of non-small cell lung cancer (NSCLC). Cancer-associated fibroblasts (CAFs) are the most abundant stromal cells in tumor microenvironment (TME), however, its role in osimertinib resistance in NSCLC is not fully understood. In this study, it was found that CAFs promoted osimertinib resistance in NSCLC cells via elevating RNA m7G modification. Methyltransferase 1 (METTL1) in NSCLC cells mediated CAFs’ effect on m7G modification, and METTL1 was associated with NSCLC progression and poor prognosis. Further study demonstrates that CAFs upregulated METTL1 in NSCLC cells by secreting HMGB1. By applying MeRIP-seq and RNA-seq, neuroepithelial cell transforming gene 1 (NET1) was identified as a target of METTL1, and enhanced m7G modification of NET1 increased NET1 expression and activated downstream AKT/NF-κB pathway. Importantly, reducing m7G modification by METTL1 knockdown significantly attenuated CAFs’ stimulatory effect on osimertinib resistance both in vitro and in vivo. Our study revealed a novel mechanism that CAFs conferred osimertinib resistance in NSCLC cells through modulating m7G modification. These findings underscore the importance of m7G modification in the communication between cancer cells and the TME, and pave the way for finding novel therapeutic strategies to overcome drug resistance by targeting m7G modification.

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