Although cisplatin is frequently used to treat gastric cancer, the resistance is the main obstacle for effective treatment. mRNA modification, N6-methyladenosine (m⁶A), is involved in the tumorigenesis of many types of cancer. As one of the largest m⁶A methyltransferase complex components, KIAA1429 bridges the catalytic m⁶A methyltransferase components, such as METTL3. In gastric cancer, KIAA1429 was reported to promote cell proliferation. However, whether KIAA1429 is involved in the resistance of gastric cancer to cisplatin remains unclear. Here, we generated cisplatin resistant gastric cancer cell lines, and compared the m⁶A content between resistant cells and wild type cells. The m⁶A content as well as KIAA1429 expression are higher in resistant cells. Interestingly, the expression of KIAA1429 was significantly increased after cisplatin treatment. We then used shRNA to knockdown KIAA1429 and found that resistant cells responded more to cisplatin treatment after KIAA1429 depletion, while overexpression of KIAA1429 decreased the sensitivity. Moreover, we identified a putative p65 binding site on the promoter area of KIAA1429 and ChIP assay confirmed the binding. p65 depletion decreased the expression of KIAA1429. YTHDF1 is the most abundant m⁶A “reader” that interacts with m⁶A modified mRNA. Mechanistically, YTHDF1 was recruited to the 3′-untranslated Region (3′-UTR) of transcriptional factor, FOXM1 by KIAA1429 and stabilized FOXM1 mRNA. More importantly, KIAA1429 knockdown increased the sensitivity of resistant cells to cisplatin in vivo. In conclusion, our results demonstrated that KIAA1429 facilitated cisplatin resistance by stabilizing FOXM1 mRNA in gastric cancer cells.

Background: Pancreatic ductal adenocarcinoma is characterized by therapy resistance and an immunosuppressive microenvironment. This study investigated the cellular mechanisms underlying chemotherapy resistance and immune evasion in PDAC, focusing on identifying key malignant epithelial subpopulations and their molecular drivers. Methods: We analyzed scRNA-seq data from 27 samples, including treatment-naive and chemotherapy-exposed primary tumors and liver metastasis. Analysis included CNV inference, gene set enrichment, cell–cell communication, NMF analysis and drug sensitivity prediction. Validation employed gemcitabine-resistant cells, western blotting and pan-cancer survival analysis of TCGA/ICGC data. Results: We identified a malignant epithelial subcluster enriched in progressive disease samples and liver metastasis. This subcluster exhibited an immune-cold phenotype, characterized by disrupted communication with immune cells, increased immunosuppressive regulatory T cells and exclusion of anti-tumor effector cells. Further, it was associated with activated oncogenic and chemoresistance pathways, multi-drug resistance to standard therapies, higher tumor mutational burden and increased KRAS mutation frequency. RARRES1 was nominated as a core upregulated gene in this subpopulation. Functional studies confirmed RARRES1 overexpression in gemcitabine-resistant cells, and pan-cancer analysis established RARRES1 as a new biomarker for poor prognosis across multiple cancer types. Conclusions: Our work defines a chemotherapy-resistant and metastasis-enriched malignant epithelial subpopulation in PDAC that drives disease progression through an immune-cold niche. We identify RARRES1 as a pivotal regulator of this process, contributing to both therapy resistance and immune exclusion, and propose it as a novel pan-cancer prognostic biomarker. These findings reveal a targetable cellular mechanism underlying poor treatment response in PDAC.