Abstract Background: Diffuse pleural mesothelioma (DPM) features frequent NF2 loss, Hippo pathway disruption, and limited therapies. We identify miR-1293 as a tumor-suppressive miRNA that targets an S100A16-centered Hippo/EMT axis involving Hippo/YAP and epithelial-mesenchymal transition (EMT) in DPM. Methods: We performed a high-throughput human miRNA mimic screen across multiple DPM cell lines with proliferation assays to identify anti-tumor miRNAs. miR-1293 expression was measured by qRT-PCR in DPM tumors and normal pleura. Targets were mapped by biotin-miR-1293 pulldown plus RNA-seq and in silico prediction, then integrated with pathway and DepMap data to define an S100A16-Hippo/EMT module. Functional effects of miR-1293 re-expression were tested in NF2-wild-type and NF2/Hippo-deficient DPM lines and in MB52 xenografts using local hydrogel-based (SFH-miR-1293) delivery in subcutaneous and orthotopic pleural models. Results: The screen identified miR-1293 as a top antiproliferative miRNA, and miR-1293 was significantly underexpressed in DPM versus normal pleura. Re-expression in miR-1293-low DPM lines reduced proliferation, colony and soft-agar growth, with minimal impact on non-malignant mesothelial cells, and induced apoptosis and cell-cycle arrest. Target mapping yielded 345 genes enriched for Hippo signaling and EMT, with additional mTORC1, IL-2/STAT5, and hypoxia signatures, and a 19-gene core S100A16-Hippo-EMT module. Within this module, S100A16 was the most essential and strongest adverse prognostic gene, highly expressed in NF2/Hippo-deficient lines (H2052, MB52, MB24) with activated YAP/TAZ/TEAD and EMT-like features. miR-1293 re-expression preferentially impaired viability and clonogenicity in these NF2/Hippo-deficient cells, with coordinated suppression of S100A16, YAP/TAZ/TEAD, and EMT markers. In vivo, SFH-miR-1293 significantly reduced tumor burden, Ki-67, and bioluminescence, increased cleaved caspase-3, and prolonged survival in xenograft and orthotopic pleural models. Conclusions: miR-1293 is a tumor-suppressive miRNA in DPM that targets an S100A16-Hippo-EMT axis and shows preferential activity in NF2/Hippo-deficient mesothelioma. Local hydrogel-based delivery elicits strong antitumor effects in vivo, supporting miR-1293 as a therapeutic candidate for DPM and a rational partner for Hippo/YAP-directed and immunotherapy strategies. Citation Format: Vivek Singh, Anand Singh, Nathanael Pruett, So-Hyun Yoon, Smrity Sahu, Yelixza Avila, Chuong D. Hoang. miR-1293 suppresses diffuse pleural mesothelioma growth by targeting a novel S100A16-Hippo-EMT axis abstract. In: Proceedings of the American Association for Cancer Research Annual Meeting 2026; Part 1 (Regular Abstracts); 2026 Apr 17-22; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2026;86(7 Suppl):Abstract nr 2064.
Singh et al. (Fri,) studied this question.