Abstract Mesothelioma is a highly aggressive malignancy of the serosal membranes. Alterations in regulatory mechanisms controlling tumor suppressor gene expression play a critical role in Mesothelioma and other malignancies. Although tumor suppressor genes are central to cancer biology, the upstream regulation networks governing their activity remain poorly defined. Here, we identify a novel molecular pathway that directly regulates BAP1 tumor suppressor gene transcription and drives oncogenic phenotypes in Mesothelioma. Using patient-derived fibroblasts harboring germline mutations, mesothelioma cell lines, and a genetic knockout mouse model, we demonstrate that disruption of this pathway markedly decreases tumor suppressor expression, whereas its activation restores gene transcription and promotes cell proliferation, migration, and invasion. These findings reveal a novel regulatory loop mechanism in which tumor suppressor gene inactivation facilitates malignant transformation, while its activation sustains tumor progression. Similar regulatory dynamics were observed across additional cancer types, including lung, colon, and cholangiocarcinoma, indicating a conserved process. This work defines a novel transcriptional axis integrating tumor suppressive and oncogenic signaling in Mesothelioma and other cancers, offering new therapeutic opportunities. Citation Format: Flavia Novelli, Lydia Giannakou, Jin Hee Kim, Joelle S. Suarez, Cristina Favaron, Qian Wang, Angela Bononi, Michele Carbone, Haining Yang. A novel regulatory pathway as a driver of malignant transformation in mesothelioma 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 612.
Novelli et al. (Fri,) studied this question.