Abstract 1708: Sex-biased function of an oncogene, YAP1, regulates medulloblastoma stem cells and immune evasion

Abstract

Sex disparity in both cancer incidence and response to therapeutics, especially immunotherapy, has become an important area of research in recent years. Brain tumors show obvious sex biases in incidence and therapy response. Medulloblastoma (MB) is the most common malignant pediatric brain tumor, and similar to other brain tumors, males have consistently higher incidence across all subgroups and at all ages. Moreover, for patients >3 years of age, females have significantly better outcomes than males. However, molecular drivers of such sex disparity in incidence and prognosis remain unclear.Here, we report a male-biased function of an oncogene, YAP1, in MB formation and immune suppression. Integrated multi-platform genomic, transcriptomic, proteomic, and in vivo transcriptional target analyses show that YAP1 promotes cancer stem cell maintenance through concurrent transcriptional activation of stemness genes, such as Sox2, and repression of differentiation regulators such as NeuroD1 and Zic1/2. YAP1 expression in MB cells also inhibits anti-tumor immune cell infiltration by directly regulating Csf1, Igf1, and Igfbp3 transcription and modulating IL6-JAK-STAT3, TNFR1, TGFb, and CCL5 Pathways. Notably, we found that YAP1 genetic deletion results in disproportionately higher survival of males than females in a spontaneous mouse model of infantile SHH MB, despite equivocal expression levels in both sexes. Consistent with our findings in mouse models, YAP1 downstream genes stratify MB patient survival in males but not females. Finally, we show that a brain-penetrant YAP1 inhibitor, verteporfin, extends survival and enhances immune infiltrates in vivo, mimicking the effects of Yap1 genetic deletion. In summary, this study demonstrates that an oncogene function may be sex-biased and underscores the need to incorporate sex as a variable in cancer mechanisms, tumor immunology, and treatment response studies. Citation Format: Nourhan Abdelfattah, Sivaraman Natarajan, Jose Maldonado, Han Nhat Tran, Hannah Borland, Rachael McMinimy, Shu-Hsia Chen, Fernando Camargo, James Olson, Joshy George, Kyuson Yun. Sex-biased function of an oncogene, YAP1, regulates medulloblastoma stem cells and immune evasion [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 1 (Regular and Invited Abstracts); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(7_Suppl):Abstract nr 1708.