Abstract 1624: Stat1 promotes lesion growth and tumor immunity of tuberin-deficient cells in lymphangioleiomyomatosis

Abstract Lymphangioleiomyomatosis (LAM) is a cystic lung disease that primarily affects women, with an estimated global prevalence of 19 per million women. LAM is caused by the invasion of metastatic smooth muscle-like cells into the lung parenchyma, leading to abnormal cell proliferation and progressive respiratory failure. LAM cells have TSC gene mutations, which occur sporadically or in people with Tuberous Sclerosis Complex. Although it is known that hyperactivation of the mechanistic target of rapamycin complex 1 (mTORC1) due to TSC2 mutations contributes to aberrant cell growth in LAM lung, tumor origin and invasive mechanism remain unclear. Integrative single-cell omics and validation analyses revealed the activation of a novel uterine-similar HOX/PBX transcriptional network in the LAM lung compared to other lung cells, suggesting that the uterus is one of the origins of LAM cells. Further omics studies indicated that STAT1 and STAT3 interact with PBX1 to increase LAM cell survival. The objective of this study is to delineate mechanisms by which STAT signaling may regulate LAM pathogenesis, with hopes to find potential therapeutic options for LAM and TSC-associated disorders. We hypothesize that STAT1 suppression attenuates LAM patient-derived (TSC2-null) cell viability and tumor growth in LAM. We first confirmed our network prediction analysis by showing that aberrant PBX1 activation upregulates STAT1 in LAM cells and tissues. Our cell viability assays show that STAT1 suppression induced TSC2-null cell apoptosis compared to controls. Similarly, our mouse models show that STAT1 suppression attenuates lung lesion and uterine tumor growth in TSC2-deficient LAM models. We also show that STAT1 activation induced PD-L1 upregulation, indicating that STAT1 helps tumor cells to evade immune surveillance in LAM. Our findings provide proof of concept that STAT1 mediates LAM tumor proliferation through two mechanisms. (1) by promoting lesion growth and (2) by promoting immune evasion via upregulation of PD-L1. STAT1 signaling is critical for LAM cell survival and could be targeted to treat LAM and TSC-associated disorders. Citation Format: Tasnim Olatoke, Jane Yu. Stat1 promotes lesion growth and tumor immunity of tuberin-deficient cells in lymphangioleiomyomatosis [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2025; Part 1 (Regular Abstracts); 2025 Apr 25-30; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2025;85(8_Suppl_1):Abstract nr 1624.