Epigenetic Mechanisms of Gene Expression in Thoracic Malignancies

Division Of Basic Sciences - Nci

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Abstract

Novel in-vitro models and correlative experiments with primary tumor/normal tissue specimens have been utilized to identify epigenomic alterations which contribute to initiation and progression of lung and esophageal cancers and malignant pleural mesotheliomas. A steady stream of manuscripts have been published by our group describing the epigenomic effects of cigarette smoke and other environmental carcinogens in normal aerodigestive tract epithelial cells and thoracic cancer cells in-vitro and in-vivo. For example, we recently demonstrated that cigarette smoke and hookah smoke mediated distinct as well as overlapping transcriptome signatures, and pathway modulations that were cell line and dose-dependent, and that these exposures upregulate Epiregulin (EREG) encoding a master regulator of EGFR signaling which has been implicated in progression of lung cancers and maintenance of cancer stem cells, while repressing Filamin A Interacting Protein 1-Like (FILIP1L) and API-3 binding protein (ABI3BP) which encode putative mediators of senescence. In collaboration with Dr. Steven Libutti we extended these studies and demonstrated that methylation of FILIP1L is a common event in human lung adenocarcinogenesis and that epigenetic silencing of FILIP1L is linked to inflammation and production of immunosuppressive mucins. A manuscript pertaining to these latter studies has been published recently. In additional studies we have demonstrated the cigarette smoke enhances esophageal carcinogenesis by disrupting a repressive feedback look between miR-145 and the pro-metastatic chromatin binding protein LOXL2. Briefly cigarette smoke up-regulates LOXL2 which increases LOXL2 occupancy within the miR-143 host gene that encodes miR143 and miR 145. Repression of the miR-143 HG reduces interaction of miR-145 with the LOXL2 transcript promoting growth and invasion of esophageal adenocarcinoma cells in-vitro and in-vivo. A manuscript pertaining to these studies was published recently as well. Additional efforts have been devoted to examining the prevalence and natural history of mesotheliomas arising in patients with BAP1 tumor predisposition syndrome (TPDS). A unique protocol evaluating the use of photon counting CT imaging, liquid biopsies, and minimally invasive surveillance has been initiated in our Branch to determine the prevalence of subclinical disease in BAP1 TPDS, as well as the natural history and epigenetics of mesotheliomas arising in these subjects. We have accrued over 30 patients since this protocol opened 1.5 years ago. We are presently receiving 2-3 referrals per month. We have identified numerous subclinical malignancies in these patients and have established a variety of novel in-vitro models to characterize epigenetic derangements in mesotheliomas resulting from BAP1 mutations. In preclinical studies performed in our lab, we have identified several highly attractive epigenetic targets in early-stage mesotheliomas, and have initiated two intervention protocols using oral and highly potent epigenetic agents to prevent malignant transformation of BAP1 mutant pleural mesothelial cells and abort or retard progression of early-stage mesothelioma to life-threatening disease in subjects with BAP1 TPDS. Both protocols have been approved by FDA and NIH IRB and will be open for patient accrual in Q1 of FY24. Our BAP1 imaging/surveillance protocol is the only such protocol in the world and has provided unparalleled opportunities to study fundamental epigenetic mechanisms of malignancy and stemness. Results of our observations and translational experiments pertaining to the first 30 patients are presently being prepared for submission for peer review. Furthermore, our BAP1 surveillance protocol efforts have directly led to first-ever clinical attempts to target epigenetic drivers as a strategy to prevent/delay cancer arising in patients with BAP1 TPDS. Results of our efforts were presented recently in formal plenary talks at a BAP1 Cancer Symposium at Ohio State University and the Biennial Meeting of the International Mesothelioma Interest Group (IMIG) in Lille, France.