Epigenetic Mechanisms of Gene Expression in Thoracic Malignancies

新的体外模型和原发肿瘤/正常组织标本的相关实验已经被用来识别与肺癌、食道癌和恶性胸膜间皮瘤的发生和发展有关的表观基因组改变。我们小组已经发表了源源不断的手稿，描述了香烟烟雾和其他环境致癌物在体外和体内对正常呼吸道上皮细胞和胸腺癌细胞的表观基因组效应。例如，我们最近证明，香烟烟雾和水烟烟雾介导了不同的和重叠的转录组信号，以及细胞系和剂量依赖的途径调制，这些暴露上调了EpiRegin(Ereg)编码的EGFR信号的主调制子，而Ereg参与了肺癌的进展和癌症干细胞的维持，同时抑制了编码可能的衰老介体的微丝A相互作用蛋白1(FILIP1L)和API-3结合蛋白(ABI3BP)。在与Steven Libuti博士的合作中，我们扩展了这些研究，并证明了FILIP1L的甲基化是人类肺腺癌发生中的常见事件，并且FILIP1L的表观遗传沉默与炎症和免疫抑制粘蛋白的产生有关。一份关于后一种研究的手稿最近出版了。在其他研究中，我们已经证明香烟烟雾通过扰乱miR-145和促转移染色质结合蛋白LOXL2之间的抑制反馈看而增强食道癌的发生。简而言之，香烟烟雾上调LOXL2，从而增加编码miR143和miR145的miR-143宿主基因中LOXL2的占有率。抑制miR-143 HG可减少miR-145与LOXL2转录本的相互作用，促进食管腺癌细胞的生长和侵袭。与这些研究有关的手稿最近也出版了。此外，还致力于研究BAP1肿瘤易感综合征(TPDS)患者间皮瘤的患病率和自然病史。我们的分支机构已经启动了一项独特的方案，评估光子计数CT成像、液体活检和微创监测的使用，以确定BAP1 TPDS亚临床疾病的患病率，以及在这些受试者中发生的间皮瘤的自然病史和表观遗传学。自从1.5年前这一方案开始实施以来，我们已经积累了30多名患者。我们目前每月收到2-3个转介。我们已经在这些患者中发现了许多亚临床恶性肿瘤，并建立了各种新的体外模型来表征由BAP1突变引起的间皮瘤的表观遗传学紊乱。在我们实验室进行的临床前研究中，我们已经在早期间皮瘤中确定了几个极具吸引力的表观遗传学靶点，并使用口服和高效表观遗传剂启动了两项干预方案，以防止BAP1突变胸膜间皮细胞的恶性转化，并在BAP1 TPDS受试者中中止或延缓早期间皮瘤向危及生命的疾病的进展。这两个方案都已获得FDA和NIH IRB的批准，并将于24财年第一季度向患者开放。我们的BAP1成像/监视方案是世界上唯一的此类方案，为研究恶性肿瘤和茎的基本表观遗传学机制提供了无与伦比的机会。我们关于前30名患者的观察和转化实验的结果目前正在准备中，以供同行审查。此外，我们的BAP1监测方案努力直接导致了首次临床尝试，将表观遗传驱动因素作为预防/推迟BAP1 TPDS患者癌症发生的策略。我们的努力结果最近在俄亥俄州立大学的BAP1癌症研讨会和在法国里尔举行的国际间皮瘤兴趣小组(IMIG)两年一次的会议上的正式全体会议上公布。

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.