Epigenetic Mechanisms of Gene Expression in Thoracic Malignancies

胸部恶性肿瘤基因表达的表观遗传机制

• 批准号: 10926133
• 负责人: DAVID SCHRUMP
• 金额: $ 81.17万
• 依托单位: DIVISION OF BASIC SCIENCES - NCI
• 依托单位国家: 美国
• 资助国家: 美国
• 起止时间: 至
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10926133
• 关键词: Adenocarcinoma Cell; Aerodigestive Tract; Asbestos; Binding Proteins; Cell Line; Chromatin; Clinical; Collaborations; DNA Methylation; Development; Disease; Dose; Environmental Carcinogens; Epidermal Growth Factor Receptor; Epigenetic Process; Epiregulin; Epithelial Cells; Esophageal Adenocarcinoma; Event; Exposure to; FDA approved; Feedback; Fiber; France; Gene Expression; Genes; Growth; Human; Image; In Vitro; Inflammation; Institutional Review Boards; Interest Group; International; Intervention; Invaded; LOXL2 gene; Life; Link; Lung; Maintenance; Malignant - descriptor; Malignant Neoplasms; Malignant Pleural Mesothelioma; Malignant neoplasm of esophagus; Malignant neoplasm of lung; Malignant neoplasm of thorax; Manuscripts; Mediating; Mediator; Mesothelioma; Methylation; Mucins; Mutation; Natural History; Neoplasms; Normal tissue morphology; Ohio; Oral; Pathway interactions; Patients; Peer Review; Photons; Pleural Mesothelial Cell; Predisposition; Prevalence; Prevention; Primary Neoplasm; Production; Proteins; Protocols documentation; Publishing; Repression; Signal Transduction; Smoke; Specimen; Stream; Syndrome; Tobacco; Transcript; United States National Institutes of Health; Universities; X-Ray Computed Tomography; cancer cell; cancer stem cell; cigarette smoke; cigarette smoking; epigenetic silencing; epigenomics; esophageal carcinogenesis; experimental study; filamin; hookah; in vitro Model; in vivo; liquid biopsy; meetings; minimally invasive; mutant; novel; novel strategies; preclinical study; prevent; senescence; stemness; symposium; transcriptome; treatment strategy; tumor; virtual

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.

已经利用与原发性肿瘤/正常组织样本的新型体外模型和相关实验来鉴定表观基因组学的改变，这有助于肺和食管癌的起始和进展，以及恶性胸膜间心瘤。我们的小组已经发表了稳定的手稿，描述了香烟烟雾和其他环境致癌物在正常的机场消化道上皮细胞和胸腔癌细胞中的表观基因组作用。 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）和API-3结合蛋白（ABI3BP）编码衰老的推定介质。与史蒂文·利布蒂（Steven Libutti）博士合作，我们扩展了这些研究，并证明FILIP1L的甲基化是人类肺腺癌发生中的一个常见事件，并且Filip1l的表观遗传沉默与免疫抑制性粘蛋白的炎症和产生有关。最近发表了与这些后者研究有关的手稿。在其他研究中，我们已经证明，香烟烟通过破坏miR-145和促氧化物染色质结合蛋白LOXL2之间的抑制反馈外观来增强食道癌的作用。短暂的香烟上调了LOXL2，这增加了编码miR143和miR 145的miR-143宿主基因内的LOXL2占用率。抑制miR-143 Hg降低了miR-145与LOXL2转录物的相互作用，从而促进了促进食管腺癌细胞的生长和入侵。最近也出版了与这些研究有关的手稿。在BAP1肿瘤易感综合征（TPDS）患者中，还致力于研究间皮瘤的患病率和自然史。一项评估光子计数CT成像，液体活检和微创监视的独特协议已在我们的分支机构中启动，以确定BAP1 TPD中亚临床疾病的患病率，以及在这些受试者中引起的中胸膜的自然史和表观遗传学。自该方案开放以来，我们已经积累了30多名患者。我们目前每月收到2-3个推荐。我们已经确定了这些患者中的许多亚临床恶性肿瘤，并建立了各种新型的体外模型，以表征BAP1突变引起的间皮瘤中表观遗传危险。在我们实验室进行的临床前研究中，我们在早期间皮瘤中确定了几个高度吸引人的表观遗传靶标，并使用口服和高度有效的表观遗传剂启动了两种干预方案，以防止BAP1突变性神经性中皮细胞的恶性转化，并在早期疾病中脱离了bap spapsymant的bap症，以对bap的疾病进行bap虫的生命。这两种方案均已获得FDA和NIH IRB的批准，并将在24财年第1季度开放患者应计。我们的BAP1成像/监视协议是世界上唯一的这种协议，并提供了研究基本表观遗传机制的无与伦比的机会，这些机制是恶性和干性的。目前，我们的观察结果和与前30名患者有关的转化实验的结果正在准备提交同行评审。此外，我们的BAP1监视方案工作直接导致了有史以来第一次临床尝试将表观遗传驱动因素作为预防/延迟BAP1 TPD患者产生的癌症的策略。最近，在俄亥俄州立大学的BAP1癌症研讨会和法国里尔市国际间皮瘤兴趣小组（IMIG）的BAP1癌症研讨会上，我们的努力结果在正式的全体会议上提出。

项目成果

Bile acid and cigarette smoke enhance the aggressive phenotype of esophageal adenocarcinoma cells by downregulation of the mitochondrial uncoupling protein-2.

• DOI: 10.18632/oncotarget.22380
• 发表时间: 2017-11-24
• 期刊: Oncotarget
• 作者: Xu Y;Feingold PL;Surman DR;Brown K;Xi S;Davis JL;Hernandez J;Schrump DS;Ripley RT
• 通讯作者: Ripley RT

Metabolomic and BH3 profiling of esophageal cancers: novel assessment methods for precision therapy.

• DOI: 10.1186/s12876-018-0823-x
• 发表时间: 2018-06-22
• 期刊: BMC gastroenterology
• 影响因子: 2.4
• 作者: Taylor Ripley R;Surman DR;Diggs LP;Trepel JB;Lee MJ;Ryan J;Davis JL;Steinberg SM;Hernandez JM;Hoang C;Kenney CM;Bond CD;Kunst TF;Letai A;Schrump DS
• 通讯作者: Schrump DS

Inhibition of histone lysine methylation enhances cancer-testis antigen expression in lung cancer cells: implications for adoptive immunotherapy of cancer.

• DOI: 10.1158/0008-5472.can-10-2442
• 发表时间: 2011-06-15
• 期刊: Cancer research
• 影响因子: 11.2
• 作者: Rao M;Chinnasamy N;Hong JA;Zhang Y;Zhang M;Xi S;Liu F;Marquez VE;Morgan RA;Schrump DS
• 通讯作者: Schrump DS