About the Lab
Dr. R. Taylor Ripley (PI) and the Thoracic Surgical Oncology Translational Laboratory team focus on metabolic reprogramming of thoracic cancers to determine whether metabolic dysregulation is a targetable process. Investigators have shown that alterations in esophageal tumor metabolism can abrogate the malignant progression of esophageal cells. Additionally, they are evaluating whether low levels of activation of the mitochondrial apoptotic machinery contribute to the malignant progression – a phenomena called, ‘Minority MOMP’. This process has identified translational targets via the novel technique ‘Dynamic BH3 Profiling (DBP)’. DBP is a clinically-actionable bioassay that can identify proteins responsible for resistance to apoptosis.
Dynamic BH3 Profiling and Minority MOMP
Thoracic cancers are primarily the result of chronic, long-term exposure to the environmental toxins cigarette smoke, bile reflux, and asbestos. These tumors develop many years after long-term exposure and harbor a high number of somatic mutations. This exposure suggests that a sustainable mechanism that repeatedly harms the cell, yet does not kill the normal cell is necessary for the accumulation of these mutations and the eventual initiation of carcinogenesis. Minority MOMP is potentially a mechanism that can explain carcinogenesis from long-term, toxic exposures in thoracic cancers.
Minority MOMP is the sub-lethal activation of the intrinsic pathway of apoptotic machinery that promotes genomic instability, cellular transformation, and tumorigenesis. Mitochondrial outer membrane permeabilization (MOMP) is the critical event that is mediated by the colocalization of Bax and Bak, membrane channel proteins, to the outer mitochondrial membrane. MOMP originally was considered the irreversible step in apoptosis. It releases toxic proteins from the mitochondrial inner membrane space into the cytoplasm thereby activating the caspase system which results in cell death. Following sub-lethal stresses, cells may survive when small percentages or a minority of mitochondria undergo MOMP. This self-limiting MOMP is below the threshold necessary to trigger apoptosis with low levels of CytoC release and caspase activation. Caspase-mediated DNA damage occurs without cell death which can explain the oncogenic transformation or carcinogenesis.
Interestingly, Minority MOMP may paradoxically make tumor cells vulnerable to mitochondrial-targeted therapy. While Minority MOMP releases toxin proteins, it simultaneously upregulates proteins that prevent cell death which make these cells resistant to apoptosis. These proteins are identified by Dynamic BH3 profiling (DBP) which is a live cell assay that measures changes in the BH3 profiles before and after drug treatment to predict response to a therapy. If the proteins that block apoptosis during Minority MOMP are identified by DBP, targeting these proteins will shift Minority MOMP to frank apoptosis and the tumor cell will die.
AATS Foundation Surgical Investigator Program: ‘Environmental Carcinogens Induce Minority MOMP and Upregulate Mcl-1 to Initiate Carcinogenesis in Thoracic Cancers.’ July 2020-21. The aim of the study is to identify the role of oncogenic pathways, including Minority MOMP (mitochondrial outer membrane permeabilization), in the link between thoracic cancers (including lung cancer, esophageal cancer, and mesothelioma) and environmental carcinogens, such as cigarette smoke, bile reflux, and asbestos.
Yuan Xu, Deborah R. Surman, Kate Brown, Laurence Diggs, Sichuan Xi, Shaojian Gao, Devikala Gurusamy, Kaitlin McLoughlin, Paul Feingold, Danny Wangsa, Darawalee Wangsa, Xi Zhang, Thomas Ried, Jeremy L Davis, Jonathan Hernandez, Chuong D. Hoang, Rhonda F. Souza, David S. Schrump, R. Taylor Ripley. ‘Bile Acid-Induced ‘Minority MOMP’ Promotes Esophageal Carcinogenesis while Maintaining Apoptotic Resistance via Mcl-1.’ Oncogene. 2020 Jan; 39(4): 877-89.
Deborah R. Surman*, Yuan Xu*, Min-Jung Lee, Jane B. Trepel, Kate Brown, Maheshwari Ramineni, Laurence P. Diggs, H. Courtney Hodges, Jeremy L. Davis, Hyun-Sung Lee, Bryan M. Burt, R. Taylor Ripley. *Authors contributed equally. Therapeutic Synergy in Esophageal Cancer and Mesothelioma is Predicted by Dynamic BH3 Profiling. Mol Cancer Ther. 2021. Pending.