About the Lab
Dr. R. Taylor Ripley is a professor of surgery and the Meyer-DeBakey Chair in Investigative Surgery who leads the Ripley-Xu Laboratory for Translational Thoracic Oncology Research.
The Ripley-Xu laboratory investigates translational functional precision oncology. A well-known problem with treating cancer is that the cancer cells develop resistance to death when treated with any drug. A part of the cell that is responsible resisting treatment is the mitochondria which acts like the engine by providing all the energy for tumor to grow while protecting it from cell death.
The lab team has shown that targeting mitochondria can sensitize tumors to therapeutics by lowering the threshold for apoptosis. They initially discovered that altering the proton gradient of the mitochondria by targeting the inner mitochondrial membrane protein, UCP2, changes the malignant potential of tumor cells. They extended these findings by determining that low levels of activation of the mitochondrial apoptotic machinery was insufficient to induce apoptosis, but sufficient to contribute to malignant progression of tumor cells – a phenomena called, Minority MOMP. Importantly, the team observed that while the apoptotic machinery is activated, the anti-apoptotic protein, Mcl-1, is also upregulated which protects the cell from death. When they targeted this protein in cultured cells, ex vivo tumors, patient-derived organoids and patient-derived xenografts, the tumors were re-sensitized to chemotherapy. These findings suggest that targeting mitochondrial undermine the resistance mechanisms of apoptosis may increase the tumors susceptibility to death.
To extent these findings in a clinically useful bioassay, they used a technique that measures mitochondrial priming through Dynamic Bcl-2 Homology domain (BH)-3 Profiling which predicts whether a therapeutic agent will decrease the apoptotic threshold of a tumor cells. The team is currently study translating these approaches in thoracic cancers which include mesothelioma, esophageal cancer and lung cancer.
Dynamic BH3 Profiling and Minority MOMP
Thoracic cancers are primarily the result of chronic, long-term exposure to the environmental toxins of 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.
Funded Projects
1. R37 (R01) CA289419: ‘Targeting the Mitochondria to Overcome Resistance to Immune Checkpoint Inhibition in Malignant Pleural Mesothelioma
2. R01 CA290173-01: ‘Novel strategies to improve mesothelioma therapy’.
3. DeGregorio Family Foundation Grant for Gastric and Esophageal Malignancies: ‘Targeting Mitochondrial Resistance to Apoptosis after Neoadjuvant Therapy in Esophageal Adenocarcinoma.’
4. Dan L. Duncan Comprehensive Cancer Center. ‘Targeting Methionine Metabolic Pathway in Mesothelioma.’
5. U24 2U24OH009077-15-00 / RFA-OH-21-007 (U24). ‘Continuation and Expansion of the National Mesothelioma Virtual Bank for Translational Research.’
6. R21 CA256466: ‘Environmental Carcinogens Induce Minority MOMP to Initiate Carcinogenesis in Lung Cancer and Mesothelioma while Maintaining Apoptotic Resistance via Mcl-1.’
7. Combination of Induction Durvalumab and Tremelimumab alone versus Durvalumab and Tremelimumab with chemotherapy for Potentially Resectable Pleural Mesothelioma (Nemo). AstraZeneca. Clinicaltrials.gov: NCT05932199. IND: 165481.
Publications
1. 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. doi: 10.1038/s41388-019-1029-6. Epub 2019 Sep 30. PMID: 31570787 PMCID: PMC8366558.
2. 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 Aug;20(8):1469-1480. doi: 10.1158/1535-7163.MCT-20-0887. Epub 2021 Jun 4. PMID: 34088830
3. Kate Brown*, Lisa M Miller Jenkins, Daniel R Crooks, Laurence P Diggs, Deborah R Surman, Sharlyn J Mazur, Stewart R Durell, Gaelyn C Lyons, Jerry C Dinan, Daniel Schilling, Marco Robello, Herman Nikolayevskiy, Robert O’Connor, Yuan Xu, Bhargav Srinivas Arimilli, Ye Yang, Andrew N Lane, Teresa W-M Fan, David S Schrump, W. Marston R Linehan, Daniel H Appella, Robert Taylor Ripley, and Ettore Appella. Targeting mutant p53 R248W reactivates WT p53 function and alters the onco-metabolic profile. Front Oncol. 2023 Jan 11:12:1094210. doi: 10.3389/fonc.2022.1094210. PMID: 36713582.
4. Paul L. Feingold*, Deborah R. Surman*, Kate Brown*, Yuan Xu*, Lucas A. McDuffie*, Vivek Shukla, Emily S. Reardon*, Daniel R. Crooks, Jane B. Trepel, Sunmin Lee, Min-Jung Lee, Laurence P. Diggs*, David G. Beer, Derek Nancarrow, Lenard M. Neckers, Jeremy L. Davis, Choung D. Hoang, Jonathan M. Hernandez, David S. Schrump, R. Taylor Ripley. Induction of Thioredoxin-Interacting Protein by the Histone Deacetylase Inhibitor, Entinostat, Enhances Cisplatin-Mediated DNA Damage and Apoptosis in Esophageal Adenocarcinoma Cells. Mol Cancer Ther. 2018 Sep; 17(9):2013-2023. doi: 10.1158/1535-7163.MCT-17-1240. Epub 2018 Jun 22. PMID: 29934340.
5. Yuan Xu, Paul L. Feingold, Deborah R. Surman, Kate Brown, Vivek Shukla, Sichuan Xi, Jeremy L, Davis, Jonathan Hernandez, David S. Schrump, R. Taylor Ripley. Bile Acid and Cigarette Smoke Enhance the Aggressive Phenotype of Esophageal Adenocarcinoma Cells by Downregulation of the Mitochondrial Uncoupling Protein-2. Oncotarget. 2017 Nov 10;8(60):101057-101071. PMID: 29254145
7. Anand Singh, Li Zhang, Nathanael Pruett, Christopher Plaisier, Robert T. Ripley, David Schrump, Chuong D. Hoang. microRNA-215-5p Treatment Suppresses Mesothelioma Progression via the MDM2-p53 Signaling Axis. Mol Ther. 2019 Sep 4;27(9):1665-1680. PMID: 3122739.
8. Anand Singh, Li Zhang, Nathanael Pruett, Christopher Plaisier, Robert T. Ripley, David Schrump, Chuong D. Hoang. Metadherin is a Prognostic Apoptosis Modulator in Mesothelioma Induced via NF-κB-mediated Signaling. Translational Oncol. 2019 June, 12(6): 859-70. doi: 10.1016/j.tranon.2019.03.005. PMID: 31054476.
