Mechanisms of disease

When people consider disease etiology, they often think about genetic or pathological causes of disease. To us, these are one of the many stressors that can affect the way cells behave. These changes, intrinsic to the cell or its milieu or the organism as a whole, accumulate over a lifetime, eventually leading to proteome changes, causing misfunction. This in turn has a negative effect on cell behavior and its network connections. In this context, we think of disease states as embodiments of exposure of cells to stressors.

stressor-to-phenotype
We use the chemical tools created by our lab to understand the complex proteome alterations that occur in specific chronically stressed cells/organisms such as in cancer, neurodegenerative diseases and microorganisms living in conditions of stress. Examples are the discovery of mechanisms behind: transforming ability of BCL6 in a subset of BCL6-driven Diffuse Large B-Cell Lymphomas (DLBCL) [Nature Medicine 2009] (collaboration with A. Melnick lab); regulation of apoptosis in small-cell lung carcinomas [Nature Chem Biol 2007] (collaboration with Jiang and Massague labs); the altered proteome and its addiction to tumor HSP90 in a subset of triple negative breast cancer [PNAS 2009]; regulation of HER2 activity in HER2 overexpressing breast cancers [Nature Chem Biol 2013, Cell Reports 2020]; transformation in JAK2-driven MPDs and potential mechanisms associated with resistance to JAK inhibitors [J Clinical Investigation 2010, Nature 2012, Blood 2014]; (collaboration with R. Levine lab); regulation of the viral oncoproteome in Kaposi sarcoma herpes virus (KHSV)-associated lymphomas [Blood 2013]; (collaboration with E. Cesarman lab); regulation of the activated STAT5 signaling and increased transcriptional activity in chronic myeloid leukemia [Nature Chem Biol 2011]; molecular signature of HSP90-addicted AML [Cell Reports 2015] (collaboration with M Guzman lab); the biochemical nature of the epichaperome networks in cancer and their therapeutic implications (interdisciplinary multimember team Nature 2016 and Nature Medicine 2018); PPI network alterations in Parkinson’s disease neurons (Nature Communications 2018, collaboration with Studer lab); mechanism of synaptic plasticity dysregulation in Alzheimer’s disease (Nature Communications 2020), to list a few.

Chiosis G, Digwal CS, Trepel JB, Neckers L. Structural and functional complexity of HSP90 in cellular homeostasis and disease. Nat Rev Mol Cell Biol. 2023. doi: 10.1038/s41580-023-00640-9. https://pubmed.ncbi.nlm.nih.gov/37524848/

Ginsberg SD, Sharma S, Norton L, Chiosis G. Targeting stressor-induced dysfunctions in protein-protein interaction networks via epichaperomes. Trends Pharmacol Sci. 2023;44(1):20-33. doi: 10.1016/j.tips.2022.10.006. https://pubmed.ncbi.nlm.nih.gov/36414432/

Rodina A, Xu C, Digwal CS, Joshi S, Patel Y, Santhaseela AR, Bay S, Merugu S, Alam A, Yan P, Yang C, Roychowdhury T, Panchal P, Shrestha L, Kang Y, Sharma S, Almodovar J, Corben A, Alpaugh ML, Modi S, Guzman ML, Fei T, Taldone T, Ginsberg SD, Erdjument-Bromage H, Neubert TA, Manova-Todorova K, Tsou MB, Young JC, Wang T, Chiosis G. Systems-level analyses of protein-protein interaction network dysfunctions via epichaperomics identify cancer-specific mechanisms of stress adaptation. Nat Commun. 2023;14(1):3742. doi: 10.1038/s41467-023-39241-7. https://www.nature.com/articles/s41467-023-39241-7

Castelli M, Yan P, Rodina A, Digwal CS, Panchal P, Chiosis G, Moroni E, Colombo G. How aberrant N-glycosylation can alter protein functionality and ligand binding: An atomistic view. Structure. 2023. doi: 10.1016/j.str.2023.05.017. https://pubmed.ncbi.nlm.nih.gov/37343552/

Bolaender A, He H, Joshi S, Sharma S, Digwal CS, Patel HJ, Sun W, Imber BS, Ochiana SO, Patel MR, Shrestha L, Shah SK, Wang S, Karimov R, Tao H, Patel PD, Martin AR, Yan P, Panchal P, Almodovar J, Corben A, Rimner A, Ginsberg SD, Lyashchenko S, Burnazi E, Ku A, Kalidindi T, Lee SG, Grkovski M, Beattie BJ, Zanzonico P, Lewis JS, Larson S, Rodina A, Pillarsetty N, Tabar V, Dunphy MP, Taldone T, Shimizu F, Chiosis G. Chemical tools for epichaperome-mediated interactome dysfunctions of the central nervous system. Nat Commun. 2021;12(1):4669. doi: 10.1038/s41467-021-24821-2. https://pubmed.ncbi.nlm.nih.gov/34344873/

Ginsberg SD, Joshi S, Sharma S, Guzman G, Wang T, Arancio O, Chiosis G. The penalty of stress - Epichaperomes negatively reshaping the brain in neurodegenerative disorders. J Neurochem. 2021;159(6):958-79. doi: 10.1111/jnc.15525. https://pubmed.ncbi.nlm.nih.gov/34657288/

Joshi S, Gomes ED, Wang T, Corben A, Taldone T, Gandu S, Xu C, Sharma S, Buddaseth S, Yan P, Chan LYL, Gokce A, Rajasekhar VK, Shrestha L, Panchal P, Almodovar J, Digwal C, Rodina A, Pillarsetty N-K, Miclea V, Peter RI, Ginsberg SD, Tang L, Mattar M, de Stanchina E, Yu KH, Lowery M, Grbovic-Huezo O, O’Reilly EM, Janjigian Y, Healey JH, Jarnagin WR, Allen PJ, Sander C, Erdjument-Bromage H, Neubert TA, Leach SD, Chiosis G. Pharmacologically controlling protein-protein interactions through epichaperomes for therapeutic vulnerability in cancer. Commun Biol. 2021;4(1):1333. doi: 10.1038/s42003-021-02842-3. https://pubmed.ncbi.nlm.nih.gov/34824367/ 

Inda MC, Joshi S, Wang T, Bolaender A, Gandu S, Koren Iii J, Che AY, Taldone T, Yan P, Sun W, Uddin M, Panchal P, Riolo M, Shah S, Barlas A, Xu K, Chan LYL, Gruzinova A, Kishinevsky S, Studer L, Fossati V, Noggle SA, White JR, de Stanchina E, Sequeira S, Anthoney KH, Steele JW, Manova-Todorova K, Patil S, Dunphy MP, Pillarsetty N, Pereira AC, Erdjument-Bromage H, Neubert TA, Rodina A, Ginsberg SD, De Marco Garcia N, Luo W, Chiosis G. The epichaperome is a mediator of toxic hippocampal stress and leads to protein connectivity-based dysfunction. Nat Commun. 2020 Jan 16;11(1):319. doi: 10.1038/s41467-019-14082-5.

Yan P, Patel HJ, Sharma S, Corben A, Wang T, Panchal P, Yang C, Sun W, Araujo TL, Rodina A, Joshi S, Robzyk K, Gandu S, White JR, de Stanchina E, Modi S, Janjigian YY, Hill EG, Liu B, Erdjument-Bromage H, Neubert TA, Que NLS, Li Z, Gewirth DT, Taldone T, Chiosis G. Molecular Stressors Engender Protein Connectivity Dysfunction through Aberrant N-Glycosylation of a Chaperone. Cell Rep. 2020 Jun 30;31(13):107840. doi: 10.1016/j.celrep.2020.107840.

Rodina A, Wang T, Yan P, Gomes ED, Dunphy MP, Pillarsetty N, Koren J, Gerecitano JF, Taldone T, Zong H, Caldas-Lopes E, Alpaugh M, Corben A, Riolo M, Beattie B, Pressl C, Peter RI, Xu C, Trondl R, Patel HJ, Shimizu F, Bolaender A, Yang C, Panchal P, Farooq MF, Kishinevsky S, Modi S, Lin O, Chu F, Patil S, Erdjument-Bromage H, Zanzonico P, Hudis C, Studer L, Roboz GJ, Cesarman E, Cerchietti L, Levine R, Melnick A, Larson SM, Lewis JS, Guzman ML, Chiosis G. The epichaperome is an integrated chaperome network that facilitates tumour survival. Nature. 2016;538(7625):397-401. PMCID: PMC5283383. Altmetric 439 PubMed

Kishinevsky S, Wang T, Rodina A, Chung SY, Xu C, Philip J, Taldone T, Joshi S, Alpaugh ML, Bolaender A, Gutbier S, Sandhu D, Fattahi F, Zimmer B, Shah SK, Chang E, Inda C, Koren J, Saurat NG, Leist M, Gross SS, Seshan VE, Klein C, Tomishima MJ, Erdjument-Bromage H, Neubert TA, Henrickson RC, Chiosis G, Studer L. HSP90-incorporating chaperome networks as biosensor for disease-related pathways in patient-specific midbrain dopamine neurons. Nature Communications. 2018;9(1):4345. 

Kourtis N, Lazaris C, Hockemeyer K, Balandran JC, Jimenez AR, Mullenders J, Gong Y, Trimarchi T, Bhatt K, Hu H, Shrestha L, Ambesi-Impiombato A, Kelliher M, Paietta E, Chiosis G, Guzman ML, Ferrando AA, Tsirigos A, Aifantis I. Oncogenic hijacking of the stress response machinery in T cell acute lymphoblastic leukemia. Nat Med. 2018;24(8):1157-66. PMCID: PMC6082694. Altmetric 462. PubMed

Zong H, Gozman A, Caldas-Lopes E, Taldone T, Sturgill E, Brennan S, Ochiana SO, Gomes-DaGama EM, Sen S, Rodina A, Koren J 3rd, Becker MW, Rudin CM, Melnick A, Levine RL, Roboz GJ, Nimer SD, Chiosis G, Guzman ML. A Hyperactive Signalosome in Acute Myeloid Leukemia Drives Addiction to a Tumor-Specific Hsp90 Species. Cell Rep. 2015 Dec 15;13(10):2159-73. doi: 10.1016/j.celrep.2015.10.073. Epub 2015 Nov 25. [PMID: 26628369] 

Marubayashi S, Koppikar P, Taldone T, Abdel-Wahab O, West N, Bhagwat N, Caldas-Lopes E, Ross KN, Gonen M, Gozman A, Ahn JH, Rodina A, Ouerfelli O, Yang G, Hedvat C, Bradner JE, Chiosis G, Levine RL. HSP90 is a therapeutic target in JAK2-dependent myeloproliferative neoplasms in mice and humans. J Clin Invest. 2010;120(10):3578-93. PMCID: PMC2947224. PubMed

Cerchietti LC, Hatzi K, Caldas-Lopes E, Yang SN, Figueroa ME, Morin RD, Hirst M, Mendez L, Shaknovich R, Cole PA, Bhalla K, Gascoyne RD, Marra M, Chiosis G, Melnick A. BCL6 repression of EP300 in human diffuse large B cell lymphoma cells provides a basis for rational combinatorial therapy. J Clin Invest. 2010;120(12):4569-82. PMCID: PMC2993589. PubMed

Koppikar P, Bhagwat N, Kilpivaara O, Manshouri T, Adli M, Hricik T, Liu F, Saunders LM, Mullally A, Abdel-Wahab O, Leung L, Weinstein A, Marubayashi S, Goel A, Gonen M, Estrov Z, Ebert BL, Chiosis G, Nimer SD, Bernstein BE, Verstovsek S, Levine RL. Heterodimeric JAK-STAT activation as a mechanism of persistence to JAK2 inhibitor therapy. Nature. 2012;489(7414):155-9. PMCID: PMC3991463. PubMed

Patel PD, Yan P, Seidler PM, Patel HJ, Sun W, Yang C, Que NS, Taldone T, Finotti P, Stephani RA, Gewirth DT, Chiosis G. Paralog-selective Hsp90 inhibitors define tumor-specific regulation of HER2. Nat Chem Biol. 2013;9(11):677-84. PMCID: PMC3982621. PubMed

Nayar U, Lu P, Goldstein RL, Vider J, Ballon G, Rodina A, Taldone T, Erdjument-Bromage H, Chomet M, Blasberg R, Melnick A, Cerchietti L, Chiosis G, Wang YL, Cesarman E. Targeting the Hsp90-associated viral oncoproteome in gammaherpesvirus-associated malignancies. Blood. 2013;122(16):2837-47. PMCID: PMC3798998. PubMed

Ambati SR, Lopes EC, Kosugi K, Mony U, Zehir A, Shah SK, Taldone T, Moreira AL, Meyers PA, Chiosis G, Moore MA. Pre-clinical efficacy of PU-H71, a novel HSP90 inhibitor, alone and in combination with bortezomib in Ewing sarcoma. Mol Oncol. 2014;8(2):323-36. PMCID: PMC3982393. PubMed

Bhagwat N, Koppikar P, Keller M, Marubayashi S, Shank K, Rampal R, Qi J, Kleppe M, Patel HJ, Shah SK, Taldone T, Bradner JE, Chiosis G, Levine RL. Improved targeting of JAK2 leads to increased therapeutic efficacy in myeloproliferative neoplasms. Blood. 2014;123(13):2075-83. PMCID: PMC3968390. PubMed

Rampal R, Ahn J, Abdel-Wahab O, Nahas M, Wang K, Lipson D, Otto GA, Yelensky R, Hricik T, McKenney AS, Chiosis G, Chung YR, Pandey S, van den Brink MR, Armstrong SA, Dogan A, Intlekofer A, Manshouri T, Park CY, Verstovsek S, Rapaport F, Stephens PJ, Miller VA, Levine RL. Genomic and functional analysis of leukemic transformation of myeloproliferative neoplasms. Proc Natl Acad Sci U S A. 2014;111(50):E5401-10. PMCID: PMC4273376. PubMed

Kucine N, Marubayashi S, Bhagwat N, Papalexi E, Koppikar P, Sanchez Martin M, Dong L, Tallman MS, Paietta E, Wang K, He J, Lipson D, Stephens P, Miller V, Rowe JM, Teruya-Feldstein J, Mullighan CG, Ferrando AA, Krivtsov A, Armstrong S, Leung L, Ochiana SO, Chiosis G, Levine RL, Kleppe M. Tumor-specific HSP90 inhibition as a therapeutic approach in JAK-mutant acute lymphoblastic leukemias. Blood. 2015;126(22):2479-83. PMCID: PMC4661170. PubMed

Goldstein RL, Yang SN, Taldone T, Chang B, Gerecitano J, Elenitoba-Johnson K, Shaknovich R, Tam W, Leonard JP, Chiosis G, Cerchietti L, Melnick A. Pharmacoproteomics identifies combinatorial therapy targets for diffuse large B cell lymphoma. J Clin Invest. 2015;125(12):4559-71. PMCID: PMC4665772. PubMed

Culjkovic-Kraljacic B, Fernando TM, Marullo R, Calvo-Vidal N, Verma A, Yang S, Tabbo F, Gaudiano M, Zahreddine H, Goldstein RL, Patel J, Taldone T, Chiosis G, Ladetto M, Ghione P, Machiorlatti R, Elemento O, Inghirami G, Melnick A, Borden KL, Cerchietti L. Combinatorial targeting of nuclear export and translation of RNA inhibits aggressive B-cell lymphomas. Blood. 2016;127(7):858-68. PMCID: PMC4760090. PubMed

Guo A, Lu P, Lee J, Zhen C, Chiosis G, Wang YL. HSP90 stabilizes B-cell receptor kinases in a multi-client interactome: PU-H71 induces CLL apoptosis in a cytoprotective microenvironment. Oncogene. 2017;36(24):3441-9. PMCID: PMC5645670. PubMed

A purine scaffold Hsp90 inhibitor destabilizes BCL-6 and has specific antitumor activity in BCL-6-dependent B cell lymphomas. Cerchietti LC, Lopes EC, Yang SN, Hatzi K, Bunting KL, Tsikitas LA, Mallik A, Robles AI, Walling J, Varticovski L, Shaknovich R, Bhalla KN, Chiosis G, Melnick A. Nat Med. 2009 Dec;15(12):1369-76.

Hsp90 inhibitor PU-H71, a multimodal inhibitor of malignancy, induces complete responses in triple-negative breast cancer models.Caldas-Lopes E, Cerchietti L, Ahn JH, Clement CC, Robles AI, Rodina A, Moulick K, Taldone T, Gozman A, Guo Y, Wu N, de Stanchina E, White J, Gross SS, Ma Y, Varticovski L, Melnick A, Chiosis G.Proc Natl Acad Sci U S A. 2009 May 19;106(20):8368-73.