Most cancer research focuses on understanding the biology of the cancer cell, but tumors are composites of many cell types, not just cancerous ones. In addition, although cancers are usually classified by the tissue in which they originate, cancer is a systemic disease that can affect many parts of the body. This is the case in particular for epithelial cancers, such as colorectal, lung, pancreatic, and renal cancers. One example of the systemic effects of cancer is cachexia, the wasting syndrome that’s especially common in people with advanced disease. Cancer can also have a wide-ranging influence on sleep and metabolism. But despite this significant connection, the systemic biological changes that can occur throughout the body in response to cancer have not been well studied.
In this project, Semir Beyaz and Tobias Janowitz aim to decode the complicated, whole-body response to cancer. The first part of this effort is aimed at studying the wide-ranging systemic effects of cancer, including how it interacts with the host’s neuroendocrine system, immune system, and microbiome. The investigators are using experimental animal models and patient samples in their research. They expect this approach to be synergistic, using the same samples to study a range of different connections. The data collected from this project will be used to develop organ system-specific models, which then can be employed to build translational models that predict disease outcomes and patient response to treatment.
PUBLISHED RESEARCH
Beyaz S, Chung C, Mou H, Bauer-Rowe KE, Xifaras ME, Ergin I, Dohnalova L, Biton M, Shekhar K, Eskiocak O, Papciak K, Ozler K, Almeqdadi M, Yueh B, Fein M, Annamalai D, Valle-Encinas E, Erdemir A, Dogum K, Shah V, Alici-Garipcan A, Meyer HV, Özata DM, Elinav E, Kucukural A, Kumar P, McAleer JP, Fox JG, Thaiss CA, Regev A, Roper J, Orkin SH, Yilmaz ÖH. Dietary suppression of MHC class II expression in intestinal epithelial cells enhances intestinal tumorigenesis. Cell Stem Cell. 2021.
Janowitz T, Kleeman S, Vonderheide RH. Reconsidering Dexamethasone for Antiemesis when Combining Chemotherapy and Immunotherapy. Oncologist. 2021.
Yang WH, Qiu Y, Stamatatos O, Janowitz T, Lukey MJ. Enhancing the Efficacy of Glutamine Metabolism Inhibitors in Cancer Therapy. Trends Cancer. 2021.
Dmitrieva-Posocco O, Wong AC, Lundgren P, Golos AM, Descamps HC, Dohnalová L, Cramer Z, Tian Y, Yueh B, Eskiocak O, Egervari G, Lan Y, Liu J, Fan J, Kim J, Madhu B, Schneider KM, Khoziainova S, Andreeva N, Wang Q, Li N, Furth EE, Bailis W, Kelsen JR, Hamilton KE, Kaestner KH, Berger SL, Epstein JA, Jain R, Li M, Beyaz S, Lengner CJ, Katona BW, Grivennikov SI, Thaiss CA, Levy M. β-Hydroxybutyrate suppresses colorectal cancer. Nature. 2022.
Petruzzelli M, Ferrer M, Schuijs MJ, Kleeman SO, Mourikis N, Hall Z, Perera D, Raghunathan S, Vacca M, Gaude E, Lukey MJ, Jodrell DI, Frezza C, Wagner EF, Venkitaraman AR, Halim TYF, Janowitz T. Early Neutrophilia Marked by Aerobic Glycolysis Sustains Host Metabolism and Delays Cancer Cachexia. Cancers (Basel). 2022.
Mou H, Eskiocak O, Özler KA, Gorman M, Yue J, Jin Y, Wang Z, Gao Y, Janowitz T, Meyer HV, Yu T, Wilkinson JE, Kucukural A, Ozata DM, Beyaz S. CRISPR-induced exon skipping of β-catenin reveals tumorigenic mutants driving distinct subtypes of liver cancer. J Pathol. 2023.
Ferrer M, Anthony TG, Ayres JS, Biffi G, Brown JC, Caan BJ, Cespedes Feliciano EM, Coll AP, Dunne RF, Goncalves MD, Grethlein J, Heymsfield SB, Hui S, Jamal-Hanjani M, Lam JM, Lewis DY, McCandlish D, Mustian KM, O’Rahilly S, Perrimon N, White EP, Janowitz T. Cachexia: A systemic consequence of progressive, unresolved disease. Cell. 2023.
Ferrer M, Mourikis N, Davidson EE, Kleeman SO, Zaccaria M, Habel J, Rubino R, Gao Q, Flint TR, Young L, Connell CM, Lukey MJ, Goncalves MD, White EP, Venkitaraman AR, Janowitz T. Ketogenic diet promotes tumor ferroptosis but induces relative corticosterone deficiency that accelerates cachexia. Cell Metab. 2023.
Lei PJ, Pereira ER, Andersson P, Amoozgar Z, Van Wijnbergen JW, O’Melia MJ, Zhou H, Chatterjee S, Ho WW, Posada JM, Kumar AS, Morita S, Menzel L, Chung C, Ergin I, Jones D, Huang P, Beyaz S, Padera TP. Cancer cell plasticity and MHC-II-mediated immune tolerance promote breast cancer metastasis to lymph nodes. J Exp Med. 2023.
Merrill JR, Inguscio A, Chung T, Demestichas B, Garcia LA, Habel J, Lewis DY, Janowitz T, Lyons SK. Sensitive, non-immunogenic in vivo imaging of cancer metastases and immunotherapy response. Cell Stress. 2023.
Rogava M, Aprati TJ, Chi WY, Melms JC, Hug C, Davis SH, Earlie EM, Chung C, Deshmukh SK, Wu S, Sledge G, Tang S, Ho P, Amin AD, Caprio L, Gurjao C, Tagore S, Ngo B, Lee MJ, Zanetti G, Wang Y, Chen S, Ge W, Melo LMN, Allies G, Rösler J, Gibney GT, Schmitz OJ, Sykes M, Creusot RJ, Tüting T, Schadendorf D, Röcken M, Eigentler TK, Molotkov A, Mintz A, Bakhoum SF, Beyaz S, Cantley LC, Sorger PK, Meckelmann SW, Tasdogan A, Liu D, Laughney AM, Izar B. Loss of Pip4k2c confers liver-metastatic organotropism through insulin-dependent PI3K-AKT pathway activation. Nat Cancer. 2024.