We are using animal models to study the role of stress responses in immunity. We also utilize CRISPR/Cas9 mutagenesis to study the role of stress signaling in cancer, particularly the development of resistance to therapy.
Survival of organisms requires adaptations to stress conditions. While acute stress conditions primarily direct cells to apoptosis, chronic conditions may irreversibly affect cell function and lead to pathologies, such as diabetes, inflammation, neurodegeneration and cancer. Dr. Tirosh’s research focuses on the molecular mechanisms of stress signaling in cancer and immunity with emphasis on the transition between acute to chronic adaptations. Because anti-cancer drugs evoke stress as their mechanism of action, a seminal interest of Dr. Tirosh is determining how stress signaling contributes to drug resistance.
One major discovery of Dr. Tirosh’s is that interference with the adaptation to stress can prevent the surface deposition of specific receptors involved in cancer. In this respect the trafficking impairment involves an opposing roles of protein disulfide isomerases, a family of enzymes which catalyze the formation of disulfide bonds in the endoplasmic reticulum.
The Tirosh laboratory is using bioinformatic, genetic and biochemical tools to approach these questions.
- Role of DnaJ proteins in cancer
- Intracellular and extracellular roles of protein disulfide isomerases in recovery from stress and immune recognition of cancer.
- Role of endoplasmic reticulum homeostasis in immune function.
- Role of mTOR in drug resistance
- Transcription networks downstream to mTOR in immune cell activation.
- Mahameed M, Boukeileh S, Obiedat A, Darawshi O, Dipta P, Rimon A, McLennan G, Fassler R, Reichmann D, Karni R, Preisinger C, Wilhelm T, Huber M, Tirosh B. (2020) Pharmacological induction of selective endoplasmic reticulum retention as a novel strategy for cancer therapy. Nature Communication, 11(1):1304
- Forno F, Maatuf Y, Boukeileh S, Dipta P, Mahameed M, Darawshi O, Ferreira V, Rada P, García-Martinez I, Gross E, Priel A, Valverde AM, Tirosh B. (2020) Aripiprazole cytotoxicity coincides with activation of the unfolded protein response in human hepatic cells. JPET, 374(3):452-461
- Kogot-Levin A, Hinden L, Riahi Y, Israeli T, Tirosh B, Cerasi E, Mizrachi EB, Tam J, Mosenzon O, Leibowitz G. (2020) Proximal Tubule mTORC1 Is a Central Player in the Pathophysiology of Diabetic Nephropathy and Its Correction by SGLT2 Inhibitors. Cell Rep. 2020 32(4):107954
- Drori A, Gammal A, Azar S, Hinden L, Hadar R, Wesley D, Nemirovski A, Szanda G, Salton M, Tirosh B, Tam J. (2020) CB1R regulates soluble leptin receptor levels via CHOP, contributing to hepatic leptin resistance. Elife. 9:e60771
- Anand A, Sharma A, Ravins M, Biswas D, Ambalavanan P, Lim KXZ, Tan RYM, Johri AK, Tirosh B*, Hanski E*. (2021) Unfolded protein response inhibitors cure group A streptococcal necrotizing fasciitis by modulating host asparagine. Sci Transl Med, 13(605):eabd7465 *equal contribution
- Dipta P, Sarsenbayeva A, Shmuel M, Forno F, Eriksson J.W., Pereira M.J., Abalo X, Wabitsch M, Thaysen-Andersen M, Tirosh B. (2021). Macrophage-derived secretome is sufficient to confer Olanzapine-mediated insulin resistance in human adipocytes. Comprehensive Psychoneuroendocrinology. 7(100073)