Michael B. Yaffe, MD, PhD
David H. Koch Professor of Biology and Biological Engineering, Massachusetts Institute of Technology
Dr. Yaffe has a joint appointment in Acute Care Surgery, Trauma, and Surgical Critical Care, and in Surgical Oncology.
Christopher Barrett, MD
Pau Creixell Morera, PhD
Vasilena Gocheva, PhD
Ingred Goretti Rica, PhD
Robert Grant, PhD
Mun Kyung Hwang, PhD
Brian Joughin, PhD
Yi Wen Kong, PhD
Fred Chiu-Lai Lam, PhD
Daniel Lim, PhD
Jesse Patterson, PhD
Ganapathy Sriram, PhD
Lucia Suarez Lopez, PhD
Bert van de Kooij, PhD
Shohreh Varmeh, PhD
The goal of our research is to understand how cells respond to stress and injury at the molecular level, and how this response can be therapeutically manipulated to improve the care of patients with trauma, critical illness or cancer. We study specific signaling pathways in the cell that respond to stress, DNA damage, and inflammatory cytokines, and use experimental and computational tools to understand and how these pathways are biochemically wired, and how the outputs of these pathways are integrated at the molecular and systems level to control the subsequent fate of the stressed and damaged cells. We are particularly interested in cross-talk between (1) stress, inflammation and immune function after trauma, (2) stress, inflammation, innate immune function and cancer, and (3) targeting stress, DNA damage, and cell cycle control pathways for cancer treatment. Our lab has a longstanding interest in inventing new technologies to address these questions including novel proteomic methods, high-throughput signaling assays and peptide library screens, RNAi screens using high-content imaging, and novel computational/bioinformatics methods, together with more traditional techniques from cell biology, physical biochemistry, structural biology, and mouse genetics.
Signaling pathways and networks that control the DNA damage response, cell cycle progression and cancer
When cells encounter stress or injury such as DNA damage, they activate complex signaling networks that regulate their ability to recover, repair the damage, and return to a homeostatic equilibrium. These networks must integrate a wide variety of signals from inside and outside the cell, transduced through protein kinase and lipid signaling pathways, to ultimately control cell cycle arrest or progression, coordinately regulate specific patterns of gene expression, and/or initiate senescence or cell death. Mutations in, or dysfunction of, protein kinase signaling pathways that normally respond to DNA damage, for example, play critical roles in tumor development and progression, while intentional targeting of these pathways can enhance the ability of commonly used DNA-damaging chemotherapy and radiation to cure cancer. We have been attacking this research area along two fronts: 1) characterizing the molecular details of the DNA damage response with a focus on protein kinases, phospho-binding domains, RNA-binding proteins, and epigenetic modulation of chromatin at the site of damage, and 2) examining whether cross-talk between various signaling pathways and the DNA damage-response can be pharmacologically manipulated to enhance the response of tumors to DNA damaging agents alone, or in combination with immunotherapy.
We showed, for example, that p53-defective tumor cells become dependent on signaling through the stress-activated p38-MK2 pathway to resist killing by chemotherapy, and have now created a variety of standard and novel conditional MK2 knock-out mice, as well as nanoparticles delivering MK2-targeted RNAi and CRISPR, to target this pathway in vivo in several cancer models. We are continuing to explore the roles of the MK2 pathway in a variety of cancer-relevant phenotypes, as well as performing CRISPR-based screens to look for new modifiers of the DNA damage response that can be therapeutically targeted. This work has led to a new focus on the role of RNA-binding proteins as critical integrators of stress and DNA damage response pathways in the cell. Finally, we discovered the phenomenon of ‘dynamic network re-wiring,’ in which tumor cell treatment with a specific schedule of signaling pathway inhibitors and DNA-damaging chemotherapy can be used to dramatically enhance cell killing in a subset of triple-negative breast cancer and non-small cell lung cancer. We are now trialing this approach in human PDX models of TNBC, in collaboration with Dr. Gerburg Wulf (Hematology-Oncology, BIDMC), as well as extending that work into colon, head and neck, and prostate cancer models.
Signaling pathways and networks that control cytokine responses and inflammation
Misregulation of cytokine feedback loops, along with inappropriate activation of the blood clotting cascade causes dysregulation of cell signaling pathways in innate immune cells (neutrophils and macrophages), resulting in tissue damage and multiple organ failure following trauma or sepsis. Our research is focused on understanding the role of the p38-MK2 pathway in cytokine control and innate immune function, and on cross-talk between cytokines, clotting factors, and neutrophil NADPH oxidase-derived ROS in tissue damage, coagulopathy, and inflammation, using biochemistry, cell biology, and mouse knock-out/knock-in models. We recently discovered a particularly important link between abnormal blood clotting and the complement pathway cytokine C5a which causes excessive production of extracellular ROS and organ damage by neutrophils after traumatic injury.
- Chief Scientific Advisor and Academic Editor, Science Signaling
- One of eight investigators nationally to win the Revolutionizing Innovative Visionary Environmental Health Research (RIVER) award from the NIH
Teaching, Training, and Education
I am heavily involved in teaching at the undergraduate, graduate, and medical school level. I teach 7.05 (Undergraduate Biochemistry) and 7.10 (Physical Chemistry of Biomolecular Systems) at MIT, as well as 7.61 (Signaling and Cell Biology), a graduate-level overview course. I also teach extensively on critical care topics to ICU residents and fellows. Every two years I teach an EMBL-sponsored Signaling in Cancer course in Spetses, Greece.
Selected Research Support
Protein kinase signaling in the genotoxic stress response; NIH, 2017-2025; PI: Michael Yaffe, MD, PhD
Modeling human phosphorylation networks through kinome-wide profiling; NIH, 2013-2018; Co-PIs: Benjamin Turk, PhD, and Michael Yaffe, MD, PhD
Analysis and Characterization of Trauma-Induced Coagulopathy, Project 9: The Role and Mechanisms of Trauma-Induced Endothelial Injury and inflammation that Results in Coagulopathy and End-Organ Damage. NIH, 2013-2019; Co-PIs: Michael Yaffe, MD, PhD, Brian Zuckerbraun MD, Mitchell Cohen MD
DAMP-Mediated Innate Immune Failure After Trauma; DoD, 2015-2020; Co-PIs: Carl Hauser MD, Leo Otterbein PhD, James Lederer PhD, Daniel Talmor MD, Simon Robson MD PhD, Michael Yaffe MD, PhD
Barrett CD, Hsu AT, Ellson CD, Miyazawa BY, Kong YW, Greenwood JD, Sanjeev Dhara S, Neal MD, Sperry JL, Park MS, Cohen MJ, Zuckerbraun BS, Yaffe MB. Blood clotting and traumatic injury with shock mediates complement-dependent neutrophil priming for extracellular ROS, ROS-dependent organ injury and coagulopathy. Clin Exp Immunology 2018 (online, in press)
Suarez-Lopez L, Sriram G, Kong YW, Morandell S, Merrick KA, Hernandez Y, Haigis KM, Yaffe MB. MK2 contributes to tumor progression by promoting M2 macrophage polarization and tumor angiogenesis. Proc Natl Acad Sci U S A 2018;115(18):E4236-E4244.
Alkan O, Schoeberl B, Shah M, Koshkaryev A, Heinemann T, Drummond DC, Yaffe MB, Raue A. Modeling chemotherapy-induced stress to identify rational combination therapies in the DNA damage response pathway. Science Signal 2018;11(540).
Dreaden EC, Kong YW, Quadir MA, Correa S, Suárez-López L, Barberio AE, Hwang MK, Shi AC, Oberlton B, Gallagher PN, Shopsowitz KE, Elias KM, Yaffe MB, Hammond PT. RNA-peptide nanoplexes drug DNA damage pathways in high-grade serous ovarian tumors. Bioeng Transl Med 2018; 3(1):26-36.
Barrett CD, Moore HB, Banerjee A, Silliman CC, Moore EE, Yaffe MB. Human neutrophil elastase mediates fibrinolysis shutdown through competitive degradation of plasminogen and generation of angiostatin. J Trauma Acute Care Surg 2017; 83(6):1053-1061.
Xiao H, Qi R, Li T, Awuah SG, Zheng Y, Wei W, Kang X, Song H, Wang Y, Yu Y, Bird MA, Jing X, Yaffe MB, Birrer MJ, Ghoroghchian PP. Maximizing synergistic activity when combining RNAi and platinum-based anticancer agents. J Am Chem Soc 2017;139(8):3033-3044.
Yaffe MB, Gough NR. Leveraging signaling research to understand and treat disease. Sci Signal 2016;9(421).