Emmanuelle Passegue, PhD
Emmanuelle Passegué, Ph.D., is the Alumni Professor of Genetics and Development (in Rehabilitation and Regenerative Medicine) and the Director of the Columbia Stem Cell Initiative at Columbia University Medical Center (CUMC). Dr. Passegué received her Ph.D. from the University Paris XI (France), and trained with Dr. Erwin Wagner (Institute for Molecular pathology, Vienna, Austria) and Dr. Irv Weissman (Stanford University, USA) before joining the University of California San Francisco (UCSF) in 2005. Dr. Passegué was a Professor of Medicine in the Hematology/Oncology Division and the Eli and Edythe Broad Center for Regenerative Medicine and Stem Cell Research at UCSF until 2016 before joining CUMC in January 2017.
Hematopoiesis & Hematopoietic Stem Cell Biology
Our laboratory studies how hematopoietic stem cells (HSC) regulate blood production during the lifetime of an ever-changing organism. This fundamental question is central to tissue development, maintenance and regeneration, and has implications for every aspect of adult physiology ranging from response to stress, development of diseases, and biology of aging. We are interested in identifying the mechanisms that control HSC activity in normal and a range of deregulated conditions, with the goal of identifying affected genes and pathways that could be used to develop new therapies to treat human myeloid malignancies and help combat physiological aging. Towards this end, we are employing a variety of cross-disciplinary approaches using mouse models and human samples.
Fighting Blood Aging by Preventing HSC Decline
The blood system is essential for organismal health and to maintain the body's ability to fight infections. HSCs self-renew and maintain blood production for life and, as such, are one of the few blood cells that truly age or initiate malignancies. While HSCs efficiently produce all mature blood cells in young individuals, they often fail with age leading to degraded blood production characterized by anemia, immunosenescence, blood cancers, and clonal hematopoiesis, which is a new contributing factor to systemic age-related organ dysfunction. Paradoxically, although HSCs numerically expand with age, their functional activity declines over time, resulting in impaired engraftment and decreased blood regeneration capacity. Our recent work on aged HSCs has identified novel molecular hallmarks of an old state, and provided unique insights into the mechanisms of stem cell aging. In particular, it showed that replication stress as a potent driver of functional exhaustion of aged HSCs, and demonstrated that defective activation of autophagy allowed the accumulation of metabolically overactivated and dysfunctional old HSCs. Our goal is to extend these investigations to develop novel rejuvenation interventions for healthier aging, which include restoring the elderly's ability to fight infections and to combat the development of blood cancers.
Manipulating Emergency Myelopoiesis Pathways to Treat Blood Deregulations
Blood production is a highly regulated process that tailors the output of the myeloid and lymphoid lineages based on hematopoietic demands and the needs of the organism. While the overall structure of the blood system and its hierarchical nature is well established, many questions still remain regarding the mechanisms controlling self-renewal activity and quiescent status of HSCs, and the lineage specifications that occur in non-self-renewing multipotent progenitors (MPP). Our investigations of emergency myelopoiesis pathways have provided new insights into the mechanisms of HSC activation and lineage commitment, and showed that a shift from glycolysis to mitochondrial metabolism changes the epigenetic landscape of activated HSCs and drives lineage poising. They also uncovered new regulatory mechanisms by showing that environmental factors produced by the bone marrow (BM) niche dictate the production of various lineage-biased multipotent progenitors and control the local expansion and differentiation of committed progenitor cells. These mechanisms normally tailor blood production to the need of the organism, but are hijacked in malignancies. Our goal is to explore the role of these mechanisms in various deregulated contexts, and to manipulate them for the treatment of blood malignancies and immune deregulations.
Hérault A, Binnewies M, Leong S, Calero-Nieto FJ, Zhang SY, Kang Y-A, Wang X, Pietras E, Chu SH, Barry-Holson K, Armstrong S, Göttgens B, Passegué E. Myeloid progenitor cluster formation drives emergency and leukemic myelopoiesis. Nature, 544:53-58, 2017.
Ho TT, Warr MR, Adelman E, Lansinger O, Flach J, Verovskaya E, Figueroa ME, Passegué E. Autophagy maintains metabolism and functional activity of a subset of aged hematopoietic stem cells. Nature, 543:205-210, 2017.
Pietras M, Mirantes-Barbeito C, Fong S, Löeffler D, Kovtonyuk LV, Zhang SY, Lakshminarasimhan R, Chin CP, Techner J-M, Will B, Nerlov C, Steidl U, Manz MG, Schroeder T, Passegué E. Interleukin-1 drives hematopoietic stem cells towards precocious myeloid differentiation at the expense of self-renewal. Nat Cell Biol, 18:607-618, 2016.
Pietras E*, Reynaud D*, Carlin D, Calero-Nieto FJ, Kang YA, Leavitt AD, Stuart JM, Gottgens B, Passegué E. Functionally distinct subsets of lineage-biased multipotent progenitors control blood production in normal and regenerative conditions. Cell Stem Cell, 17:35-46, 2015. (*equal contribution)
Flach J, Bakker ST, Mohrin M, Conroy PC, Pietras EM, Reynaud D, Alvarez S, Diolaiti ME, Ugarte F, Forsberg EC, Le Beau MM, Stohr BA, Méndez J, Morrison CG, Passegué E. Replication stress is a potent driver of functional decline in aging hematopoietic stem cells. Nature, 512:198-202, 2014.
Pietras EM, Lakshminarasimhan R, Techner JM, Fong S, Flach J, Binnewies M, Passegué E. Re-entry into quiescence protects hematopoietic stem cells from the killing effect of chronic exposure to type I interferons. J Exp Med, 211:245-262, 2014.
Schepers K, Pietras EM, Reynaud D, Flach J, Binnewies M, Garg T, Wagers AJ, Hsiao EC, Passegué E. Myeloproliferative neoplasia remodels the endosteal bone marrow niche into a self-reinforcing leukemic niche. Cell Stem Cell, 13:285-299, 2013.
Warr MR, Binnewies M, Flach J, Reynaud D, Garg T, Malhotra R, Debnath J, Passegué E. FOXO3A directs a protective autophagy program in haematopoietic stem cells. Nature, 494:323-327, 2013.
Reynaud D, Pietras EM, Barry-Holson K, Mir A, Binnewies M, Jeanne M, Sala-Torra O, Radich JP, Passegué E. IL-6 controls leukemic multipotent progenitor cell fate and contributes to chronic myelogenous leukemia development. Cancer Cell, 20:661-673, 2011.
Mohrin M, Bourke E, Alexander D, Warr M, Barry-Holson K, LeBeau M, Morrison CG, Passegué E. Hematopoietic stem cell quiescence promotes error prone DNA repair and mutagenesis. Cell Stem Cell, 7:174-485, 2010.
Santaguida M, Schepers K, King B, Sabnis AJ, Forsberg EC, Attema JL, Braun BS, Passegué E. JunB protects against myeloid malignancies by limiting hematopoietic stem cell proliferation and differentiation without affecting self-renewal. Cancer Cell, 15:341-352, 2009.