Research Focus

Stem cells persist throughout life in our tissues by undergoing self-renewing divisions in which stem cells divide to form more stem cells. Research from our laboratory and others suggests that many cancers arise from the inappropriate activation of these self-renewal mechanisms, causing cells to proliferate out of control.

Our goal is to better understand the mechanisms that maintain adult tissues and how cancer cells hijack these mechanisms to enable the formation of tumors. To do this, we compare the processes by which stem cells and cancer cells replicate themselves. A better understanding of these mechanisms offers the potential for new regenerative medicine and cancer therapies. By promoting these mechanisms in the context of tissue injury, we can stimulate regeneration. By inhibiting these mechanisms in the context of cancer, we hope to develop anticancer therapies.

Research Projects

Stem Cell Self-Renewal

Stem Cell Aging

The Self-Replication of Cancer Cells

Stem Cell Self-Renewal
Stem Cell Self-Renewal
The maintenance of many adult tissues depends on the persistence of stem cells throughout life. Stem cells are maintained in adult tissues by self-renewal, the process by which stem cells divide to make more stem cells. By better understanding this process, we gain insights into how tissues develop and regenerate, how reduced self-renewal can lead to degenerative disease and how increased self-renewal can lead to tumorigenesis. We have discovered that networks of proto-oncogenes and tumor suppressors that control cancer cell proliferation also regulate stem cell self-renewal but that these networks do not generically regulate the proliferation of all cells. Restricted progenitor proliferation does not require many of the mechanisms that regulate stem cell self-renewal.

To go beyond traditional studies of individual gene products, we are developing new methods to study aspects of cellular physiology, such as the regulation of proteostasis and metabolism, that have been studied only to a limited extent in somatic stem cells. Studies of these mechanisms in stem cells have the potential to reveal ways in which they are used differently by different kinds of dividing somatic cells and how these differences regulate tissue homeostasis.

We also study the extrinsic mechanisms by which the niche regulates stem cell maintenance. Our studies focus on the hematopoietic system, where we have discovered that quiescent hematopoietic stem cells (HSCs) reside in a perivascular niche in which endothelial cells and leptin receptor-expressing perivascular stromal cells secrete factors that promote HSC maintenance. The discovery and characterization of this niche has allowed us to identify new mechanisms by which HSCs and the niche regulate each other, including the identification of new growth factors and the ways in which the niche changes in response to injury.

Stem Cell Aging

Stem Cell AgingMuch of age-related morbidity in mammals may be determined by the influence of aging on stem cell function. We have found that stem cells from the hematopoietic and nervous systems undergo strikingly conserved changes in their properties as they age, including declining self-renewal capacity.

We have identified a network of heterochronic gene products that regulates stem cell maintenance throughout life while also regulating the temporal changes in stem cell properties required to match the changing growth and regeneration demands of fetal and adult tissues. For example, Hmga2 expression declines while let-7 expression and Ink4a expression increase with age, reducing stem cell frequency and function in multiple tissues. By deleting Ink4a from mice, we partly rescued the decline in stem cell function with age and enhanced the regenerative capacity of aging tissues. Networks of proto-oncogenes and tumor suppressors thus change throughout life to balance tissue regeneration with tumor suppression. Proto-oncogenic signals dominate during fetal development when tissue growth is rapid but cancer risk is low, and tumor-suppressor mechanisms are amplified during aging when there is little tissue growth but cancer risk is high.

The Self-Replication of Cancer Cells

Cancer stem cell biologyCancer cells hijack stem cell self-renewal mechanisms by acquiring mutations that overactivate these pathways. By comparing the mechanisms that regulate the self-renewal of normal stem cells and the self-replication of cancer cells, we identify differences that represent potential vulnerabilities that can be targeted to kill cancer cells. For example, ion gradients are rarely studied in cancer cells. However, we have discovered that the ability of cancer cells to maintain subcellular ion gradients appears to be persistently stressed and that inhibitors of ion transporters can have synthetic lethal effects when combined with targeted agents that inhibit oncogenic signaling pathways.

We are particularly interested in the mechanisms that regulate melanoma metastasis. We have discovered that the distant metastasis of melanoma cells is limited by high levels of reactive oxygen species that arise in melanoma cells during metastasis. Our data suggest that this causes oxidative stress that kills the vast majority of melanoma cells as they attempt to metastasize, potentially explaining why distant metastasis is such an inefficient process. The rare cells that successfully metastasize appear to undergo metabolic changes that enhance their capacity to cope with oxidative stress. Our results suggest that rather than treating cancer with antioxidants, we should be treating with pro-oxidants that exacerbate oxidative stress or that inhibit the ability of cancer cells to metabolically adapt.

About Dr. Morrison

Sean Morrison, Stem Cell Research

Sean J. Morrison is the director of the Children’s Medical Center Research Institute (CRI) at UT Southwestern and a Howard Hughes Medical Institute investigator. He holds the Mary McDermott Cook Chair in Pediatric Genetics and the Kathryne and Gene Bishop Distinguished Chair in Pediatric Research. Dr. Morrison completed a B.Sc. in biology and chemistry at Dalhousie University (1991), a Ph.D. in immunology at Stanford University (1996), and a postdoctoral fellowship in neurobiology at Caltech (1999). From 1999 to 2011, Dr. Morrison was a professor at the University of Michigan, where he directed their Center for Stem Cell Biology.

Among other awards, Dr. Morrison received the Presidential Early Career Award for Scientists and Engineers (2003) and a MERIT Award from the National Institute on Aging (2009). He was elected to the National Academy of Medicine (2018) and the National Academy of Sciences (2020). Dr. Morrison served as the President of the International Society for Stem Cell Research (2015-2016) and has been active in public policy issues surrounding stem cell research, testifying before the U.S. Congress, and serving as a leader in the successful “Proposal 2” campaign to protect and regulate stem cell research in Michigan’s state constitution.

Curriculum Vitae

Selected Publications

Tasdogan, A., Faubert, B., Ramesh, V., Ubellacker, J.M., Shen, B., Solmonson, A., Murphy, M.M., Gu, Z., Gu, W., Martin, M., Kasitinon, S.Y., Vandergriff, T., Mathews, T.P., Zhao, Z., Schadendorf, D., DeBerardinis, R.J., and Morrison S,J. (2020). Metabolic heterogeneity confers differences in melanoma metastatic potential. Nature 577, 115-120. (PubMed)

Shen, B., Vardy, K., Hughes, P., Tasdogan, A., Zhao, Z., Yue, R., Crane, G.M., and Morrison, S.J. (2019). Integrin alpha11 is an Osteolectin receptor and is required for the maintenance of adult skeletal bone mass. eLife, pii: e42274 (PubMed)

Comazzetto, S., Murphy, M.M., Berto, S., Jeffery, E., Zhao, Z., and Morrison, S.J. (2018). Restricted Hematopoietic Progenitors and Erythropoiesis Require SCF from Leptin Receptor+ Niche Cells in the Bone Marrow. Cell Stem Cell 24, 477-486. (PubMed)

Agathocleous, M., Meecham, C.E., Burgess, R.J., Piskounova, E., Zhao, Z., Crane, G.M., Cowin, B.L., Bruner, E., Murphy, M.M., Chen, W., Spangrude, G.J., Hu, Z., DeBerardinis, R.J., and Morrison, S.J. (2017). Ascorbate regulates haematopoietic stem cell function and leukaemogenesis. Nature 549, 476-481. (PubMed)

Yue, R., Zhou, B.O., and Morrison, S.J. (2016). Clec11a/osteolectin is an osteogenic growth factor that promotes the maintenance of the adult skeleton. eLife pii:e18782. (PubMed)

Acar, M., Kocherlakota, K.S., Murphy, M.M., Peyer, J.G., Oguro, H., Inra, C.N., Jaiyeola, C.J., Zhao, Z., Luby-Phelps, K., and Morrison, S.J. (2015). Deep imaging of bone marrow shows non-dividing stem cells are mainly perisinusoidal. Nature 526, 126-130. (PubMed)

Piskounova, E., Agathocleous, M., Murphy, M.M., Hu, Z., Mann, S., Zhao, Z., Leitch, A.M., Johnson, T.M., DeBerardinis, R.J., and Morrison, S.J. (2015). Oxidative stress inhibits distant metastasis by human melanoma cells. Nature 527, 186-191. (PubMed)

Inra, C., Zhou, B.O., Acar, M., Murphy, M.M., Zhao, Z., and Morrison, S.J. (2015). A perisinusoidal niche for extramedullary hematopoiesis in the spleen. Nature 527, 466-471. (PubMed)

Zhou, B.O., Yue, R., Murphy, M.M., Peyer, J.G., and Morrison, S.J. (2014). Leptin-receptor-expressing mesenchymal stromal cells represent the main source of bone formed by adult bone marrow. Cell Stem Cell 15, 154-168. (PubMed)


Lab News


Lab Members

Madison Arora

Research Technician

Arin Aurora, Ph.D.

Assistant Professor, Research

Jimuel Bulatao

Senior Animal Technician

Rebecca Burgess, Ph.D.

Ruth L. Kirschstein NRSA Fellow

Dan Cassidy

Research Technician

Andrew DeVilbiss, Ph.D.

Ruth L. Kirschstein NRSA Fellow

Liming Du, Ph.D.

Postdoctoral Fellow

Shay Geula, Ph.D.

Gruss Lipper Israeli Fellow

Elise Jeffery, Ph.D

Damon Runyon Foundation Fellow

Nergis Kara, Ph.D.

Postdoctoral Fellow

Ashley Leach

Research Technician

Ashley Lesser

Research Technician

Mark Mannino

M.D./Ph.D. Student

Tom Mathews, Ph.D.

Research Specialist

Corbin Meacham, Ph.D.

American Cancer Society Fellow

Salma Merchant, Ph.D.

Postdoctoral Fellow

Sarah Muh

Research Assistant

Megan Nitcher, B.S.

Lab Manager/Mouse Colony Manager

Animesh Paul, B.S.

Ph.D. Student

Julia Phan, B.S.

M.D./Ph.D. Student

Jade Pool

Research Technician

Vijayashree Ramesh, M.S.

Research Scientist

Tao Wei, Ph.D.

Postdoctoral Fellow

Yuanyuan Xue, Ph.D.

Postdoctoral Fellow

Jingzhu Zhang, Ph.D.

Postdoctoral Fellow

Sylvia Zhao, Ph.D.

Assistant Professor, Research

Michalis Agathocleous, Ph.D.

Assistant Professor, Children’s Medical Center Research Institute at UT Southwestern

Postdoctoral Fellow (2012-2017)

Kati Ahlqvist, Ph.D.

Postdoctoral Researcher, University of Helsinki, Centre of Excellence in Stem Cell Metabolism

Human Frontier Science Program Fellow (2016-2018)

Johanna Buchstaller, Ph.D.

Data Science and Analytics Consultant, Slalom Consulting

Postdoctoral Fellow (2004-2011)

Sergei Chuikov, Ph.D.

Associate, Howard Hughes Medical Institute

Postdoctoral Fellow (2005-2011)

Genevieve Crane, M.D., Ph.D.

Staff Hematopathologist, Cleveland Clinic

M.D./Ph.D. Student (2000-2004)

Lei Ding, Ph.D.

Assistant Professor, Columbia University

Postdoctoral Fellow (2007-2013)

Ugur Esckiocak, Ph.D.

Associate Director, In Vivo, Compass Therapeutics

Postdoctoral Fellow (2011-2016)

Jennifer Gill, M.D., Ph.D.

Assistant Professor,Department of Dermatology, UT Southwestern Medical Center

Clinical Fellow (2015-2020)

Shenghui He, Ph.D.

Assistant Professor, University of North Carolina

Ph.D. Student/ Postdoctoral Fellow (2004-2010)

Chris Inra, M.D., Ph.D.

Assistant Professor, Medicine, John Hopkins

M.D./Ph.D. Student (2011-2015)

Toshihide Iwashita, Ph.D.

Professor of Pathology, Hamamatsu University School of Medicine

Postdoctoral Fellow (2000-2005)

Nancy Joseph, M.D., Ph.D.

Associate Professor of Pathology & Associate Director of Clinical Cancer Genomics Laboratory, UCSF Medical Center

M.D./Ph.D. Student (2001-2006)

Mark Kiel, M.D., Ph.D.

CSO and co-founder, Genomenon, Inc.

M.D./Ph.D. Student (2004-2008)

Injune Kim, Ph.D.

Associate Professor, Korea Advanced Inst. of Science and Technology (KAIST)

Postdoctoral Fellow (2002-2008)

Jae Lee, M.D., Ph.D.

Radiation Oncologist, Princeton Radiation Oncology

M.D./Ph.D. Student (2006-2010)

Boaz Levi, Ph.D.

Assistant Investigator, Applied Genomics, Allen Institute for Brain Science

Postdoctoral Fellow (2006-2011)

Qing Li, Ph.D.

Assistant Professor of Internal Medicine, University of Michigan

Postdoctoral Fellow (2009-2010)

Jeffrey Magee, M.D.

Assistant Professor, Washington University

Pediatrics Fellow (2008-2013)

John Mich, Ph.D.

Scientist II, Allen Institute for Brain Science

Postdoctoral Fellow (2010-2014)

Anna Molofsky, M.D., Ph.D.

Assistant Professor of Psychiatry, University of California at San Francisco

M.D./Ph.D. Student, (2001-2005)

Jack Mosher, Ph.D.

Scientific Affairs Manager, International Society for Stem Cell Research

Postdoctoral Fellow (2001-2006)

Malea Murphy, Ph.D.

Manager, Integrated Microscopy & Imaging Laboratory, College of Medicine, Texas A&M University

Postdoctoral Fellow (2012-2019)

Daisuke Nakada, M.D., Ph.D.

Assistant Professor, Baylor College of Medicine

Postdoctoral Fellow (2006-2011)

Hideyuki Oguro, Ph.D.

Associate Director, Cellular Engineering, Jackson Laboratory for Genomic Medicine

Postdoctoral Fellow (2012 - 2016)

Ricardo Pardal, Ph.D.

Professor, The Neuroscience Institute, Seville, Spain

Postdoctoral Fellow (2001-2004)

Michel Perron, Ph.D.

Research Scientist, Gilead Sciences

Postdoctoral Fellow (2007-2008)

James Peyer, Ph.D.

Partner, Apollo Ventures

Ph.D. Student (2010-2015)

Elena Piskounova, Ph.D

Assistant Professor, Dermatology, Weill Cornell Medical College

Helen Hay Whitney Fellow

Le Qi , Ph.D.

Postdoctoral Fellow, University of California, Los Angeles

Ph.D. Student, HHMI International Predoctoral Fellow (2014 -2021)

Elsa Quintana, Ph.D.

Director, Revolution Medicines

Postdoctoral Fellow (2005-2011)

Michael Savona, Ph.D.

Associate Professor of Medicine, Vanderbilt University

Postdoctoral Fellow (2006-2008)

Mark Shackleton, Ph.D.

Director of Oncology at Alfred Health, Monash University

Postdoctoral Fellow (2006-2009)

Issei Shimada, Ph.D.

Lecturer, Graduate School of Medicine Sciences, Nagoya City University

Postdoctoral Fellow (2011-2015)

Robert Signer, Ph.D.

Assistant Professor, Department of Medicine, University of California, San Diego

Postdoctoral Fellow (2009 - 2015)

Bo Shen, Ph.D.

Assistant Investigator, National Institute of Biological Sciences, Beijing

Ruth L. Kirschstein NRSA Fellow (2015-2021)

Guy Slutsky, Ph.D.

Project Manager, Kadimastem

Postdoctoral Fellow (2005-2007)

Alpaslan Tasdogan, M.D., Ph.D.

Associate Professor, Department of Dermatology, University of Essen-Duisburg

German National Academy of Sciences Leopoldina Postdoctoral Fellow (2016-2021)

Merritt Taylor, Ph.D.

Associate Professor, Grand Valley State University

Postdoctoral Fellow (2001-2007)

Jessalyn Ubellacker, Ph.D.

Assistant Professor, Molecular Metabolism, Harvard T.H. Chan School of Public Health

Postdoctoral Fellow (2018-2021)

Omer Yilmaz, M.D., Ph.D.

Assistant Professor, Koch Institute, Massachusetts Institute of Technology

M.D./Ph.D. Student (2001-2006)

Stacy Yuan, Ph.D.

MSTP Student, UT Southwestern Medical School

M.D./Ph.D. Student (2014-2019)

Rui Yue, Ph.D.

Professor, Tongji University in Shanghai

Postdoctoral Fellow (2011-2017)

Bo Zhou, Ph.D.

Assistant Professor, Chinese Academy of Sciences

Postdoctoral Fellow (2011-2016)

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