MORRISON LAB

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 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 enormous potential to yield 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

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

Much 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 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 J. Morrison is the director of the Children’s Medical Center Research Institute (CRI) at UT Southwestern, the Mary McDermott Cook Chair in Pediatric Genetics, the Kathryne and Gene Bishop Distinguished Chair in Pediatric Research, and a Howard Hughes Medical Institute investigator. Dr. Morrison obtained his B.Sc. in biology and chemistry from Dalhousie University (1991), his Ph.D. in immunology at Stanford University (1996) and his 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. His laboratory studies the mechanisms that regulate stem cell function in adult tissues and the ways in which those mechanisms get hijacked by cancer cells to enable tumor formation.

Dr. Morrison was a Searle Scholar (2000-2003) and received the Presidential Early Career Award for Scientists and Engineers (2003), the International Society for Hematology and Stem Cell’s McCulloch and Till Award (2007), the American Association of Anatomists Harland Winfield Mossman Award (2008) and a MERIT Award from the National Institute on Aging (2009). He recently served as President of the International Society for Stem Cell Research (2015). Dr. Morrison has also been active in public policy issues surrounding stem cells. He twice testified before Congress and was a leader in the successful “Proposal 2” campaign to protect and regulate stem cell research in Michigan’s state constitution.

Selected Publications

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., 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)


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Lab News

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  • Sean Morrison Receives Individual Investigator Award from the Cancer Prevention and Research Institute of Texas (CPRIT)

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  • Making Strides in Childhood Cancer Research

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  • CRI Scientist Receives Award for Excellence in Postdoctoral Research

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Lab Members

Michalis Agathocleous, Ph.D.

Michalis Agathocleous, Ph.D.

Royal Commission for the Exhibition of 1851 Research Fellow

Kati Ahlqvist, Ph.D.

Kati Ahlqvist, Ph.D.

Human Frontier Science Program Fellow

Arin Aurora, Ph.D.

Arin Aurora, Ph.D.

Assistant Professor, Research

Rebecca Burgess, Ph.D.

Rebecca Burgess, Ph.D.

Ruth L. Kirschstein NRSA Fellow

Stefano Comazzetto, Ph.D

Stefano Comazzetto, Ph.D

EMBO Fellow

Andrew DeVilbiss, Ph.D.

Andrew DeVilbiss, Ph.D.

Ruth L. Kirschstein NRSA Fellow

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

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

Clinical Fellow, Dermatology

Albert Gross, BS, LATG

Albert Gross, BS, LATG

Mouse Colony Manager

Salma Hasan, Ph.D.

Salma Hasan, Ph.D.

Postdoctoral Fellow

Danielle Herubin

Danielle Herubin

Research Assistant

Elise Jeffery, Ph.D

Elise Jeffery, Ph.D

Damon Runyon Foundation Fellow

Vishal Khivansara, M.S.

Vishal Khivansara, M.S.

Senior Research Associate

Ashley Leach

Ashley Leach

Research Technician

Corbin Meacham, Ph.D.

Corbin Meacham, Ph.D.

American Cancer Society Fellow

Malea Murphy, Ph.D.

Malea Murphy, Ph.D.

Ruth L. Kirschstein NRSA Fellow

Jinsuke Nishino, M.D., Ph.D

Jinsuke Nishino, M.D., Ph.D

Research Scientist

Elena Piskounova, Ph.D

Elena Piskounova, Ph.D

Helen Hay Whitney Fellow

Le Qi

Le Qi

HHMI International Predoctoral Fellow

Vijayashree Ramesh, M.S.

Vijayashree Ramesh, M.S.

Research Scientist

Bo Shen, Ph.D.

Bo Shen, Ph.D.

Postdoctoral Fellow

Alpaslan (Aslan) Tasdogan, M.D., Ph.D.

Alpaslan (Aslan) Tasdogan, M.D., Ph.D.

Else-Kröner Fellow

Stacy Yuan

Stacy Yuan

M.D./Ph.D. Student, Ruth L. Kirschstein NRSA Predoctoral Fellow

Sylvia Zhao, Ph.D.

Sylvia Zhao, Ph.D.

Assistant Professor, Research

Johanna Buchstaller, Ph.D.

Johanna Buchstaller, Ph.D.

Research Laboratory Specialist, University of Michigan

Postdoctoral Fellow (2004-2011)

Sergei Chuikov, Ph.D.

Sergei Chuikov, Ph.D.

Research Investigator, University of Michigan

Postdoctoral Fellow (2005-2011)

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

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

Resident in Pathology, Cornell University

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

Lei Ding, Ph.D.

Lei Ding, Ph.D.

Assistant Professor, Columbia University

Postdoctoral Fellow (2007-2013)

Ugur Esckiocak, Ph.D.

Ugur Esckiocak, Ph.D.

Scientist II, Compass Therapeutics LLC

Postdoctoral Fellow (2011-2016)

Shenghui He, Ph.D.

Shenghui He, Ph.D.

Postdoctoral Fellow, University of North Carolina

Ph.D. Student/ Postdoctoral Fellow (2004-2012)

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

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

M.D. Trainee UT Southwestern Medical Center

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

Toshihide Iwashita, Ph.D.

Toshihide Iwashita, Ph.D.

Professor of Pathology, Hamamatsu University School of Medicine

Postdoctoral Fellow (2000-2005)

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

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

Assistant Professor, University of California at San Francisco

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

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

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

CSO and co-founder, Genomenon, Inc.

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

Injune Kim, Ph.D.

Injune Kim, Ph.D.

Associate Professor, KAIST

Postdoctoral Fellow (2002-2008)

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

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

MD/PhD Resident in Radiation Oncology University of Michigan Health System

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

Boaz Levi, Ph.D.

Boaz Levi, Ph.D.

Manager, In Vitro Human Cell Types Allen Institute for Brain Science

Postdoctoral Fellow (2006-2011)

Qing Li, Ph.D.

Qing Li, Ph.D.

Assistant Professor of Internal Medicine, University of Michigan

Postdoctoral Fellow (2009-2010)

Jeffrey Magee, M.D.

Jeffrey Magee, M.D.

Assistant Professor, Washington University

Pediatrics Fellow (2008-2013)

John Mich, Ph.D.

John Mich, Ph.D.

Scientist II, Allen Institute for Brain Science

Postdoctoral Fellow (2010-2014)

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

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

Assistant Professor, University of California at San Francisco

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

Jack Mosher, Ph.D.

Jack Mosher, Ph.D.

Scientific Affairs Manager, International Society for Stem Cell Research

Postdoctoral Fellow (2001-2006)

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

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

Assistant Professor, Baylor College of Medicine

Postdoctoral Fellow (2006-2011)

Hideyuki Oguro, Ph.D.

Hideyuki Oguro, Ph.D.

Associate Director, Cellular Engineering, Jackson Laboratory for Genomic Medicine

Postdoctoral Fellow (2012 - 2016)

Ricardo Pardal, Ph.D.

Ricardo Pardal, Ph.D.

Associate Professor and Ramon y Cajal Fellow, University of Seville, Spain

Postdoctoral Fellow (2001-2004)

Michel Perron, Ph.D.

Michel Perron, Ph.D.

Research Scientist, Gilead Sciences

Postdoctoral Fellow (2007-2008)

James Peyer, Ph.D.

James Peyer, Ph.D.

Associate, McKinsey & Co.

Ph.D. Student (2010-2015)

Elsa Quintana, Ph.D.

Elsa Quintana, Ph.D.

Senior Scientist, OncoMed Pharmaceuticals

Postdoctoral Fellow (2005-2011)

Michael Savona, Ph.D.

Michael Savona, Ph.D.

Associate Professor of Medicine, Vanderbilt University

Postdoctoral Fellow (2006-2008)

Mark Shackleton, Ph.D.

Mark Shackleton, Ph.D.

Group Leader, Melanoma Research Laboratory Peter MacCallum Cancer Centre

Postdoctoral Fellow (2006-2009)

Issei Shimada, Ph.D.

Issei Shimada, Ph.D.

Postdoctoral Fellow UT Southwestern Medical Center

Postdoctoral Fellow (2011-2015)

Guy Slutsky, Ph.D.

Guy Slutsky, Ph.D.

Head of ALS Unit, Kadimastem

Postdoctoral Fellow (2005-2007)

Merritt Taylor, Ph.D.

Merritt Taylor, Ph.D.

Associate Professor, Grand Valley State University

Postdoctoral Fellow (2001-2007)

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

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

Assistant Professor, MIT and Pathologist, Massachusetts General

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

Rui Yue, Ph.D.

Rui Yue, Ph.D.

Professor, Tongji University in Shanghai

Postdoctoral Fellow (2011-2017)

Bo Zhou, Ph.D.

Bo Zhou, Ph.D.

Assistant Professor, Chinese Academy of Sciences

Postdoctoral Fellow (2011-2016)