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
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 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.
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)
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Lab News

Life at the Institute: Le Qi
December 8, 2020
Sean Morrison Presented with Excellence in Postdoctoral Mentoring Award
September 23, 2020UT Southwestern’s Postdoctoral Association (PDA) has selected Dr. Sean Morrison, director of Children’s Medical Center Research Institute at UT Southwestern…
Lab Members

Liming Du, Ph.D.

Claire Embree

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

Michalis Agathocleous, Ph.D.
Postdoctoral Fellow (2012-2017)

Kati Ahlqvist, Ph.D.
Human Frontier Science Program Fellow (2016-2018)

Johanna Buchstaller, Ph.D.
Postdoctoral Fellow (2004-2011)

Sergei Chuikov, Ph.D.
Postdoctoral Fellow (2005-2011)

Genevieve Crane, M.D., Ph.D.
M.D./Ph.D. Student (2000-2004)

Lei Ding, Ph.D.
Postdoctoral Fellow (2007-2013)

Ugur Esckiocak, Ph.D.
Postdoctoral Fellow (2011-2016)

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

Chris Inra, M.D., Ph.D.
M.D./Ph.D. Student (2011-2015)

Toshihide Iwashita, Ph.D.
Postdoctoral Fellow (2000-2005)

Nancy Joseph, M.D., Ph.D.
M.D./Ph.D. Student (2001-2006)

Mark Kiel, M.D., Ph.D.
M.D./Ph.D. Student (2004-2008)

Injune Kim, Ph.D.
Postdoctoral Fellow (2002-2008)

Jae Lee, M.D., Ph.D.
M.D./Ph.D. Student (2006-2010)

Boaz Levi, Ph.D.
Postdoctoral Fellow (2006-2011)

Qing Li, Ph.D.
Postdoctoral Fellow (2009-2010)

Jeffrey Magee, M.D.
Pediatrics Fellow (2008-2013)

John Mich, Ph.D.
Postdoctoral Fellow (2010-2014)

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

Jack Mosher, Ph.D.
Postdoctoral Fellow (2001-2006)

Malea Murphy, Ph.D.
Postdoctoral Fellow (2012-2019)

Daisuke Nakada, M.D., Ph.D.
Postdoctoral Fellow (2006-2011)

Hideyuki Oguro, Ph.D.
Postdoctoral Fellow (2012 - 2016)

Ricardo Pardal, Ph.D.
Postdoctoral Fellow (2001-2004)

Michel Perron, Ph.D.
Postdoctoral Fellow (2007-2008)

James Peyer, Ph.D.
Ph.D. Student (2010-2015)

Elena Piskounova, Ph.D
Helen Hay Whitney Fellow

Elsa Quintana, Ph.D.
Postdoctoral Fellow (2005-2011)

Michael Savona, Ph.D.
Postdoctoral Fellow (2006-2008)

Mark Shackleton, Ph.D.
Postdoctoral Fellow (2006-2009)

Issei Shimada, Ph.D.
Postdoctoral Fellow (2011-2015)

Robert Signer, Ph.D.
Postdoctoral Fellow (2009 - 2015)

Guy Slutsky, Ph.D.
Postdoctoral Fellow (2005-2007)

Merritt Taylor, Ph.D.
Postdoctoral Fellow (2001-2007)

Omer Yilmaz, M.D., Ph.D.
M.D./Ph.D. Student (2001-2006)

Stacy Yuan, Ph.D.
M.D./Ph.D. Student (2014-2019)

Rui Yue, Ph.D.
Postdoctoral Fellow (2011-2017)

Bo Zhou, Ph.D.
Postdoctoral Fellow (2011-2016)