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.
Stem Cell Self-Renewal
We study the cell-intrinsic and cell-extrinsic mechanisms that regulate stem cell self-renewal and the roles these mechanisms play in tissue homeostasis and cancer. 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 identified a series of mechanisms that distinguish stem cell self-renewal from restricted progenitor proliferation as well as self-renewal mechanisms that are conserved among stem cells in different tissues. We are currently focused on areas of cellular physiology that are understudied in stem cells, including metabolism and proteostasis.
We focus on hematopoietic stem cells (HSCs) and the specialized microenvironments, or niches, in which they reside. We identified the location and cellular composition of the HSC niche in bone marrow, including the Leptin Receptor+ (LepR+) stromal cells that are the major source of factors for HSC maintenance. These LepR+ cells also include the skeletal stem cells that are the main source of new osteoblasts and adipocytes in adult bone marrow. We discovered bone-forming growth factors that are produced by the LepR+ cells and that maintain and repair the adult skeleton. LepR+ cells also give rise to osteogenic and adipogenic progenitors that create niches for hematopoietic stem and progenitor cells. We also identified the HSC niche for extramedullary hematopoiesis in the spleen that is activated when the bone marrow is damaged by chemotherapy, radiation, or cancer. This is an exciting time in niche biology as we now have the possibility of going beyond growth factors to ask what other mechanisms niches use to regulate stem and progenitor cell function. Recent studies from our lab have identified metabolic and mechanical regulation.
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. 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 increase in tumor suppressor expression during aging delays the development of cancer but also impairs stem cell function and tissue regenerative capacity.
Cancer Progression
Cancer cells hijack stem cell self-renewal mechanisms by acquiring mutations that over-activate 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.
We are particularly interested in the mechanisms that regulate melanoma metastasis. We discovered that the survival of melanoma cells during metastasis is limited by oxidative stress. The rare cells that survive metastasis appear to undergo metabolic changes that enhance oxidative stress resistance. By better understanding these mechanisms, we hope to develop pro-oxidant therapies that inhibit cancer progression by exacerbating the oxidative stress experienced by cancer cells.
Cancer cells, including melanoma, often metastasize regionally through lymphatics before metastasizing systemically through the blood. We found that melanoma cells in lymph experience less oxidative stress and form more metastases than melanoma cells in the blood. This is true in both patient-derived melanomas in immunocompromised mice and mouse melanomas in syngeneic, immunocompetent mice. Cells metastasizing through blood, but not lymph, appear to undergo ferroptosis, a form of cell death marked by lipid oxidation. Multiple differences between lymph and blood may contribute to this difference in oxidative stress, including higher levels of oleic acid in lymph. Oleic acid is a monounsaturated fatty acid that can protect cancer cells from ferroptosis by reducing the abundance of oxidizable polyunsaturated fatty acids in phospholipids. We found it is incorporated by melanoma cells in lymph and promotes their survival in the blood. This offers a potential explanation for a clinical behavior that is the basis for much of cancer staging and treatment—the tendency of melanomas and epithelial cancers to metastasize first through lymphatics and then through the blood.
Sean J. Morrison is the director of the Children’s Medical Center Research Institute at UT Southwestern (CRI) 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 its 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 is a member of 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.
Dozens of graduate students and postdoctoral fellows who trained in the Morrison laboratory have gone on to independent academic faculty positions, while others have taken leadership roles in private research institutes or biotechnology companies. In 2020, Dr. Morrison received the Excellence in Postdoctoral Mentoring Award from the UT Southwestern Postdoctoral Association.
2021
Shen, B., A. Tasdogan, J.M. Ubellacker, J. Zhang, E.D. Nosyreva, L. Du, M.M. Murphy, S. Hu, Y. Yi, N. Kara, X. Liu, S. Guela, Y. Jia, V. Ramesh, C. Embree, E.C. Mitchell, Y.C. Zhao, L.A. Ju, H. Zhao, G.M. Crane, Z. Zhao, R. Syeda, and S.J. Morrison. (2021). A mechanosensitive peri-arteriolar niche for osteogenesis and lymphopoiesis. Nature 591:438-444. (PubMed)
2020
Ubellacker, J.M., A. Tasdogan, V. Ramesh, B. Shen, E.C. Mitchell, M.S. Martin, M.L. McCormick, A.B. Durham, D.R. Spitz, Z. Zhao, T.P. Mathews, and S.J. Morrison. (2020). Lymph protects metastasizing melanoma cells from ferroptosis. Nature 585:113-118. (PubMed)
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)
2019
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)
2018
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)
2017
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)
2016
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)
2015
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)
2014
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)
Signer, R.A.J., Magee, J.A., Salic, A., and Morrison, S.J. (2014). Haematopoietic stem cells require a highly regulate protein synthesis rate. Nature 509, 49-54. (PubMed)
Nakada, D., Oguro, H., Levi, B., Ryan, N., Kitano, A., Saitoh, Y., Takeichi, M., Wendt, G., and Morrison, S.J. (2014). Oestrogen increases haematopoietic stem-cell self-renewal in females and during pregnancy. Nature 505, 555-558. (PubMed)
Morrison, S.J., and Scadden, D.T. (2014). The bone marrow niche for haematopoietic stem cells. Nature 505, 327-334. (PubMed)
2013
Li, Q., Bohin, N., Wen, T., Ng, V., Magee, J., Chen, S.C., Shannon, K., and Morrison, S.J. (2013). Oncogenic Nras has bimodal effects on stem cells that sustainably increase competitiveness. Nature 504, 143-147. (PubMed)
Meacham, C.E., and Morrison, S.J. (2013). Tumor heterogeneity and cancer cell plasticity. Nature 501, 328-337. (PubMed)
Ding, L., and Morrison, S.J. (2013). Haematopoietic stem cells and early lymphoid progenitors occupy distinct bone marrow niches. Nature 495, 231-235. (PubMed)
2012
Ding, L., Saunders, T.L., Enikolopov, G., and Morrison, S.J. (2012). Endothelial and perivascular cells maintain hematopoietic stem cells. Nature 481, 457-462. (PubMed)
2010
Nakada, D., Saunders, T.L., and Morrison, S.J. (2010). Lkb1 regulates cell cycle and energy metabolism in haematopoietic stem cells. Nature 468, 653-658. (PubMed)
Chuikov, S., Levi, B.P., Smith, M.L., and Morrison, S.J. (2010). Prdm16 promotes stem cell maintenance in multiple tissues, partly by regulating oxidative stress. Nat Cell Biol 12, 999-1006. (PubMed)
2009
Shackleton, M., Quintana, E., Fearon, E., and Morrison, S.J. (2009). Heterogeneity in cancer: cancer stem cells versus clonal evolution. Cell 138, 822-829. (PubMed)
2008
Quintana, E., Shackleton, M., Sabel, M., Fullen, D., Johnson, T.M., and Morrison, S.J. (2008). Efficient tumor formation by single human melanoma cells. Nature 456, 593-598. (PubMed)
Nishino, J., Kim, I., Chada, K., and Morrison, S.J. (2008). Hmga2 promotes neural stem cell self-renewal in young, but not old, mice by reducing p16 Ink4a and p19Arf expression. Cell 135, 227-239. (PubMed)
Morrison, S.J., and Spradling, A. (2008). Stem Cells and Niches: Mechanisms that promote stem cell maintenance throughout life. Cell 132, 598-611. (PubMed)
2007
Kiel, M.J., He, S., Ashkenazi, R., Gentry, S.N., Teta, M., Kushner, J.A., Jackson, T.L., and Morrison, S.J. (2007). Hematopoietic stem cells do not asymmetrically segregate chromosomes or retain bromodeoxyuridine. Nature 449, 238-242. (PubMed)
Kim, I., Saunders, T.L., and Morrison, S.J. (2007). Sox17 dependence distinguishes the transcriptional regulation of fetal from adult hematopoietic stem cells. Cell 130, 470-483. (PubMed)
2006
Molofsky, A.V., Slutsky, S.G., Joseph, N.M., He, S., Pardal, R., Krishnamurthy, J., Sharpless, N., and Morrison, S.J. (2006). Increasing p16 Ink4a expression decreases forebrain progenitor function and neurogenesis during ageing. Nature 443, 448-452. (PubMed)
Morrison, S.J., and Kimble, J. (2006). Asymmetric and symmetric stem-cell divisions in development and cancer. Nature 441, 1068-1074. (PubMed)
Yilmaz, O.H., Valdez, R., Theisen, B., Guo, W., Ferguson, D., Wu, H., and Morrison, S.J. (2006). Pten dependence distinguishes haematopoietic stem cells from leukaemia-initiating cells. Nature 441, 475-482. (PubMed)
2005
Kiel, M.J., Yilmaz, O.H., Iwashita, T., Terhorst, C., and Morrison, S.J. (2005). SLAM family receptors distinguish hematopoietic stem and progenitor cells and reveal endothelial niches for stem cells. Cell 121, 1109-1121. (PubMed)
2003
Molofsky, A.V., Pardal, R., Iwashita, T., Park, I.K., Clarke, M.F., and Morrison, S.J. (2003). Bmi-1 dependence distinguishes neural stem cell self-renewal from progenitor proliferation. Nature 425, 962-967. (PubMed)
DALLAS – Oct. 21, 2022 – New research from Children’s Medical Center Research Institute at UT Southwestern (CRI) found that different skeletal…
Skokie, IL— The International Society for Stem Cell Research (ISSCR) is honoring Sean J. Morrison, Ph.D., Director of Children’s Medical…
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UM Cellular and Molecular Biology Program (2004-2013)
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UM Medical Scientist Training Program (2001-2005)
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UTSW Genetics and Development Graduate Program (2010-2015)
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UTSW Cancer Biology (2014 -2021)
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