MORRISON LAB

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.