Sean Morrison Laboratory, the Hamon Laboratory for Stem Cell and Cancer Biology
We are investigating the mechanisms that regulate stem cell function in the nervous and hematopoietic systems. We have focused on the mechanisms that regulate stem cell self-renewal and stem cell aging because these processes encompass fundamental questions in cell and developmental biology. Since cancer cells hijack these self-renewal mechanisms, we also evaluate the role these mechanisms play
Stem Cell Self-Renewal
The maintenance of many adult tissues depends upon 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 found 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.
Proto-oncogenes tend to promote tissue regeneration by promoting stem cell function but must be balanced with tumor-suppressor activity to avoid neoplastic proliferation. Gate keeping tumor suppressors tend to inhibit regeneration by negatively regulating cell division, but also prevent cancer. Care-taking tumor suppressors tend to promote stem cell maintenance and tissue regeneration by protecting cellular and genomic integrity.
We take forward and reverse genetic approaches to identify new genes that regulate stem cell self-renewal. Each time we identify a self-renewal regulator we learn something new about how self-renewal occurs by examining the downstream mechanisms by which the gene product functions. For example, we have identified two proto-oncogenic chromatin regulators, Bmi-1 and Hmga2, that promote stem cell self-renewal by negatively regulating the expression of the Ink4a and Arf tumor suppressors.
These studies demonstrated that the networks of proto-oncogenes and tumor suppressors that regulate stem cell self-renewal change throughout life in response to changing tissue demands and the changing risk of cancer. Imbalances within these networks cause cancer or premature declines in stem cell activity that resemble degenerative disease or premature aging.
Stem Cell Aging
Until recently there has been little insight into why aging tissues exhibit reduced regenerative capacity. Aging is also associated with increased cancer incidence in tissues that contain stem cells. These observations suggest a link between aging and stem cell function because stem cells drive the regeneration of most tissues, and because many cancers arise as a consequence of mutations that accumulate in stem cells during 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 discovered that the networks of proto-oncogenes and tumor suppressors that regulate stem cell self-renewal and cancer cell proliferation (see above) also regulate stem cell aging. For example, Hmga2 expression declines and Ink4a expression increases with age, reducing stem cell frequency and function. By deleting Ink4a from mice, we partially rescued the decline in stem cell function with age and enhanced the regenerative capacity of aging tissues.
Indeed, we have identified an entire pathway of genes upstream of Ink4a that regulates changes in stem cell function during aging. In this way, networks of proto-oncogenes and tumor suppressors 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. We use forward and reverse genetics to identify the molecular mechanisms that allow these networks to strike this dynamic balance.
Stem Cell Self-Renewal and Cancer Cell Proliferation
Cancer cells often hijack stem cell self-renewal mechanisms by acquiring mutations that over-activate these pathways. Even when this occurs, we have discovered it is possible to identify mechanistic differences between normal stem cell self-renewal and cancer cell proliferation. For example, deletion of the PTEN tumor suppressor has different effects on the self-renewal of normal hematopoietic stem cells and the proliferation of leukemia cells. Conditional deletion of PTEN in adult hematopoietic cells rapidly leads to leukemogenesis. In contrast, PTEN deletion cell autonomously leads to the depletion of hematopoietic stem cells.
These effects of PTEN deficiency can be inhibited by the drug rapamycin, which inhibits mTOR, a kinase that is activated after PTEN deletion. Our studies suggest that the degree of mTOR activation is a key determinant of stem cell maintenance. Rapamycin treatment of PTEN-deficient mice not only eliminates leukemia cells but also restores normal hematopoietic stem cell function. Mechanistic differences between normal stem cells and cancer cells can thus be targeted to eliminate cancer cells without damaging normal stem cells. Identification of additional such drugs will reduce the toxicity of chemotherapy and facilitate normal tissue regeneration after cancer treatment.
Cell 18: 510). Click image to enlarge.
Not all cancer cells have the same capacity to proliferate. In some cancers most cancer cells appear to have a limited ability to proliferate, while in the same tumors, minority populations of “cancer stem cells” retain the capacity to proliferate indefinitely. Data from our lab and others indicate that many acute and chronic myeloid leukemias follow a cancer stem cell model. In both cases, leukemogenic cells are rare, phenotypically distinct from the vast majority of other leukemia cells, and robustly hierarchically organized.
However, it is not clear how generalizable the cancer stem cell model is. In other human and mouse cancers we have studied, including melanoma, tumorigenic capacity is a common attribute of many cancer cells and we have been unable to find any clear evidence of hierarchical organization. Our impression is that the growth and progression of many cancers are driven by minority populations of cancer stem cells.
It will be critical to determine which cancers follow the stem cell model and which do not to devise appropriate therapeutic strategies.