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Background

Under normal circumstances, the regular turnover of cells in developed tissues is offset by the work of adult stem cells. The discovery that solid tumors contain a distinct subpopulation of cells that have stem cell characteristics led to the stem cell concept of cancer, which proposes that a subpopulation of self-renewing tumor cells, also termed cancer stem cells, is responsible for tumorigenesis and metastasis. The cancer stem cell hypothesis departs from traditional models of oncogenesis, which postulate that genetic alterations may transform any mature, differentiated cell and that, therefore, all cancer cells are equally capable of tumor initiation.

Cancer stem cells are not only capable of self-renewal and differentiation, but may also confer virulence via immune system evasion and multidrug resistance, explaining two of the most challenging aspects of cancer: resistance and recurrence. Often, radiation or chemotherapy shrinks tumors, sometimes to the point where they are no longer detected, yet the disease returns. Cancer stem cells may be especially resistant to eradication for two reasons. First, chemotherapy selectively targets rapidly dividing cells, whereas cancer stem cells tend to divide slowly. Second, cancer stem cells, like normal stem cells, congregate in niches—specific physical areas within a tissue that may afford protection from damage. Therapeutic targeting of cancer stem cells and an understanding of their virulence mechanisms holds promise for the development of more effective therapies and the eventual eradication of cancer.

However, fundamental questions remain unanswered, and the barriers in bringing recent advances to the clinic are substantial. In many forms of leukemia and in all solid tumors, for example, it is not known if the target of malignant transformation is a native stem cell or progeny differentiated cell. Also, while it is known that cancer stem cells resist conventional chemotherapy, it is unclear whether such resistance is the principal basis of treatment failure. Development of new stem cell-directed therapies requires a more detailed understanding of the molecular and genetic properties of cancer stem cells and their normal tissue counterparts.

Focus

The overarching goal of the HSCI Cancer program is to identify critical genes and pathways that sufficiently distinguish cancer from normal stem cells, and hence serve as candidate targets for therapy. This knowledge is essential to developing novel treatments that can target malignant stem cells while sparing their normal counterparts. One collaborative project focuses on defining how tumor-initiating cells relate to their normal counterparts, and the traits shared among cancer stem cells from different tissue origins (brain, intestine and blood in particular). The project also aims to establish anatomic and molecular definitions of the normal somatic stem cell microenvironment (niche) and characteristics of the cancer niche, therefore identifying critical pathways in interactions of stem cells with the tumor microenvironment.

Sample Projects

An ongoing project tests the hypothesis that lung tumor propagating cells are distinguishable from normal lung stem cells at the molecular level. In particular, the project aims to identify the cells-of-origin of a specific type of lung tumor and key pathways that operate in lung tumor-propagating cells, prospectively identifying metastatic lung cancer cells.

Pancreatic ductal adenocarcinoma (PDAC) is one of the most lethal human malignancies. One of our projects is looking at the role of an oncogene (K-RAS) in the self-renewal and maintenance of cancer stem cells in pancreatic tumors.

Normal and malignant stem cells are by definition rare populations, and the study of both in vivo has been hampered by an inability to track individual cells precisely and dynamically. A fourth project of the Cancer Program aims to address the need to develop experimental systems that allow directed implantation of single cells into spatially defined niches, and to follow the fate of such cells in vivo.

Pilot Grants

Extending the Program

The Cancer Program is more than just the projects it funds.  It reaches beyond its specific projects to collaborate with other programs, such as with the Blood Program on leukemia.  It leverages the HSCI Seed Grant Program that supports early stage work, e.g., eight seed grants focusing on cancer have been funded to date.  It ensures that the community stays at the cutting edge of thinking in the field by having leading experts from around the world come to campus as part of HSCI’s Distinguished Speakers Forum and other events.  As a result, it builds an active community of experts who share their knowledge as they tackle the critical questions posed by a complex and challenging disease.