Julio A. Aguirre-Ghiso, Ph.D.
Institutional Affiliation
Associate Professor
Director of Head and Neck Cancer Basic Research
Tisch Cancer Institute at Mount Sinai
Mount Sinai School of Medicine
http://www.mountsinai.org/Find%20A%20Faculty/profile.do?id=0000072500004566813101&officeDrawer=biz
Education
University of Buenos Aires, M.Sc.
University of Buenos Aires, Ph.D.
Postdoctoral Work
Mount Sinai School of Medicine
Research
Functional Genomics Approach to Discover Cancer Dormancy Regulating Genes
Impact
Over the years we have set out to understand why, after treatment of the primary lesion, many patients still carry residual cancer that can remain silent or dormant sometimes for decades. Because these dormant tumor cells are invariably the source of local or distant recurrences we believe that understanding the biology of disseminated tumor cells, whether actively proliferating or dormant, is essential to prevent the occurrence of metastasis. Three major goals can be achieved: 1- therapies to induce and/or maintain dormancy, 2- therapies to eradicate disseminated tumor cells while dormant and 3- cellular markers or biomarkers that will inform on the existence of dormant disease in a patient.
Summary of Research
In head and neck cancer as well as other aggressive cancers survival rates have improved only marginally in the last 30 years. Surgery and therapy allow clearing the initially diagnosed tumor. However, invariably more than half of the patients will develop recurrent cancer lesions in the area close to where the original tumor was found or in separate organs like the lung (also called metastasis). In order to prevent the appearance of these secondary tumors it is crucial to understand the behavior of cancer cells left behind after surgery and therapy. In many cases cancer recurrences can appear at a rate of 5% per year after treatment and can be asymptomatic for as long as 10 years. This has suggested that residual cancer cells may remain in a dormant-sleeping state. Current evidence in the stem cell field suggests that normal stem cells in human tissues reside in a dormant state and are only called into action when needed, for example for skin wound healing. It has been proposed, but not proven, that cancer stem cells in general may adopt this dormant state by recapitulating some of the functions they undertook before becoming cancerous. We have now discovered that cancer stem cells from head and neck tumors can also adopt a dormant-sleeping state depending on the signals that surround them. We thought that if this is happening in patients our findings might be an important starting point to further understand how head and neck cancer stem cells become dormant. If we can know how they become dormant and survive during this phase, we could attack them while dormant and eradicate them before they start growing again.
We have studied a head and neck carcinoma tumor that has the ability to shift between growing and quiescent states depending on the environment that surrounds the tumor cells. We hypothesized that the ability to transit between these states is similar to what normal stem cells do when they are quiescent or recruited by specific signals. In the last two years our work has explored whether tumor stem or initiating cells recently identified in head and neck tumors can also be reprogrammed into a dormant state. Our results reveal that indeed head and neck cancer initiating or stem cells can be reprogrammed into a dormant-sleeping state by conditions that impose “stress-damage” on the cells. We think this situation may be recapitulated when tumor stem cells are exposed to strenuous conditions during radiation- or chemo-therapy. We have also discovered that the tumor “stem” cells are more a functional consequence of the expression of determined genes in any tumor cells rather than a cell entity that persists over time indivisible of its stem cell properties. This model has also allowed us to gain important knowledge on the genes that regulate quiescence and survival of dormant tumor cells.
The knowledge on cancer stem cells in head and neck cancer is scarce. These studies might have a major impact in how patients in remission are followed and treated. In the long term our studies may lead to strategies to identify and attack residual dormant tumor stem cells, favoring the eradication of the disease before it resumes growth.
|
