The Hartwell Foundation

 

2012 Biomedical Research Collaboration Award

Memphis, TN, November 23, 2012 -- The Hartwell Foundation officially announced a Biomedical Research Collaboration Award to David C. Lyden, MD, Ph.D., 2008 Hartwell Investigator and Associate Professor, Departments of Pediatrics, and Cell and Developmental Biology, Weill Medical College of Cornell University and Jack D. Bui, MD, Ph.D., 2010 Hartwell Investigator and Assistant Professor, Department of Pathology, University of California, San Diego, for their proposal “Overcoming Cancer Metastasis: Exosomes as Metastatic and Anti-Metastatic Factors”. The researchers will receive $635,028 in combined direct cost over three years. Both Cornell and UC San Diego are named to the Foundation’s 2012 Top Ten Centers of Biomedical Research.

Approximately 20% of all children diagnosed with cancer die, most often due to metastasis. For two childhood cancers the survival rate is especially low; a mere 51% of children with medulloblastoma survive, and for certain sarcomas, the rate of survival nationwide is a dismal 30-36%. Moreover, for survivors, the side effects of conventional chemotherapy and radiation can also have devastating consequences on normal development. For example, many children with medulloblastoma suffer from deafness and lowered IQ after radiation therapy. Clearly, new approaches to treating these childhood cancers are desperately needed.

David Lyden is a pediatric neuro-oncologist and clinical research scientist who is a specialist in brain tumor biology. As a 2008 Hartwell Investigator he has made several fundamental discoveries about the role of bone marrow-derived stem and progenitor cells in tumor formation of new blood vessels and in tumor metastasis. The Lyden lab has described how medulloblastoma brain tumors that rarely metastasize and seem to spread by local extension, actually release small membranous vesicles (exosomes) containing protein, DNA, and other factors. Remarkably, the released exosomes appear to ‘educate’ bone marrow cells to inhibit metastasis of high grade tumors. For example, bone marrow obtained from mice with tumors that are poorly metastatic can inhibit metastasis of highly metastatic tumors. Conversely, bone marrow that has been exposed to exosomes from highly metastatic tumors can facilitate metastasis of poorly metastatic tumors. Lyden has identified c-MET as a critical protein present in the exosomes, which when targeted to bone marrow can induce metastasis-promoting activity, making this the first demonstration of the transfer of oncogenic information from the cancer cells to other cells in the tumor microenvironment.

Jack Bui is a board-certified clinical pathologist and research scientist. He serves as Associate Director of the Immunogenetics and Transplantation Laboratory in the Department of Pathology and the Director of the UCSD Diagnostic Immunology and Immunogenetics Laboratory at the Center for Advanced Laboratory Medicine. As a 2010 Hartwell Investigator, his research focuses on mouse models of tumor formation; how the innate immune system recognizes developing tumor cells and how immune cells can be manipulated to control tumor formation. The Bui lab has described how certain sarcoma cancer tumor cells release a protein cytokine called IL-17D that will cause bone marrow cells to reject high grade tumors.

Lyden and Bui will combine their areas of expertise to combat childhood cancer. Together, they will dissect the molecular make-up of exosomes released by medulloblastomas and sarcomas. They seek to define the mechanism by which exosomes educate bone marrow derived cells to promote or inhibit metastasis and to what extent IL-17D anti-tumor activity can antagonize the metastasis-promoting activity of c-MET present in exosomes. By understanding the “exosome signature” from metastatic and non-metastatic medulloblastomas and sarcomas they plan to identify candidate therapeutic targets for these childhood cancers.

Exosomes are small membranous vesicles on the order of 40-100nM diameter derived from membrane-bound intracellular compartments inside of cells. Once formed, the intracellular vesicles are secreted into the extracellular environment as exosomes, which may then circulate in the lymph and blood. The composition of formed exosomes will vary depending upon their origin, which is important because they are known to have the capability to fuse with other cells in a process that may transfer genetic material, proteins and other mediators as a unique means of cell-cell communication. While the precise physiologic function of exosomes remains unknown, they are now recognized as playing an important role in the promotion of tumor growth and metastasis.

Metastasis is a multistep process that requires tumor cells to acquire certain properties that will allow them to escape from the primary tumor site. Host cells within the tumor microenvironment play a key role in influencing metastatic behavior, and many are derived from the bone marrow. Cell-to-cell communication has been thought to occur principally through the release of soluble cytokines (chemicals that may stimulate or inhibit the function of surrounding cells), but it is now known that exosome-based transfer of information makes an important contribution, as well.

Fostering collaborations between investigators of complementary scientific strengths is one of the objectives of The Hartwell Foundation Mission to fund innovative, early-stage applied biomedical research with the potential to benefit children.

 

2008 Hartwell Investigator David Lyden, MD, Ph.D., Cornell University

2010 Hartwell Investigator Jack Bui, MD, Ph.D., University of California, San Diego

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