Research by Type:
| NFCR Center for Metastasis Research |
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PURPOSE: To identify and target fundamental molecular changes in cancer cells that allow them to metastasize. To translate those basic research findings into strategies that prevent metastasis and treat patients who have metastatic cancer. Focusing on metastasis is key because more than 90% of cancer morbidity (poor quality of life, pain, impaired function of organs) and mortality (deaths) are directly related to metastasis. METHOD: We have assembled a team of investigator whose expertise spans many scientific disciplines. Because metastasis is such a complex, multi-step process, it must be studied from a variety of approaches. Our team will focus on the most fundamental, challenging problems related to metastasis using state-of-the-art methods and interactive collaborations. Research strategies with utilize tools from molecular biology, biochemistry, cell biology, genetics and in vivo biology.
Four fundamental questions are the focus of the proposed studies: (1) Why do some cancer cells metastasize while others do not? (2) Why are some patients more susceptible to metastasis than others? (3) What determines where cancer cells metastasize and their efficiency in (4) What are the signals that tumor cells give to and receive from their surrounding STRATEGIES: Each of these questions will be addressed by collaborative interactions among the members of the NFCR Center for Metastasis Research. We have assembled a team of investigators who are: (1) experts in their respective areas; (2) actively collaborate; (3) will take on high risk- high reward projects; (4) complementary with regard to strategies. KEY FINDINGS: Of the approximately 30 known metastasis suppressing genes, NFCR funds have discovered 6 of them (KISS1, BRMS1, VOUP, TXNIP, MKK4, P38). Together, Center researchers have pioneered the concept that metastasis suppressions (or mimics) could be used to render cancer a chronic disease by keeping metastasis dormant. They continue to develop those strategies in melanoma and breast, prostate and ovarian cancers.
The KISS1 metastasis suppressor gene encodes a polypeptide precursor that can be processed into smaller peptides (kisspeptins) which have roles in cancer metastasis. Center researchers have observed that KISS1 renders cells that have already departed the primary tumor incapable of dividing in other tissues. This property portends well for KISS1 as a therapeutic, since most tumors have been shedding cells for many months to years by the time they are diagnosed. Center researchers are determining the biochemical structure of KISS1 and are also collaboratively focused on understanding the beneficial cross-talk between the kisspeptins and other proteins. Once they know the partners of KISS1 proteins, they can design molecules that can mimic its behavior, leading to the development of novel anti-cancer therapies to prevent metastasis from happening or keep it dormant. If this can be achieved, it could bring the cancer under control and give patients more hope for a cure and a longer life. The three most common cancers - lung, breast, prostate - preferentially metastasize to bone. The morbidity in terms of pain and fractures is enormous, accounting for a $12.6 billion burden in the U.S. alone. While the impact is great, very little is known about the molecular basis of bone metastasis. Drs. Welch, Mastro, and DeWald are studying the mechanism by which breast and prostate tumor cells co-opt the bone microenvironment to destroy it. In breast cancer, Drs. Mastro and Welch have identified a previously unsuspected mechanism by which tumor cells eliminate bone-forming cells. Those findings may explain why bone is not repaired after the tumor cells have been eliminated. The Mastro laboratory has developed a bioreactor system to study bone metastasis. The ability to utilize a well-controlled model opens the possibility of dissecting the molecular events responsible for bone metastasis. As those molecules are identified, they represent targets for therapeutic intervention. INVESTIGATORS Danny R. Welch, Ph.D. Andrea M. Mastro, Ph.D. Daryll B. DeWald, Ph.D. Andra R. Frost, M.D. Scott W. Ballinger, Ph.D. Douglas R. Hurst, Ph.D. Robert Sikes, Ph.D.
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RESEARCH PRIORITIES: The problem of metastasis is not tumor-type dependent. But we will focus the majority of our efforts on breast and prostate cancer and melanoma. Additional studies will involve colon pancreatic and ovarian cancers.
Though the mechanism of action of BRMS1 has been elucidated to a significant extent by the collaborative efforts of the DeWald, Hurst and Welch labs, many of its actions in the nucleus are not yet fully understood. To determine the cadre of proteins that have a role in its mechanism of action, these labs are utilizing biochemical, genomic, and proteomic strategies.
