Univ. of Alabama/ Penn State Univ./Univ. of Chicago

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.

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.

• To define the genetic changes responsible for cancer metastasis
• To identify the molecular basis for metastasis to bone
• To identify models that mimic the pathology of cancer metastasis
• To define the cross-talk between tumor cells and their microenvironment.

STRATEGIES: 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 20 known metastasis suppressing genes, Drs. Welch and Rinker-Schaeffer have discovered 6 of them (KISS1, BRMS1, VOUP, TXNIP, MKK4, P38). Together they 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 breast, prostate and ovarian cancers.

Even though the metastasis suppressors are defined functionally, the mechanisms by which they mediate blockage are not known. Drs. Welch and DeWald are utilizing genomic and proteomic strategies to study the downstream changes in cells.

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 US alone. While the impact is great, very little is known about the molecular basis of bone metastasis. Drs. Welch, Mastro and Cooper 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. They are working on gene- and mesenchymal stem cell therapies to overcome the loss of bone.

Tumor cells do not exist in isolation. They are in constant communication with surrounding cells, both sending and receiving information. In addition to the bone cell communication, Drs. Frost and Welch are studying how signals are received from the structural cells of the breast (fibroblasts) to control development of breast cancer and metastasis.

Researchers at the NFCR Center

INITIAL INVESTIGATORS:

Danny R. Welch, Ph.D.
Leonard H. Robinson Professor of Pathology
Senior Member - UAB Comprehensive Cancer Center
University of Alabama – Birmingham

Andrea M. Mastro, Ph.D.
Professor of Biochemistry and Molecular Biology
Pennsylvania State University

Carrie W. Rinker-Schaeffer, Ph.D.
Associate Professor of Urology
University of Chicago

Daryll B. DeWald, Ph.D.
Professor and of Biology
Utah State University

Andra R. Frost, M.D.
Professor of Pathology
University of Alabama – Birmingham

Carlton R. Cooper, Ph..D.
Assistant Professor of Biology
University of Delaware