Professor of Pathology
Senior Scientist - Comprehensive Cancer Center, Center for Metabolic
Bone Disease, Cell Adhesion and Matrix Research Center, Gene Therapy Center

Education:
B.S. in Biological Sciences from the University of California at Irvine;
Ph.D. in Biomedical Sciences from The University of Texas at Houston

Awards/Recognitions:
American Cancer Society Chairman's Award; Sigma Xi Scientific Research
Society;National Cancer Institute, Department of Defense, Susan G. Komen
Breast Cancer Research Foundation, National Foundation for Cancer
Research

Research Interests:
Cancer Biology. The major cause of cancer deaths is the ability of tumor cells to spread to distant organs, a process termed metastasis. Metastasis is the ultimate step in a tumor cells progression toward autonomy from the host. Our goal is to determine the mechanisms by which tumor cells acquire the ability to metastasize. We know that two basic cellular changes are involved: turning on metastasis promoters and turning off metastasis suppressors. Our laboratory has focused on metastasis suppressors and we have cloned four of them KISS1, BRMS1, TXNIP and CRSP3. When cells are engineered to re-express metastasis suppressors, metastasis is suppressed without blocking tumor formation. The current focus of the lab is to understand the mechanisms by which these molecules block metastasis.

Based upon differential growth of tumor cells at orthotopic sites (i.e., mammary fat pad for breast cancers; intradermal for melanoma, etc.) compared to the sites of metastatic colonization, it is clear that metastasis suppressors are altering how tumor cells interact with the surrounding microenvironment. They can do this at multiple cellular levels. BRMS1 appears to be acting at the level of gene transcription (i.e., it is interacting with members of the histone deacetylase complex) to affect signaling via the phosphoinositide pathways and via NFkappaB. CRSP3, TXNIP and KISS1 appear to form a pathway for metastasis suppression in human melanoma; however, downstream effectors are not yet defined.

Keeping the them of tumor cell interactions with the microenvironment, another project in the lab involves determining how breast cancers home to bone (i.e., the most common site of breast cancer spread is to the bones.). We have developed fluorescent models of breast cancer which allows us to detect single cells inside a bone without having to use histology. Using these models, we have recently demonstrated that breast carcinoma cells enter the bone and manipulate normal bone homeostasis by killing osteoblasts. Current studies involve dissecting the mechanisms by which tumor cells induce osteoblast apoptosis.

This lab offers the opportunity to study tumor cell biology from the DNA level through the in vivo level. We use molecular biology, biochemistry, cell culture and animals to address the issues raised above. The laboratory is also highly interactive, team oriented and collaborative. We have ongoing collaborations with other research groups from UAB, Penn State, Mass General, U. Chicago, National Cancer Institute, Cleveland Clinic and Utah State. In short, we believe that these research projects will lead to a more complete understanding of the fundamental mechanisms underlying tumor progression. Moreover, novel, effective treatments will result from this research.

Selected Publications:

Seraj, M.J.*, Samant, R.S.*, Verderame, M.F., Welch, D.R. (2000) Functional evidence for a novel human breast carcinoma metastasis suppressor, BRMS1, encoded at chromosome 11q13 * Contributed equally to this work. Cancer Research 60: 2764-2769.

Shevde-Samant, L.A. and Welch, D.R. (2003) Metastasis suppressor pathways an evolving paradigm. Cancer Letters 198: 1-20.

Meehan, W.J., Samant, R.S., Hopper, J.E., Carrozza, M.J., Shevde, L.S., Workman, J.L., Eckert, K.E., Verderame, M.F. and Welch, D.R. (2004) Interaction of the BRMS1 metastasis suppressor with RBP1 and the mSin3 histone deacetylase complex. Journal of Biological Chemistry 279: 1562-1569.

Harms, J.F., Welch, D.R., Samant, R.S., Shevde, L.A., Miele, M.E., Babu, G.R., Goldberg, S.F., Gilman, V.R., Sosnowski, D.M., Campo, D.A., Gay, C.V., Budgeon, L.R., Mercer, R., Jewell, J., Mastro, A.M., Donahue, H.J., Erin, N., Debies, M.T., Meehan, W.J., Jones, A.L., Mbalaviele, G., Nickols, A., Christensen, N.D., Melly, R., Beck, L.N., Kent, J., Rader, R.K., Kotyk, J.J., Pagel, M.D., Westlin, W.F., Griggs, D.W., (2004) A small molecule antagonist of the _v3 integrin suppresses MDA-MB-435 skeletal metastasis. Clinical and Experimental Metastasis 21: 119-128.

DeWald, D.B., Torabinejad, J. Samant, R.S., Johnston, D., Erin, N., Shope, J.C., Xie, Y., Welch, D.R. (2005) Metastasis suppression by BRMS1 involves reduction of phosphoinositide signaling in MDA-MB-435 breast carcinoma cells. Cancer Research 65: 713-717.

Cicek,M., Fukuyama, R., Welch,D.R., Sizemore, N., Casey, G. (2005) Breast cancer metastasis suppressor (BRMS1) inhibits gene expression by targeting NFB activity. Cancer Research 65: 3586-3595.

Phadke, P.A., Mercer, R.R., Harms, J.F., Jia, Y., Kappes, J.C., Frost, A.R., Jewell, J.L., Bussard, K.M., Nelson, S., Moore, C., Gay, C.V., Mastro, A.M., Welch, D.R. (2006) Kinetics of metastatic breast cancer cell trafficking in bone. Clinical Cancer Research (In press).

Danny R. Welch, Ph.D.

UAB Address: Volker Hall G019B

Phone: (205) 934-2956

Fax: (205) 975-1126

E-mail: danwelch@uab.edu