Danny R. Welch, PhD
Adjunct faculty of Department of Molecular & Integrative Physiology
Ph.D.: The University of Texas - Houston
Postdoctoral: The University of Texas - MD Anderson Cancer Center
More than 90% of the morbidity and mortality associated with cancer is directly or indirectly due to metastasis - the spread of tumor cells to distant organs where they establish secondary colonies. Metastasis is the ultimate step in a tumor cell's progression toward autonomy from the host. Our goal is to determine the mechanisms by which tumor cells acquire the ability to metastasize.
Two genetic changes have been discovered: turning on "metastasis promoters" and turning off "metastasis suppressors". Our laboratory has focused on metastasis suppressors and we have cloned six of them KISS1, BRMS1, TXNIP, CRSP3 and two microRNA. When metastatic cancer 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 alter how tumor cells interact with the surrounding microenvironment. They can do this at multiple cellular levels. BRMS1 (breast cancer metastasis suppressor 1) acts at the level of gene transcription by contributing to chromatin structure. BRMS1 interacts with members of several histone deacetylase complexes to affect cellular communication via the phosphoinositide, Akt and NfkappaB signaling pathways. BRMS1 also selectively regulates expression of several microRNA. Similarly, CRSP3 and TXNIP participate in transcriptional regulation of metastasis-associated genes.
KISS1 was discovered in melanomas, but has subsequently been implicated in breast cancer. The mechanism of by which KISS1 suppresses metastasis is unusual - cells expressing KISS1 complete all of the early steps of the metastatic process, but fail to colonize tissues once they have seeded them. This finding opens a new avenue for anti-metastatic therapies, a new and exciting direction of research in our lab. Current projects include: understanding how KISS1 causes dormancy in a paracrine manner; defining the processing of nascent KISS1 protein into active polypeptides (termed kisspeptins); characterizing how KISS1 reverts cancer cell metabolism to a more normal state (i.e., reverses the so-called Warburg Effect); and disco very of KISS1/kisspeptin mimetics.
Another project, in collaboration with Scott Ballinger at UAB, has developed a new mouse and cell model to study nuclear-mitochondrial interactions, termed MNX (mitochondria-nuclear exchange) mice. Using this model, we have collected data showing that mitochondrial haplotypes exert 'dominant' effects on tumorigenicity and metastasis, among other diseases.
The common thread connecting metastasis suppressors is that they regulate tumor cell interactions with the various microenvironments in which tumor cells find themselves. Although the lab has focused on breast cancers, we have studies on-going in melanoma, pancreatic cancer, and ovarian cancer.
This lab offers the opportunity for self-motivated and self-reliant scientists to study tumor cell biology from the DNA level through the in vivo level. We use molecular biology, genetics, biochemistry, cell culture and animals to address the issues raised above. The laboratory environment is highly interactive, team oriented, translationally minded and collaborative. We have ongoing collaborations with other research groups from UAB, U. Chicago, Penn State, National Cancer Institute, UCLA, and Washington State University as well as other institutes around the world. 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.
Carolyn Vivian, MS
(Bold = trainee)
- Welch, D.R. & Tomasovic, S.P. Implications of tumor progression on clinical oncology. Clinical and Experimental Metastasis (1985) 3:151-188. † PMID: 3902300
- Welch, D.R., Lobl, T.J., Seftor, E.A., Wack, P.J., Aeed, P.A., Yohem, K.H., Seftor, R.E.B. & Hendrix, M.J.C. Use of the membrane invasion culture system (MICS) as a screen for anti-invasive agents. International Journal of Cancer (1989) 43:449-457. † PMID: 2925275
- Welch, D.R., Schissel, D.J., Howrey, R.P. & Aeed, P.A. Tumor-elicited polymorphonuclear cells, in contrast to 'normal' circulating polymorphonuclear cells, stimulate invasive and metastatic potentials of rat mammary adenocarcinoma cells. Proceedings of the National Academy of Science (USA) (1989) 86:5859-5863. † PMID: 2762301
- Welch, D.R., Chen, P., M.E. Miele., Bower, J.M., McGary, C.T., Stanbridge, E.J. & Weissman, B.E. Microcell-mediated transfer of chromosome 6 into metastatic human C8161 melanoma cells suppresses metastasis, but not inhibit tumorigenicity. Oncogene (1994) 9: 255-262. † PMID: 8302587
- Phillips, K.*, Welch, D.R.*, Miele, M.E., Lee, J.-H., Wei., L.L., and Weissman, B.E. Suppression of MDA-MB-435 breast carcinoma cell metastasis following the introduction of human chromosome 11. Cancer Research (1996) 56: 1222-1227. * Contributed equally to this work. † PMID: 8640802
- Lee, J.-H., Miele, M.E., Hicks, D.J., Phillips, K.K., Trent, J.M., Weissman, B.E. and Welch, D.R. (1996) KiSS-1, A novel malignant melanoma metastasis-suppressor genes identified in chromosome 6-malignant melanoma microcell hybrids. Journal of the National Cancer Institute 88: 1731-1737. † PMID: 8944003
- Welch, D.R. Technical considerations when studying cancer metastasis in vivo. (1997) Clinical and Experimental Metastasis 15(3): 272-306. † PMID: 9174129
- Lee, J.-H. and Welch, D.R. (1997) Identification of highly expressed genes in metastasis-suppressed chromosome 6/human malignant melanoma hybrid cells using subtractive hybridization and differential display. International Journal of Cancer 71: 1035-1044. † PMID: 9185708
- Dennis, J.U., Dean, N.M., Bennett, C.F., Griffith, J.W., Lang, C.M. and Welch, D.R. (1998) Human melanoma metastasis is inhibited following ex vivo treatment with an antisense oligonucleotide to protein kinase C-α. Cancer Letters 128: 65-70. † PMID: 9652794
- Goldberg, S.F.*, Harms, J.F.*, Quon, K. and Welch, D.R. (2000) Metastasis-suppressed C8161 melanoma cells arrest in lung but fail to proliferate. Clinical and Experimental Metastasis 17: 601-607. * Contributed equally to this work. (although dated 1999, actually submitted and published 2000) † PMID: 10845559
- 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. † PMID: 10850410
- Harms J.F., Budgeon L.R., Christensen N.D., Welch D.R. (2002) Maintaining GFP tissue fluorescence through bone decalcification and long-term storage. Biotechniques 33(6): 1197-1200. † PMID: 12503297
- Goldberg, S.F., Miele, M.E., Hatta, N., Takata, M., Paquette-Straub, C., Freedman, L.P. and Welch, D.R. (2003) Melanoma metastasis suppression by chromosome 6: Evidence for a pathway regulated by DRIP130/CRSP3 and VDUP1. Cancer Research 63: 432-440. † PMID: 12543799
- Harms, J.F. and Welch, D.R. (2003) MDA-MB-435 human breast carcinoma metastasis to bone. Clinical and Experimental Metastasis 20: 327-334. † PMID: 12856720
- 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. † PMID: 14581478
- 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 αvβ3 integrin suppresses MDA-MB-435 skeletal metastasis. Clinical and Experimental Metastasis 21: 119-128. † PMID: 15168729
- 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 - Priority Report 65: 713-717. † PMID: 15705865
- Richert,M.M., Phadke,P.A., Matters,G.L., DiGirolamo,D.J., Washington,S., Demers,L.M., Bond,J.S., Manni,A., and Welch,D.R. (2005) Metastasis of hormone-independent breast cancer to lung and bone is decreased by α-difluoromethylornithine treatment. Breast Cancer Research 7: R819-R827. (doi:10.1186/bcr1292 † PMID: 16168128 PMCID: PMC1242150)
- 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 12: 1431-1440. † PMID: 16533765 PMCID: PMC1523260
- Hurst, D.R., Mehta, A., Moore, B.P., Phadke, P.A., Meehan, W.J., Accavitti, M.A., Shevde, L.A., Hopper, J.E., Xie, Y., Welch, D.R., and Samant, R.S. (2006) Breast cancer metastasis suppressor 1 (BRMS1) is stabilized by the Hsp90 chaperone. Biochemical and Biophysical Research Communications 348: 1429-1435. (doi:10.1016/j.bbrc.2006.08.005. † PMID: 16919237 PMCID: PMC1557677)
- Nash, K.T., Phadke, P.A., Navenot,J -M., Hurst, D.R., Accavitti-Loper, M.A., Sztul, E., Vaidya, K.S., Frost, A.R., Kappes, J.C., Peiper, S.C. and Welch, D.R. (2007) KISS1 metastasis suppressor secretion is required for multiple organ metastasis suppression and for the maintenance of disseminated cells in a dormant state. Journal of the National Cancer Institute 99: 309-321. (doi:10.1093/jnci/djk053) PMID: 17312308 PMCID: PMC1820615 †
- Eccles, S.A. and Welch, D.R. (2007) Metastasis: recent discoveries and novel therapeutic strategies. The Lancet 369: 1742-1757. (doi:10.1016/S0140-6736(07)60781-8) PMID: 17512859 PMC2214903 †
- Phadke, P.A., Vaidya, K.S., Nash, K.T., Hurst, D.R. and Welch, D.R. (2008) BRMS1 suppresses breast cancer experimental metastasis to multiple organs by inhibiting several steps of the metastatic process. American Journal of Pathology 172: 809-817 (doi: 10.2353/ajpath.2008.070772 02/14/2008) PMID: 18276787 PMC2258257 †.
- Hurst, D.R., Xie, Y., Vaidya, K.S., Mehta, A., Moore, B.P., Accavitti-Loper, M.A., Samant, R.S., Saxena, R., Silveira, A.C., and Welch, D.R. (2008) BRMS1:ARID4A direct interaction is required for transcription repression but not metastasis suppression. Journal of Biological Chemistry. 283: 7438-7444 (doi: 10.1074/jbc.M709446200 01/22/2008) PMID: 18211900 PMCID: PMC2293288 †.
- Vaidya, K.S., Harihar, S., Phadke, P.A., Stafford, L.J., Hicks, D.G., Casey, G., DeWald, D.B. and Welch, D.R. (2008) Breast Cancer Metastasis Suppressor-1 differentially modulates growth factor signaling. Journal of Biological Chemistry 283: 28354-28360 (doi/10.1074/jbc.M710068200 07/29/2008) PMID: 18664570 †
- Silveira, A.C., Hurst, D.R., Vaidya, K.S., Ayer, D.E. and Welch, D.R. (2009) Over-expression of the BRMS1 family member SUDS3 does not suppress metastasis of human cancer cells. Cancer Letters 276: 32-37 (doi:10.1016/j.canlet.2008.10.024) PMID: 19070953.†
- Hurst, D.R., Edmonds, M.D., Scott, G.K., Benz, C.C. and Welch, D.R. (2009) Breast cancer metastasis suppressor 1 BRMS1 up-regulates miR-146 that suppresses breast cancer metastasis. Cancer Research 69: 1279-1283 (doi:10.1158/0008-5472.CAN-08-3559) PMID: 19190326. †
- Edmonds,M.D., Hurst,D.R., Vaidya,K.S., Stafford,L.J., Chen,D., Welch,D.R. (2009) Breast Cancer Metastasis Suppressor 1 (BRMS1) coordinately regulates metastasis-associated microRNA expression. International Journal of Cancer 125(8): 1778-1785 (10.1002/ijc.24616). PMID: 19585508 PMC2749950 †
- Bodenstine, T.M., Vaidya, K.S., Ismail, A., Beck, B.H., Cook, L.M., Diers, A.R., Landar, A., Welch, D.R. (2010) Homotypic gap junctional communication contributing to metastasis increases with PKA kinase activity and is unaffected by PI3K inhibition. Cancer Research 70: 10002-10011 (doi: 10.1158/0008-5472. CAN-10-2606) PMID: 21098703.
- Bodenstine, T.M., Beck, B.H., Cao, X., Cook, L.M., Ismail, A., Powers, J.K., Mastro, A.M., and Welch, D.R. (2011) Pre-osteoblastic MC3T3-E1 cells promote breast cancer growth in bone in a murine xenograft model. Chinese Journal of Cancer 30: 189-196 PMID: 21352696.