Danny R. Welch, Ph.D.
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.
|Thomas Beadnell, Ph.D.
|Adam Scheid, Ph.D.
|Carolyn Vivian, MS
Senior Research Associate