Our laboratory is primarily interested in understanding the mechanisms underlying metastasis and therapeutic side effects. We are particularly focused on breast cancer and the Krüppel-like transcription factor 8 (KLF8), a protein frequently overexpressed in multiple types of cancer. We are also interested in understanding the mechanisms behind tumor resistance to anticancer therapies.
Metastasis is responsible for 90% of all cancer deaths. It requires for some tumor cells to leave the primary tumor mass, enter, travel with and leave the blood or lymph circulation, and land on a different tissue or organ to form the secondary tumor in a distant location in the body. Our laboratory seeks to understand role of KLF8 in various cellular processes successful metastasis relies on. The first cellular process is epithelial-mesenchymal transition (EMT), the change of epithelial to mesenchymal morphology and function for some cells to depart from the primary tumor and start the journey of metastasis. The second process is degradation of the extracellular protein matrix by the cell on the journey to pave their way towards the vascular vessels. The third process is transendothelial migration, a mechanism the metastatic tumor cell uses to penetrate the vascular walls and enter or exit the circulation. In addition, both tumor angiogenesis, the formation of new vessels within the tumor, and cytoskeletal re-organization are required for the primary tumor growth as well as colonization, the outgrowth of a micrometastasis to form a clinically relevant secondary tumor. Our work, together with that of other laboratories, has demonstrated the role of KLF8 in regulating some of these processes contributing to metastasis.
Side effects and resistance are two of the most challenging aspects of anticancer therapies. Cancer cells smartly hijack or design multiple cellular and molecular mechanisms to evade destruction by anticancer therapies. This is particularly true for cancer stem cells, a very small subset of relatively quiescent cells in the tumor that are endowed with the ability to self-renew and differentiate into non-stem daughter cells, the major component of the tumor bulk. Cancer cells can create tumor-specific microenvironment both outside and inside the cells to minimize the cellular and molecular exposure to, and opportunities of action of, therapeutic agents, and maximize the power for molecular repair and cellular regeneration once therapy-induced damages have occurred. Our work along with that of other groups, has demonstrated the role of EMT and DNA damage response in supporting cancer stem cells and promoting drug resistance. Our work, in collaboration with other colleagues, has also shown tumor-specific anticancer effect of the cerium oxide nanoparticles that sensitize tumor cells to ionized irradiation via tissue acidity based manipulation of reduction-oxidation reactions. We are also investigating mechanisms underlying side effects and resistance for chemotherapy and targeted therapy.
We employ a broad range of biochemical, molecular and cellular biological and signaling approaches such as inducible expression/knockdown/knockout, two/three dimensional cell culture, xenograft and genetically engineered mouse models of cancer, whole animal live imaging and patient tissue samples.
Grants from the National Cancer Institute, American Cancer Society, Susan Komen for the Cure, NYSTEM, Florida Breast Cancer Foundation, Florida department of Health Bankhead-Coley Cancer Biomedical Research Program, and Florida department of Health Ed and Ethel Moore Alzheimer’s Disease Research Program provided partial support for some of this research.