Lymph node metastasis is the phenotypic feature of solid tumors most predictive of mortality, yet, to date, we possess little biologic understanding ofthe processes directing lymphatic metastasis, and no understanding of the dynamic interaction between tumors and the lymph node microenvironment. Given that shear resistant adhesion molecules are essential for achieving tissue specific homing of blood-borne cells. We propose, similarly, that shear-resistant binding initiates lymph node lodgment, a process mediated by engagement of pertinent receptor(s) and ligand(s) specialized to function under low shear stress conditions. Thus, lymph node metastasis in cancer is a specific receptor-mediated process operant under low shear conditions characteristic of lymphatic flow. Our published work has established L-selectin as a mediator in part, of interaction between tumor cells and lymphocytes under conditions of lymphodynamic shear stress. Additionally, our preliminary work has shown that extracellular elements ofthe lymph node parenchyma, such as laminin, similarly support binding of tumor cells under these same conditions. Based on these preliminary results, the specific aims of our proposed work are: (1) To examine the role Integrin receptors play in supporting head and neck cancer cell binding to lymphocytes within lymphodynamic fluid shears, (2) To examine head and neck cancer cell binding to known extracellular matrix elements of the lymph node parenchyma and to specifically examine integrins and CD44 as mediators of such activity under conditions of lymphodynamic fluid shears, and (3) To characterize the effect of integrin receptor and CD44 receptor knockdown on the process of lymphatic metastasis in vivo. Through this work, to be performed under the mentorship of Dr. Mark Evers and Dr. Massoud Motamedi at the University of Texas Medical Branch, I look to further my short-term goal of training in the areas of small animal modeling of lymphatic metastasis and small animal optical imaging, as well as my long term goal of transitioning into independence as a successful, extramurally funded head and neck surgeon-scientist. I will accomplish this by a combining close career and scientific mentoring with exposure to multi-disciplinary cancer research groups within UTMB and abroad. In the long term, I aim to understand tumor cell biology within the lymph node in ways that will allow for the development of tumor markers predictive of the metastatic phenotype, thus enabling better application of currently available therapies.
Understanding of the interplay between metastatic tumor cells and lymph node constituent cells may drive insight into the process of tumor tolerance, thus uncovering new areas of therapeutic development for patients with a disease that has seen no improvement in survival in over 5 decades. Additionally, principles learned through these tumor models will surely have impact on the study of cancer metastasis and tumor tolerance in general, thus greatly impacting public health.
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