The Migration Networks Project is designed to understand how key steps in the onset and progression of metastatic disease are regulated. Our overall goal is to identify new targets for therapeutic intervention in metastatic disease, the most frequent cause of mortality in cancer patients.
We focus on four general aspects of invasion and metastasis: motility responses to growth factor stimulation, acquisition of a motile phenotype during epithelial to mesenchymal transition (EMT), dissemination of metastasis to the CNS and acquisition of resistance to therapy. We will generate quantitative data to describe cell behavior during EMT and growth factor-elicited motility. The status of signaling pathways, gene expression and alternative splicing will be interrogated and used to take a systems approach to develop computational models to elucidate how molecular networks are dysregulated to yield aggressive cell behavior. The models will include physico-chemical mechanistic simulations, statistical models for signal-response relationships, and topological models that integrate transcriptional, signaling and cytoskeletal regulatory processes. The experiments will employ mammary epithelia cells, breast cancer cells, xenografts and syngeneic tumor models, and lymphoma. We therefore expand upon on our experience with mammary carcinoma during the last funding period and integrate a powerful new lymphoma model for in vivo gene discovery. The work in this program dovetails well with the mitogenesis and DNA damage/therapeutics programs. All three programs consider ErbB signaling and both this and the therapeutics program specifically examine breast cancer and lymphoma cells. The three programs also all consider the problem of acquired resistance to chemotherapy during cancer progression. Reagents, data, ideas and hypotheses will flow frequently between the three Projects.
Specific Aim 1 - Application of biophysical cell migration and biochemical signaling models to Mena/EGFR synergy in tumor cell motility dysregulation
Specific Aim 2 - Signaling network models for EMT-dependent growth factor-induced motility
Specific Aim 3 - Integrated transcriptomic and proteomic topology modeling of EMT dysregulation
Specific Aim 4 - Systems analysis of motility dysregulation in metastasis and chemotherapeutic resistance