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The Gallo laboratory is interested in the understanding and therapeutic targeting of signaling pathways that govern cancer progression. In particular, we have focused on the mixed-lineage kinase (MLK) family (Figure 1) and their roles in cancer invasion and metastasis, particularly in the context of breast cancer. We have demonstrated a critical role for MLK3 in triple-negative breast cancer metastasis (Figure 2), in regulating both focal adhesion turnover during cell migration and gene expression during invasion and metastasis. In addition we are studying the roles of MLK family members and related signaling in lung cancer, glioblastoma, and melanoma.
Figure 1 MLK family members.
Triple-negative breast cancers (TNBCs) have high rates of metastasis and early metastatic recurrence and lack targeted therapies. During cancer metastasis, individual or small groups of tumor cells must break away from the primary tumor, invade through extracellular matrix, intravasate through the endothelial layer of the vasculature to enter the bloodstream. Subpopulations of these “circulating tumor cells” are responsible for metastatic colonization. We are studying the molecular characteristics of circulating tumor cells derived from a TNBC model, including their gene expression and signaling pathways, with the aim of identifying important druggable targets to combat breast cancer metastasis.
Estrogen receptor-positive (ER+) breast tumors are typically less aggressive than TNBCs and often respond to endocrine therapies, but endocrine resistance and late metastatic recurrence are major causes of mortality in these women. Late metastatic recurrence is thought to occur upon reacativation of dormant tumor cells that have disseminated to distant organs. We are investigating pathways responsible for reactivation of dormant tumor cells, in order to identify appropriate drug targets.
Figure 2. MLK3 signaling in triple-negative breast cancer.
Our laboratory uses diverse approaches and techniques to study mechanisms of tumor proliferation, invasion and metastatic outgrowth including 3D organotypic assays, cell biology, animal models, mass spectrometry, and biochemical techniques.
We collaborate with the Conrad lab (Microbiology & Molecular Genetics) in identifying mechanisms and alternative therapeutic strategies for endocrine resistant breast cancer. In collaboration with the Neubig lab in Pharmacology & Toxicology, we are exploring appropriate combination therapies in drug-resistant melanoma.