The long-term goal of our research is to define the pathways that integrate activation of growth factor, chemokine and adhesion receptors to the regulation of morphogenesis, cell polarity, growth, differentiation, adhesion, and migration during cancer and in response to injury. We have a long-standing research interest on the role of protein tyrosine phosphorylation in tumorigenesis and inflammation.
Our early research led to seminal discoveries that defined the critical pathways employed by the Bcr-Abl tyrosine kinase to induce human leukemias. Currently, we are employing novel animal models to investigate the role of tyrosine kinase signaling networks in the regulation of cell polarity, growth, differentiation, adhesion and migration required for tumor progression and inflammatory responses. In particular, we are dissecting the pathways that modulate the crosstalk between multiple cell types during tumor progression and metastasis. Disrupting these “intercellular conversations” is expected to generate new targets for therapeutic intervention. Specifically, we focus on the role of the Abl family of tyrosine kinases, Abl1 and Abl2 (Arg), and associated actin regulatory proteins in diverse cellular processes leading to changes in cell morphology, motility, invasion, adhesion, as well as cell growth and survival.
Among the research areas currently being pursued in our laboratory are defining the mechanisms that regulate the cross-talk between cancer cells and associated cells in the tumor microenvironment. We have recently uncovered a previously unknown role for Abl kinases in the regulation of tumor-bone interactions by breast cancer cells and showed that Abl kinases promote breast cancer osteolytic metastasis by activating transcriptional networks dependent on TAZ and STAT5. Moreover, we found that ABL kinases promote metastasis of lung cancer cells harboring EGFR or KRAS mutations. Inactivation of ABL kinases suppresses lung cancer cell metastasis and ABL kinases are required for expression of pro-metastasis genes in lung cancer cells. ABL-mediated activation of the TAZ and β-catenin transcriptional co-activators is required for lung adenocarcinoma metastasis, and ABL kinases activate TAZ- and β-catenin by decreasing their interaction with the β-TrCP ubiquitin ligase leading to increased protein stability. High-level expression of ABL1, ABL2 and a subset of ABL-dependent TAZ- and β-catenin-target genes correlates with shortened survival of lung adenocarcinoma patients. Thus, ABL-specific allosteric inhibitors might be effective to treat metastatic lung cancer with an activated ABL pathway signature.
The ultimate goal of our studies is to develop novel therapies for the treatment of metastatic solid tumors by targeting not only cancer cells but also associated stromal cells in the tumor microenvironment.