Ann Marie Pendergast
Anthony R. Means Cancer Biology Professor
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 b-catenin transcriptional co-activators is required for lung adenocarcinoma metastasis, and ABL kinases activate TAZ- and b-catenin by decreasing their interaction with the b-TrCP ubiquitin ligase leading to increased protein stability. High-level expression of ABL1
and a subset of ABL-dependent TAZ- and b-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.
Current Research Interests
Bone metastasis is a frequent complication of cancer, occurring in up to 70% of patients with advanced breast or prostate cancer. Breast cancer metastasis to the bone is associated with decreased survival, and patients with bone metastases experience severe pain, pathologic fractures, life-threatening hypercalcemia, spinal cord compression, and other nerve-compression syndromes. A greater understanding of the mechanisms that promote metastasis to the bone is required to identify actionable targets to treat this disease.
We have uncovered a novel role for the ABL family kinases in the regulation of breast cancer metastasis to the bone. Using next-generation sequencing we found that ABL kinases regulate the expression of multiple genes that modulate tumor-bone interactions. Gene Set Enrichment Analysis (GSEA) of multiple databases revealed that a gene signature consisting of 273 genes important for breast cancer bone metastasis was down-regulated in ABL1/ABL2 knockdown cells. Notably, we showed that inactivation of the ABL kinases elicited down-regulation of the Hippo pathway signature as well as the JAK/STAT and Cytokine/Cytokine Receptor pathway signatures. Among the transcripts that were markedly decreased in ABL1/ABL2 knockdown cells were the Hippo pathway regulator TAZ and the STAT5A transcription factor. Using rescue strategies, we showed that ABL kinases modulated the expression of pro-bone metastasis factors via co-activation of the TAZ and STAT5 transcription networks, and that expression of activated TAZ and STAT5 rescued metastatic activity in ABL1/ABL2-knockdown breast cancer cells in mouse models.
Notably, we found that treatment of tumor-bearing mice with selective allosteric inhibitors targeting the ABL kinases, or silencing ABL1 and ABL2 in breast cancer cells markedly impaired bone metastasis and blocked tumor-induced osteolysis. These findings have far-reaching implications for the treatment of metastatic breast cancer. The clinical relevance of our findings is further supported by our discovery that high-level expression of ABL2 and eight validated downstream targets correlated with decreased disease-free survival in a data set of 971 invasive breast cancer patients. These findings were published in Wang et al. 2016 Science Signaling 9, issue 413: ra12 (cover article of the February 2, 2016 issue).
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