Pendergast, Ann MarieHoj, Jacob Peter2020-06-092022-05-272020https://hdl.handle.net/10161/20910<p>Brain metastases are a devastating consequence of lung cancer resulting in significantly increased mortality. Currently, no effective therapies exist to treat brain metastases due to a lack of actionable targets and failure of systemic therapies to penetrate the blood-brain barrier (BBB). Using in vivo mouse models of brain metastasis combined with mechanistic cell signaling and transcriptomic approaches, the studies presented herein identify two actionable signaling pathways required during the colonization of metastatic lung cancer cells in the brain. First, we identify an autocrine AXL-ABL2-TAZ signaling axis in lung adenocarcinoma brain metastasis whereby nuclear accumulation of the TAZ transcriptional co-activator drives expression of ABL2 and AXL encoding protein tyrosine kinases which engage in bidirectional signaling. Activation of the ABL2 kinase in turn results in increased tyrosine phosphorylation of TAZ and enhances TAZ nuclear localization, thereby establishing an autocrine feed forward signaling loop. In addition to driving expression of ABL2 and AXL, TAZ also drives transcriptional activation of a number of neuronal-related gene targets, including L1CAM which was previously shown to promote metastatic colonization and outgrowth in the brain. Importantly, pharmacologic inhibition of the ABL kinases with BBB-penetrant ABL allosteric inhibitors disrupts AXL-ABL2-TAZ signaling and extends survival in brain metastasis-bearing mice. We also characterize an additional transcriptional program driven by Heat Shock Factor 1 (HSF1) and E2F family transcription factors during brain metastasis colonization that is required for survival of lung cancer cells at this organ site. Interestingly, the transcriptional program driven by HSF1 in the setting of brain metastasis is strikingly divergent from the canonical heat shock response, and loss of HSF1 markedly impairs colonization of tumor cells in in vivo models of brain metastasis. We identify ABL2 as a regulator of HSF1 and E2F protein expression and find that inhibition of ABL2 robustly impairs HSF1-E2F target gene expression. Collectively, our findings reveal ABL2 as a central hub of both AXL-ABL2-TAZ signaling and HSF1-E2F-coregulated transcription and provide evidence supporting the use of ABL kinase allosteric inhibitors for the treatment of lung cancer brain metastases.</p>PharmacologyCellular biologyMolecular biologyABL kinasesAXLBrain metastasisHSF1L1CAMLung adenocarcinomaDissertation