Cancer invasion: reciprocity between the extracellular matrix and intrinsic ERK signaling

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PROJECT SUMMARY - from parent award Cancer cell invasion is the major cause of lung cancer morbidity. Invasion remain untargeted, in part due to an incomplete understanding of the molecular underpinnings of the cellular process. The long-term goal is to identify the mechanisms that drive lung adenocarcinoma invasion. The overall objective here is to elucidate the Tenascin-C and ERK signaling mechanisms that drive LUAD invasion. The central hypothesis is that ERK and Tenascin-C work together to induce LUAD invasion. This is based on our preliminary data. We show that Tenascin-C is expressed early after tumor initiation by activating upstream mutations in the ERK pathway. We also show that Tenascin-C and ERK are both expressed at the invasive edge of tumors, and that Tenascin-C induces ERK activity and ERK-dependent tumor cell invasion in vitro. The central hypothesis will be tested by pursuing three specific aims: 1) Determine the cell source and stimulus for Tenascin-C production in early LUAD, 2) Determine the mechanism by which Tenascin-C signals to LUAD tumor cells, and 3) Identify mechanisms of ERK-mediated LUAD invasion. Under the first aim, we will test if fibroblasts produce Tenascin-C in response to increased strain. In aim 2, we will determine if Tenascin-C signals to induce tumor cell invasion by activating tumor cell integrins and ERK. In aim 3, we will test if LOK/Ezrin are critical ERK effectors that drive the mesenchymal-mode invasion observed in LUAD. This will determine the mechanisms by which the lung cancer extracellular matrix interacts with oncogenic RAS/ERK signaling to drive invasion. The research proposed in this application is innovative, because it tests a new model of Tenascin-C induction, develops a computation model of tumor growth within the lung and under stretch, uses organotypic cultures, and tests a new, druggable ERK effector in the invasion process. The proposed research is significant because it is expected to advance our understanding of lung cancer with new knowledge of how mechanochemical signaling between the stroma and cancer confers cancer invasion. Ultimately, such knowledge has the potential to provide strong scientific justification for the development of new therapies to target invasion and reduce lung cancer morbidity and mortality.