PROJECT SUMMARY Lung cancer is the #1 cause of cancer death in the US. The 5-year rate of cancer recurrence and death remains high, even for patients with early tumors. An incomplete understanding of the molecular and physical underpinnings of early tumor progression limits advances in treatment. The long-term goal is to identify the fundamental mechanical and biochemical interactions that control the progression of early lesions to lung adenocarcinoma (LUAD). The overall objective here is to elucidate the mechanical interactions involved in LUAD progression. The central hypothesis is that increased strain functions in a feedforward loop with tumor growth and ECM deposition to promote LUAD progression. This is based on our preliminary data. We computationally predict that strain from respiration is increased at the tumor edge. We also show that the tumor edge has increased proliferative signaling and is surrounded by alveolar deformation indicative of circumferential strain. The central hypothesis will be tested by pursuing three specific aims: 1) Determine how strain controls early lung tumor growth, 2) Identify mechanical factors that modulate invasive progression, and 3) Determine how fibrotic ECM deposition controls the progression of pre-cancerous lung adenomas. Under the first aim, we will test if strain induces activation of tumor growth signaling at the tumor edge, thereby expanding the area of amplified strain. In aim 2, we will test if alveolar wall strains induced by tumor expansion leads to wall failure, the initial step invasive progression. In aim 3, we test if fibrotic stiffening of the lung causes higher strain amplitudes at the tumor edge, which promotes LUAD progression. This will determine the physical mechanisms that contribute to the progression of benign adenomas to lung cancer progression. The research proposed in this application is innovative, because it tests a new model: strain-mediated mechanobiological signaling in early lung cancer progression and because it employs new approaches to stretch live lung tissue and quantify strain and tissue damage and a novel specimen-specific computational modeling and simulation pipeline to determine the contribution of strain to the growth and invasion of early LUAD. The proposed research is significant because it will provide new knowledge of how biomechanical signaling, such as excessive strain and fibrosis, contributes to early cancer progression. Such knowledge has the potential to provide strong scientific justification for the study of mechanobiology in other solid tumors that metastasize to the lung and the development of neoadjuvant therapies to reduce fibrosis to limit lung cancer progression and mortality. Our new approaches to modeling will be implemented in the open source FEBio software, and the suite of subject-specific models will be distributed via the FEBio model repository, facilitating innovation by other scientists.

Project Narrative The proposed basic research is relevant to public health because it focuses on a fundamental biomechanical interactions in lung cancer progression. The work will lay the foundation for the development of new strategies to prevent and treat lung cancer morbidity and mortality.