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.