Oncogenic activation of ERK in alveolar epithelium initiates cell transformation and lung adenocarcinoma (LUAD), the most common type of lung cancer. These “initiated cells” can lie dormant for decades. Once awakened, if the cancer is caught early, before it has invaded throughout the lung and body, patients have a better prognosis. Changes in the extracellular matrix of the early tumor microenvironment can push initiated cells to become invasive and aggressive, causing tumor progression that results in metastasis. We discovered that extracellular matrix protein Tenascin-C induces early tumors to progress to aggressive cancer by signaling through integrins to activate tumor cell focal adhesion kinase (FAK). Fibroblasts express Tenascin-C in response to lung injury and FAK inhibition blocks Tenascin-C expression and injury-induced tumor progression. This work suggests that FAK inhibitors might benefit patients with early tumors driven by injury.