Collagen Production and Niche Engineering: A Novel Strategy for Cancer Cells to Survive Acidosis and Evolve

Abstract

Ductal Carcinoma in situ (DCIS) is an avascular disease characterized by profound acidosis. Pre-malignant cells within this niche must adapt to acidosis to survive and thrive. A component of this acid-adaptation involves extracellular matrix remodeling leading to niche construction and remodeling. Using discovery proteomics, we identified that collagen producing enzyme PLODs are upregulated in acid-adapted breast cancer cells. Second harmonic generation microscopy showed significant collagen deposition within DCIS lesions of patients. In vitro analyses identified that acid-adaptation involves production of rare collagens that can be regulated by Ras and SMAD pathway. Secretome analysis showed upregulation ECM remodeling enzymes such as TGM2 and LOXL2. Comparison of acid induced collagens in vitro and in patient data showed correlation between rare collagens production and survival of patients. We conclude acidosis induces collagen production by cancer cells and promote growth independent of basal membrane attachment. The independently produced collagen can be used for niche construction and engineering as an adaptation strategy of cancer cells to survive and evolve.