Evolutionary dynamics can be used to control cancers when a cure is not clinically considered to be achievable. Understanding Darwinian intratumoral interactions of microenvironmental selection forces can be used to steer tumor progression towards a less invasive trajectory. Here, we approach intratumoral heterogeneity and evolution as a dynamic interaction among subpopulations through the application of small, but selective biological forces such as intracellular pH (pHi) and/or extracellular pH (pHe) vulnerabilities. Increased glycolysis is a prominent phenotype of cancer cells under hypoxia or normoxia (Warburg effect). Glycolysis leads to an important aspect of cancer metabolism: reduced pHe and higher pHi. We recently showed that decreasing pHi and targeting pHi sensitive enzymes can reverse the Warburg effect (WE) phenotype and inhibit tumor progression. Herein, we used diclofenac (DIC) repurposed to control MCT activity, and Koningic acid (KA) that is a GAPDH partial inhibitor, and observed that we can control the subpopulation of cancer cells with WE phenotype within a tumor in favor of a less aggressive phenotype without a WE to control progression and metastasis. In a 3D spheroid co-cultures, we showed that our strategy can control the growth of more aggressive MDA-MB-231 cells, while sparing the less aggressive MCF7 cells. In an animal model, we show that our approach can reduce tumor growth and metastasis. We thus propose that evolutionary dynamics can be used to control tumor cells’ clonal or sub-clonal populations in favor of slower growth and less damage to patients. We propose that this can result in cancer control for tumors where cure is not an option.

Summary: 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.