Abstract 171: Acid-induced collagen remodeling promotes cancer progress as a result of niche engineering
Authors: Niazi Ava , Joseph Johnson J. , Gillies Robert J. , Damaghi Mehdi 
Published: August 2018

Abstract
Growing tumors are dynamic and nonlinear ecosystems, wherein cancer cells in tumors adapt to their local microenvironment, and these adaptations further modify the environment, inducing more changes. From nascent intraductal neoplasms to a disseminated metastatic disease, several levels of evolutionary adaptations and selections occur. Here, we focus on one example of such an adaptation mechanism, namely, niche construction and remodeling promoted by adaptation to acidosis, which itself is a metabolic adaptation to the early harsh environment in intraductal neoplasms. Early carcinogenesis is an avascular and hypoxic disease leading to extracellular acidosis. Hence, we investigated how acid-adapted tumor cells engineer their niche to support their growth, proliferation, and invasion. We show that relatively rare collagens are produced by acid-adapted cancer cells to create an environment that contributes to their survival. We found collagen and other fibrillar structure in the periluminal region of DCIS lesions using Second Harmonic Generation Microscopy (SHG). We compared the microarray of DCIS samples to normal tissue and observed that Col10a1 and Col11a1 were significantly increased. We have shown previously that DCIS lesions are acidic. To test if these were related, we adapted low grade MCF7 and DCIS-10AT breast cancer cells to growth in acidic conditions and probed them for collagen production using qPCR, western blotting and Immunofluorescence. We found acid adaptation increases number of collagens including Col10a1, Col11a1, and different subtypes of Col4. Further, we developed a window chamber model to study the collagen remodeling real time through intra-vital microscopy. SNARF and collagen imaging simultaneously showed the collagen structural modifications in acidic regions. Further proteomic and secretome analysis of acid adapted cells versus non-adapted cells identified additional enzymes involved in collagen remodeling such as TGM2 and LOXL2 that have been shown to play major role in matrix remodeling. These findings were also validated by western blot and ICC. To test the role of collagens in viability of cancer cells we grew acid adapted and non-adapted MCF7 cells as 3D spheroids and treat them with FAK inhibitors. FAK inhibitors dramatically affected the acid adapted spheroids. The specific role of each of collagen genes in survival and invasion is still under study. We discuss that adaptation to acidosis induces cancer cells to adopt strategies that assist them to be more independent, particularly in harsh conditions such periluminal areas of DCIS that they don't have access to stroma cells; they produce the collagen they need and will remodel it by the enzymes produced by themselves to be able to survive, grow, and invade. Finally these adaptation mechanisms may present a vulnerability to design new therapeutics against the emerging aggressive phenotypes during cancer cell evolution.
Citation Format: Ava Niazi, Johnson J. Joseph, Robert J. Gillies, Mehdi Damaghi. Acid-induced collagen remodeling promotes cancer progress as a result of niche engineering [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2018; 2018 Apr 14-18; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2018;78(13 Suppl):Abstract nr 171.