Abstract LT014: Extracellular matrix stiffness regulates cellular response to anticancer drugs in breast and lung cancer cells

Abstract

Abstract Physical properties of tumor microenvironment provide key signaling cues that regulate tumorigenic growth of cancer cells. Mechanical properties of tumor microenvironment are principally related to the extracellular matrix (ECM) present around tumor cells. A strong correlation exists between ECM stiffness and tumor growth corroborating the fact that variations in ECM stiffness are vital to regulate metastasis. Though, the effect on ECM stiffness on growth and migration of cancer cells is well documented, its role in regulating cellular response against anticancer drug is relatively unknown. Here we investigated the effect ECM stiffness has on breast (MCF-7) and lung (A549) cancer cells response to conventional as well as non-conventional anticancer phytochemicals at cellular and sub-cellular levels. Using 2D polyacrylamide gels crosslinked to collagen (2D-PA matrix) we probed matrix stiffness dependent cellular responses against clinical anticancer drug doxorubicin and anticancer phytochemicals derived from Tinospora extract. Cell viability measurements indicated that IC50 values varied in matrix stiffness dependent manner. Cells appeared to be less susceptible to these anticancer agents at lower stiffness compared to high stiffness matrices. Fluorescence microscopy observation at sub-cellular level indicated that drug-driven response on cytoskeleton organization is highly matrix stiffness dependent in nature. Further, the drug response on morphological parameters such as karyoplasmic ratio and cell-shape index was significantly affected by the matrix stiffness. ECM stiffness also governed the drug effect on cellular organelle architecture and functioning. We observed a strong correlation between ECM stiffness and the drug response to mitochondrial structure, potential and metabolic activity. Considering the direct relation of cell adhesion to substrate mechanosensing, we probed the matrix stiffness-dependent response of anticancer drugs on cell adhesion and deadhesion kinetics. Our analysis revealed that ECM stiffness significantly affected the effect of anticancer drugs on cell adhesion and deadhesion kinetics. Subsequent analysis on cellular mitogenic signaling indicated differential activation of MAPK signaling pathway via ECM stiffness-dependent manner. Taken together, these observations strongly suggested that cellular and subcellular responses of anticancer drugs are significantly governed by ECM stiffness in breast and lung cancer cells. Citation Format: Atul Bharde, Snigdha Nadagauda, Megha Gaur, Vaishnavi Borade. Extracellular matrix stiffness regulates cellular response to anticancer drugs in breast and lung cancer cells [abstract]. In: Proceedings of the AACR Virtual Special Conference on the Evolving Tumor Microenvironment in Cancer Progression: Mechanisms and Emerging Therapeutic Opportunities; in association with the Tumor Microenvironment (TME) Working Group; 2021 Jan 11-12. Philadelphia (PA): AACR; Cancer Res 2021;81(5 Suppl):Abstract nr LT014.