Biophysical Society Thematic Meeting | Singapore

Mechanobiology of Disease

Tuesday Speaker Abstracts

Rho-ROCK-Myosin Based Cellular Contractility Regulates Distinct Modes of Invasion in Paclitaxel and Cisplatin Resistant Ovarian Cancer Cells Aastha Kapoor 1 , Snehal Gaikwad 2 , Alakesh Das 1 , Melissa Monteiro 1 , Sejal Desai 1 , Amirali B. Bukhari 2 , Pankaj Mogha 3 , Abhijit Majumder 3 , Abhijit De 2 , Pritha Ray 2 , Shamik Sen 1 . 1 Indian Institute of technology, Bombay, Mumbai, India, 2 Tata Memorial Centre, Mumbai, India, 3 Indian Institute of technology, Bombay, Mumbai, India. Low survival rates in advanced stage epithelial ovarian cancer patients is attributed to acquisition of drug resistance against widely used chemotherapy drugs cisplatin and paclitaxel. Cellular and sub-cellular differences in drug resistant and normal cancers are responsible for lapse of chemotherapy. In our study, we analysed cellular biophysical differences between drug resistant and drug sensitive ovarian cancer cells to understand their modes of invasion. It is known, that drug sensitive cancers utilize two modes of invasion to spread to secondary locations – amoeboid invasion and mesenchymal invasion. In amoeboid invasion cancer cells utilize the force generated by their cytoskeleton and molecular motors to push through the surrounding extracellular matrix (ECM). In mesenchymal mode on the other hand cancer cells secrete proteases which degrades the surrounding matrix to allow unobstructed movement. While in drug sensitive cancer cells mesenchymal mode is the preferred means of invasion with amoeboid mode coming into play only when former is suppressed, in case of drug resistant cancer cells, we found that, it is drug-type dependent. Cells which have been treated with repetitive doses of paclitaxel, acquire amoeboid mode of invasion while those treated with cisplatin drug retain mesenchymal mode. Surprisingly, even though different drugs impart different modes of invasion to resistant cancer cells, the key regulator of both these mechanisms is common. We have identified cellular contractility as the primary contributor in both these cases, without which mesenchymal cancer cells lose protease secretion, and amoeboid cancer cells their migration and invasion potential. We have also identified Rho-ROCK-Myosin pathway as the key regulator of contractility in both these cases, which raises the exciting possibility of targeting this pathway for treatment of both types of drug-resistant ovarian cancers.

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