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Mechanobiology of Disease
Tuesday Speaker Abstracts
13
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.