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THE STRUCTURE OF THE CELL NUCLEUS AND CANCER CHEMORESISTANCE
thesisposted on 10.06.2019, 19:11 by Farzaneh Atrian afyani
Cancers have the ability to develop resistance to traditional therapies. The important role of the tumor microenvironment in transforming nonaggressive tumor cells into an aggressive and chemoresistant cancer has been abundantly addressed. Mechanical cues from the tumor environment, such as matrix stiffness and geometry, transfer to the cell nucleus via the cytoskeleton and change nuclear morphology (e. g, chromatin organization, size and shape). Such alterations are known to accompany or follow the acquisition of chemoresistance. Nuclear matrix proteins such as the Nuclear Mitotic Apparatus (NuMA) are highly involved in higher order chromatin organization and contribute to sustain the physical structure of the cell nucleus, but it is
yet to be determined how such structural proteins respond to microenvironmental changes. We have shown previously that tumors cultured in curved geometry (similar to the ductal architecture of breast tissue) display significantly different drug sensitivities compared to those cultured on a flat surface, and that a major morphological difference between these two culture conditions is nuclear shape (i.e., circularity). Our hypothesis is that mechanical cues from the tumor microenvironment alter nuclear features that control the phenotypic response of cancer cells to antiproliferative drugs. Morphological analysis of the cell nucleus in the curved conformation as well as hydrogel and hanging drop systems (with amorphous geometry) showed that only nodules in the curved set-up have nuclear morphometry (shape and size) similar to that of breast tumors of the corresponding subtypes in vivo. In addition, we compared the sensitivity of triple negative breast tumors to cisplatin, with proven efficacy in the clinics, and SAHA, an epigenetic drug that so far failed in breast cancer treatment. Our results suggest higher sensitivity to cisplatin and lower sensitivity to SAHA of breast cancer cells cultured in duct-like geometry compared to the amorphous systems. To evaluate the importance of nuclear morphometry in drug response we altered nuclear size and shape using latrunculin. Under this condition, the number of apoptotic and growth-arrested cells increased following treatments with cisplatin and SAHA, respectively.