Evaluating different aspects of cell biology associated with changes in ploidy of tumor and normal cells: signaling pathways and real time microscopy

Abstract

Aneuploidy and genomic instability are well established as carcinomas and sarcomas characteristics, although the main mechanisms responsible for the origin and maintenance, as well as its impact on the disease and response to therapy yet have many open questions. Given the importance of cancer as a cause of death and the major problem that is drug resistance developed by tumors making them refractory to treatment, it is important to study more deeply problems associated with the change of ploidy. That is, formulating new questions related to the increasing knowledge of regulatory molecules and pathways associated with tumor aggressiveness, proliferative activity and migration of different tumor cell types in culture. Some models are well established in our laboratory for the modulation of ploidy studies in tumor and normal cells: 1) the development of 3D cell cultures, initially with human breast cancer cells and now extended to cancer cells lung, which intended to represent a closer condition of micro avascular metastases; 2) use of different compounds to interfere with cell cycle progression to modulate changes in ploidy and/or chromosomal instability, allowing explore in greater depth the changes of regulatory pathways; 3) the interference progression of mitosis by treatment with drugs acting on the cytoskeleton, or chrysotile fibers and / or carbon nanotubes lead to a delayed cytokinesis and increased in aneuploid population. Within this context, the main objective of this project is the study of mechanisms associated with modulation of changes in DNA and/or chromosomal instability, to elucidate the involvement of Hippo pathway and its association with Aurora A and B kinases in control of the fate of tumor cells. To this end, we will use cell biology and molecular approaches, including real-time microscopy and inhibition processes for drug or RNA interference and FUCCI. It is crucial to assess the involvement of cytoskeletal elements in these processes, as well as the chromosomal and phenotypic changes that occur in cells and evaluating their potential impact on disease progression. This should contribute to the identification of potential new therapeutic approaches for cancer. (AU)