Cell Cycle & Cancer Biomarkers

The main interest of the Cell Cycle & Cancer Biomarkers laboratory (CCCB) is to understand and define oncogenic mechanisms of cell cycle regulators with the ultimate goal to translate this knowledge to the clinic.

One of the main hallmarks of tumoral cells is their limitless proliferation capacity. Deregulation of cell division is a common feature in multiple types of tumors. Tumor cells cancel the checkpoint mechanisms of the cell cycle, resulting in the accumulation of genetic aberrations and Chromosomal Instability (CIN), providing cancer cells with increased genetic plasticity and adaptation capacity. The more aggressive a tumoral cell is, the more expression of cell cycle-related genes, which correlates with increased genomic instability. Indeed, aberrant expression of cell cycle and cell division genes often correlates with tumoral poor prognosis.

Paradoxically, in certain animal tumor models, elevated CIN negatively influences organism fitness, and is poorly tolerated by cancer cells, conferring a good prognosis to the patients. Such an opposing relationship suggests that there may be an optimal level of CIN for tumor progression and that cells need to compensate for high deleterious CIN through genetic adaptations.

We pretend to use cell cycle regulators and CIN-related genes, as biomarkers for cancer therapy, with the goal to find new therapeutic opportunities. Concomitantly, this will provide us the possibility to understand the mechanisms by which those cell cycle regulators modulate the oncogenic status of tumoral cells.

We address this by three different approaches:

1. Drug Sensitivity Screenings: Cell division and CIN genes are often overexpressed in tumors, and this commonly confers poor prognosis to the patients. We want to evaluate if the expression of CIN genes can predict sensitivity to different pharmacologic drugs.

2. Cell Cycle Drugs Resistance Mechanisms: A recurring problem in therapies with kinase inhibitors is the appearance of drug resistance mechanisms and therefore the loss of efficacy over time. Given the recent emergence of a new generation of cell division cancer drugs, the need to identify new resistance mechanisms increased substantially.

3. Mitotic regulators: Oncogenes or tumor suppressors?: An interesting feature of cell division genes is that they are often overexpressed in cancer, and this confers poor prognosis to the patients. This is typically symbolized by the master mitotic regulator Plk1 (Polo-Like Kinase 1). Plk1 has been considered an oncogene for decades. Surprisingly, in recent years, solid data emerged indicating that Plk1 can also have a role as a tumor suppressor. The logical and immediate question that then arises is: When can Plk1 act as a tumor suppressor or as an oncogene?

We intend to answer all these questions, through multidisciplinary approaches, using molecular and cellular biology techniques, "omics" studies, and the use of genetically modified animals to have a physiological and preclinical impact.


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