Chromosomal Instability and Tumorigenesis

Our group focuses on the study of Gastric Cancer (GC), the fifth most diagnosed cancer and the third with the highest mortality globally, through two parallel and sometimes complementary approaches and lines of research:

  1. Understanding how mitotic checkpoint deregulation affects tumorigenesis.

GC is a solid tumour characterized by high rates of chromosomal instability (CIN) and aneuploidy, in many cases responsible for failure during mitosis due to overactivation of the mitotic checkpoint known as the spindle assembly checkpoint (SAC). Over the years, our laboratory has analyzed the expression levels of SAC proteins, correlating CIN  with the key mitotic proteins MAD2 and BUBR1. Interference of the corresponding genes modifies the migration and invasion of GC-derived cells, and plays a key role in the balance of tumour stem cells, regulating symmetric and asymmetric division and thus the capacity for self-renewal and differentiation to progenitor cells, so our studies are aimed at the molecular mechanism involved in these processes, which are widely related to tumour malignancy.

  1. Study of the biomolecular mechanism of action of anti-tumour metallopharmaceuticals with unconventional structures.

Cisplatin (and its derivatives) are used in clinical practice due to their high efficacy against testicular and ovarian tumours. However, they have numerous side effects (hemato-, oto- and nephro-toxicity), and the emergence of resistance mechanisms has led research into the design of new metallic structures. In our group, we work with two large families of prototypes:

- Trans Platinum(II) complexes. This family of complexes was dismissed for years by the scientific community due to the low activity of transplatinum. However, our group has published different structures with better activity and able to overcome cisplatin drug resistance. In addition, we have found that many of them present a cell death mechanism partially independent of p53. This is interesting because in more than 50% of solid tumours this protein is mutated, and a non-functional p53 would lead to therapy failure.

- Metal complexes conjugated to biospecific ligands. The conjugation of specific ligands, such as lipids, etc., is a strategy that seeks to increase cellular uptake through specific drug-cell receptor recognition. Another type of specific ligands of interest are those with proven biological activity, such as thiosemicarbazones (TSCN). These types of ligands have a high affinity for metal centres and great versatility in terms of their coordination. Their antitumour properties are due to several causes, the main one being the inhibition of ribonucleotide reductase, which is overexpressed in many types of cancer. In addition, there is a synergistic effect between the properties of metal centres such as Cu(II), Pd(II) or Pt(II) and TSCN, which reinforces the antitumour potential of the drug resulting from their combination.

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