Molecular Oncology Programme

Cell Division and Cancer Group

Group Leader:  Marcos Malumbres
Research highlights

Recent research in our laboratory has focused on several aspects of the control of cancer cell proliferation by the cell cycle machinery.We are currently studying the relevance of critical cell cycle kinases such as cyclin-dependent kinases, Plk1 or the PP2Ainhibitory kinase Mastl in cancer cells from different origins. Although mostly overlooked in the past, we are also studying major phosphatases such as PP2A or Cdc14 using genetic models. In addition, we have generated mouse models with gain-of-or loss-of-mutations in miR-203, a microRNA with relevant properties in the control of self-renewal and differentiation properties of stem cells (Patent EP 17382304.8).

The cell cycle kinase Plk1 controls vascular homeostasis

Among cell cycle enzymes, Polo-like kinase 1 (Plk1) is an essential kinase with multiple roles in centrosome maturation and separation, DNA replication, chromosome segregation, and cytokinesis. In human cancer, Plk1 is upregulated and its expression frequently correlates with poor prognosis in a variety of tumour types such as breast or lung cancer, among others. Pioneering work in model organisms such as flies or mammalian cells in culture demonstrated that inhibition of this kinase resulted in prometaphase arrest due to monopolar spindles or misaligned chromosomes, as well as in specific defects duringcytokinesis. Not surprisingly, a number of Plk1 small-molecule inhibitors are currently under scrutiny in clinical trials for cancertherapy. One of these inhibitors, volasertib, recently receivedthe Breakthrough Therapy designation by the FDA owing to its therapeutic effect in acute myeloid leukaemia.

We have recently analysed the relevance of this kinase usinggenetically engineered mouse models. Our results uncovered a new function for this protein in the maintenance of the proper structure of the arteries. Plk1 regulates the contractile response ofsmooth muscle cells to changes in blood pressure. Mechanisticallythis kinase regulates the activation of the RhoA GTPase, a centralnode in the actomyosin changes required for cell contractility (FIGURE). This function is actually related to the known role ofPlk1 in controlling actomyosin dynamics during the later steps ofmitosis and cytokinesis. In fact, the control of myosin contractilityby Polo-like kinases is conserved through evolution from yeast to humans. Similarly to its genetic inactivation, the use of Plk1 inhibitors resulted in defects in vascular structure and functionin mice. These data do not preclude the use of Plk1 inhibitors in the clinic but suggest that understanding their toxicity effectswill be critical for the proper design of therapeutic strategiesagainst cancer. In addition, as RhoA is a critical mediator ofmajor oncogenic and metastatic pathways, the use of low doses of Plk1 inhibitors could be considered as a potential therapeuticstrategy to limit the activation of these pathways in cancer cells

Mastl-PP2A in the cell cycle and cancer

During the last few years, the cell cycle kinase Mastl (also known as Greatwall) has emerged as a key player in the regulation of the PP2A phosphatase during mitosis. Mastl phosphorylates two small proteins, endosulfine (ENSA) and ARPP19, which in their phosphorylated form bind and inhibit PP2A-B55 complexes. In vertebrates, PP2A-B55 complexes counteract the phosphorylation of CDK substrates, and Mastl-dependent inhibition of PP2A-B55 prevents the activity of this phosphatase during mitosis, thus contributing to the phosphorylation of mitotic phospho-proteins. Recent data, including our own, suggest that B55 subunits are inactivated and Mastl is overexpressed in specific tumours such as oral squamous cell carcinoma, colon cancer, neuroblastoma and breast tumours. Our recent work also suggests a new function for B55 subunits in the control of chromosome structure during mitosis. Our current efforts are focused on understanding how B55 participates in chromosome segregation and malignant transformation using cellular and in vivo models.