Cancer Cell Biology Programme

Epithelial Carcinogenesis Group

Group Leader:  Francisco Real
Research highlights
Pancreas cancer molecular pathophysiology

While the genetic/genomic changes associated with PDAC have been extensively described in the last few years by the genome consortia, the precursor lesions and molecular changes that precede tumour development are less well established. We have acquired extensive evidence indicating that incomplete acinar cell differentiation is associated with a scenario of preinflammation or inflammation and with predisposition to PDAC development using mutant KRas-driven genetic mouse models. These studies provide the basis for the pharmacological – or genetic manipulation of acinar differentiation as a tumour preventative strategy.

One of the transcription factors we focused on is NR5A2, a member of the nuclear receptor family for which putative endogenous ligands as well as pharmacological agonists have recently been identified. NR5A2 germline heterozygosity leads to no overt pancreatic phenotype but it is associated with a pre-inflammatory state that sensitises mice to the oncogenic effects of mutant KRas. Interestingly, NR5a2 pancreas-specific heterozygosity − in conjunction with activation of mutant KRas in the pancreas (KPN+/- mice) − leads to a progressive loss of the exocrine parenchyma, development of cystic tumours with variable degrees of mucinous differentiation, dysplasia, and to adenocarcinoma (FIGURE 1). In patients, cystic tumours have variable risks of undergoing malignant transformation and are becoming a very important clinical problem because they are being increasingly diagnosed in healthy adults thanks to improved imaging techniques. We plan to exploit this new mouse model of pancreatic cystic tumours in order to explore, in collaboration with B. Gauthier (CABIMER, Sevilla), whether pharmacological stimulation of Nr5a2 activity can prevent the Nr5a2 haploinsufficient phenotype in the context of both pancreatitis and cancer.

Urothelial carcinoma (UC) genetics, biology, and clinical translation

Our main goals are to refine current knowledge on the genomic landscape of UC and to apply this in the clinical setting.

Through exome sequencing we identified mutations in STAG2, coding for a cohesin subunit, and in RBM10, coding for a splicing regulator, as new UC genes that are more broadly involved in human cancer. STAG2 inactivation in UC is not associated with aneuploidy, suggesting that regulation of chromatin architecture and gene expression mediate its tumour suppressor role. In collaboration with Ana Losada, we have developed a conditional Stag2 knockout strain; the cooperation of Stag2 inactivation with other genetic alterations occurring in UC (i.e. Pik3ca, Hras, and Tp53) is being analysed.

RBM10 is mutated in several epithelial tumours. Its inactivation in UC is not associated with stage or grade, but it occurs mainly in tumours with urothelial differentiation. In collaboration with J. Valcárcel (CRG, Barcelona), we have generated a conditional Rbm10 knockout strain and are analysing the molecular mechanisms through which this gene contributes to UC development using a combination of cellular, molecular and bioinformatics approaches.

These studies are complemented with the use of normal murine urothelial organoids, for which we have established robust culture methods and have shown their ability to undergo urothelial differentiation. In addition, we are expanding these studies to human bladder cancers in order to develop precision medicine strategies.

 

Within the context of a project funded by the AECC, we have analysed whether UC molecular taxonomy is able to predict response to neoadjuvant chemotherapy (NAC). Patients with tumours having a Basal/Squamous (BASQ)-like phenotype defined by immunohistochemistry are almost 4 times more likely to achieve a pathological complete response to platinumbased NAC. These studies will guide new clinical trials including molecular stratification criteria. This work is carried out in collaboration with Núria Malats, A. Font, D. Castellano, and an extended group of Spanish uro-oncologists.