GATA6 role in pancreatic cancer progression and metastasis

Pancreatic ductal adenocarcinoma (PDAC) is a highly aggressive malignancy, it is resistant to most therapies and it is therefore almost invariably lethal. It has been shown that pancreatic tumors with an epithelial gene expression signature have a better outcome, as opposed to tumors with a quasi-mesenchymal phenotype. We have shown that the transcription factor GATA6 has a crucial role in maintaining the epithelial identity in PDAC cells and blocks pancreatic carcinogenesis, suggesting that it might act as a tumor suppressor in PDAC. We have generated and characterized a pancreas-specific conditional knock- out model for Gata6, where we described how this transcription factor is essential for the complete and full differentiation of acinar cells. When we combined this model with a mouse model for PDAC, where a mutant KRasG12V allele is expressed during pancreatic development, we observed a significant acceleration of tumorigenesis. Gata6 was also spontaneously lost in tumors induced only by mutant KRasG12V, as a rather late event during tumor progression. Most importantly, GATA6 expression was lost in a significant percentage of human PDAC samples, in association with an altered differentiation (E-cadherinlow, KRT14+). Preliminary data also suggest that GATA6 expression might be important for patient stratification, thus allowing more targeted therapy. We now aim at creating a mouse model that more accurately recapitulates the physiological process of spontaneous loss of GATA6 expression late during PDAC development. To do so, we will generate a mouse line where deletion of Gata6 and expression of mutant KRasG12V can be uncoupled in time, by taking advantage of two recombination systems, Flp/frt and Cre/loxP. In parallel, we will study the different behavior of human and mouse GATA6+ and GATA6- PDAC primary samples and cell lines in an orthotopic transplantation model and we will generate GATA6-reporter cell lines, where we will be able to follow and analyze the modulation of GATA6 expression during tumor growth and spreading in an orthotopic transplantation model. These studies will expand our knowledge on the proposed tumor suppressive function of GATA6 in the pancreas, and most interestingly, will provide information on the possible role of GATA6 as a predictor of prognosis and response to therapy. This will allow a better stratification of patients, aimed at developing novel, more effective, targeted therapies.

Pancreatic cancer is a very deadly disease for which we still do not have any effective therapy. Since there are no reliable risk factors and the disease course is usually asymptomatic until very late, patients already have an advanced or metastatic disease at the time of diagnosis. Additionally, even those who can receive surgery, almost invariably suffer from relapse and succumb to the disease within few months. In all, up to 90% of patients with pancreatic cancer have metastases at death. Despite this, the mechanisms that drive the progression of pancreatic cancer towards the metastatic stage are still relatively unknown. It is known that the maintenance of cell identity suppresses tumor initiation and tumor progression. We had evidence that a gene important for cell identity, GATA6, is blocking pancreatic cancer initiation. Here we wanted to investigate whether it also blocks tumor progression and metastases. A detailed understanding of the processes driving tumor progression and metastasis is the key first step towards the development of better cures for patients. We have combined the analysis of different types of patient-derived material, including tissue from surgical resection, cell lines established from tumors, and sequencing data available from the literature, with the development of experimental models specific for the study of late tumor stages. This has allowed us to show that GATA6 blocks pancreatic cancer progression and metastasis because it locks the cells in a more benign state. Pancreatic cancer cells tend to lose GATA6 in order to overcome this block, and when they lose it, they acquire more aggressive features and are more resistant to certain therapies. Our results could be the basis for future studies aimed at finding ways to avoid the loss of GATA6 as a potential therapeutic strategy to avoid progression and metastases.