The most prevalent form of pancreatic cancer, Pancreatic Ductal AdenoCarcinoma (PDAC) is usually divided into two subtypes, a classical subtype and a basal subtype. The latter is highly aggressive and tends towards early metastasis. One of the distinguishing features between the two subtypes is that the classical subtype exhibits the protein GATA6. This is no longer present in the basal subtype, while the protein DeltaNp63 can be detected in this type.
The study team led by Paola Martinelli, who, at the time of the study, was research group leader at the Institute of Cancer Research and member of the Comprehensive Cancer Center of MedUni Vienna and Vienna General Hospital, found that the switch-over of the cancer cells from the classical to the basal type occurs in two stages: first of all, GATA6 is lost but this is not yet sufficient for the expression of DeltaNp63. Only after the concomitant loss of two additional proteins, transcription factors HNF1A and HNF4A, does DeltaNp63 emerge and the tumour switch to the aggressive form. Martinelli comments: "This suggests that reinstating the classical subtype could serve to reduce metastasis. Moreover, the tumour would once again be easier for the immune system to detect, since GATA6 not only hinders the ability of tumours to adapt to their surroundings but also blocks the mechanisms that hide tumours from the immune system."
The study was financed by an Austrian Science Fund (FWF) research grant and contributions from Fellinger Cancer Research and the Ingrid Shaker-Nessmann Cancer Research Association.
A GATA6-centred gene regulatory network involving HNFs and ΔNp63 controls plasticity and immune escape in pancreatic cancer. Bernhard Kloesch, Vivien Ionasz, Sumit Paliwa, Natascha Hruschka, Jaime Martinez de Villarrea, Rupert Öllinger, Sebastian Mueller, Hans Peter Dienes, Martin Schindl, Elisabeth S Gruber, Judith Stift, Dietmar Herndler-Brandstetter, Gwen A Lomberk, Barbara Seidler, Dieter Saur, Roland Rad, Raul A Urrutia, Francisco X Real, Paola Martinelli. http://dx.doi.org/10.1136/gutjnl-2020-321397