TY - JOUR
T1 - A GATA6-centred gene regulatory network involving HNFs and "np63 controls plasticity and immune escape in pancreatic cancer
AU - Kloesch, Bernhard
AU - Ionasz, Vivien
AU - Paliwal, Sumit
AU - Hruschka, Natascha
AU - Martinez De Villarreal, Jaime
AU - Öllinger, Rupert
AU - Mueller, Sebastian
AU - Dienes, Hans Peter
AU - Schindl, Martin
AU - Gruber, Elisabeth S.
AU - Stift, Judith
AU - Herndler-Brandstetter, Dietmar
AU - Lomberk, Gwen A.
AU - Seidler, Barbara
AU - Saur, Dieter
AU - Rad, Roland
AU - Urrutia, Raul A.
AU - Real, Francisco X.
AU - Martinelli, Paola
N1 - Publisher Copyright:
© 2022 BMJ Publishing Group. All rights reserved.
PY - 2022/4/1
Y1 - 2022/4/1
N2 - Objective Molecular taxonomy of tumours is the foundation of personalised medicine and is becoming of paramount importance for therapeutic purposes. Four transcriptomics-based classification systems of pancreatic ductal adenocarcinoma (PDAC) exist, which consistently identified a subtype of highly aggressive PDACs with basal-like features, including "Np63 expression and loss of the epithelial master regulator GATA6. We investigated the precise molecular events driving PDAC progression and the emergence of the basal programme. Design We combined the analysis of patient-derived transcriptomics datasets and tissue samples with mechanistic experiments using a novel dual-recombinase mouse model for Gata6 deletion at late stages of KRas G12D -driven pancreatic tumorigenesis (Gata6 LateKO). Results This comprehensive human-to-mouse approach showed that GATA6 loss is necessary, but not sufficient, for the expression of "Np63 and the basal programme in patients and in mice. The concomitant loss of HNF1A and HNF4A, likely through epigenetic silencing, is required for the full phenotype switch. Moreover, Gata6 deletion in mice dramatically increased the metastatic rate, with a propensity for lung metastases. Through RNA-Seq analysis of primary cells isolated from mouse tumours, we show that Gata6 inhibits tumour cell plasticity and immune evasion, consistent with patient-derived data, suggesting that GATA6 works as a barrier for acquiring the fully developed basal and metastatic phenotype. Conclusions Our work provides both a mechanistic molecular link between the basal phenotype and metastasis and a valuable preclinical tool to investigate the most aggressive subtype of PDAC. These data, therefore, are important for understanding the pathobiological features underlying the heterogeneity of pancreatic cancer in both mice and human.
AB - Objective Molecular taxonomy of tumours is the foundation of personalised medicine and is becoming of paramount importance for therapeutic purposes. Four transcriptomics-based classification systems of pancreatic ductal adenocarcinoma (PDAC) exist, which consistently identified a subtype of highly aggressive PDACs with basal-like features, including "Np63 expression and loss of the epithelial master regulator GATA6. We investigated the precise molecular events driving PDAC progression and the emergence of the basal programme. Design We combined the analysis of patient-derived transcriptomics datasets and tissue samples with mechanistic experiments using a novel dual-recombinase mouse model for Gata6 deletion at late stages of KRas G12D -driven pancreatic tumorigenesis (Gata6 LateKO). Results This comprehensive human-to-mouse approach showed that GATA6 loss is necessary, but not sufficient, for the expression of "Np63 and the basal programme in patients and in mice. The concomitant loss of HNF1A and HNF4A, likely through epigenetic silencing, is required for the full phenotype switch. Moreover, Gata6 deletion in mice dramatically increased the metastatic rate, with a propensity for lung metastases. Through RNA-Seq analysis of primary cells isolated from mouse tumours, we show that Gata6 inhibits tumour cell plasticity and immune evasion, consistent with patient-derived data, suggesting that GATA6 works as a barrier for acquiring the fully developed basal and metastatic phenotype. Conclusions Our work provides both a mechanistic molecular link between the basal phenotype and metastasis and a valuable preclinical tool to investigate the most aggressive subtype of PDAC. These data, therefore, are important for understanding the pathobiological features underlying the heterogeneity of pancreatic cancer in both mice and human.
KW - epithelial differentiation
KW - molecular mechanisms
KW - pancreatic cancer
UR - http://www.scopus.com/inward/record.url?scp=85104197617&partnerID=8YFLogxK
U2 - 10.1136/gutjnl-2020-321397
DO - 10.1136/gutjnl-2020-321397
M3 - Article
C2 - 33846140
AN - SCOPUS:85104197617
SN - 0017-5749
VL - 71
SP - 766
EP - 777
JO - Gut
JF - Gut
IS - 4
ER -