A GATA6-centred gene regulatory network involving HNFs and ΔNp63 controls plasticity and immune escape in pancreatic cancer.
A GATA6-centred gene regulatory network involving HNFs and ΔNp63 controls plasticity and immune escape in pancreatic cancer.
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DOI：
10.1136/gutjnl-2020-321397
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发表时间：
2022-04
期刊：
影响因子：
24.5
通讯作者：
Martinelli, Paola
中科院分区：
文献类型：
--
作者：
Kloesch, Bernhard;Ionasz, Vivien;Paliwal, Sumit;Hruschka, Natascha;Martinez de Villarreal, Jaime;Ollinger, Rupert;Mueller, Sebastian;Dienes, Hans Peter;Schindl, Martin;Gruber, Elisabeth S.;Stift, Judith;Herndler-Brandstetter, Dietmar;Lomberk, Gwen A.;Seidler, Barbara;Saur, Dieter;Rad, Roland;Urrutia, Raul A.;Real, Francisco X.;Martinelli, Paola
肿瘤的分子分类学是个体化医疗的基础，在治疗方面正变得至关重要。存在四种基于转录组学的胰腺导管腺癌（PDAC）分类系统，它们一致地鉴定出具有基底样特征的高侵袭性PDAC亚型，包括ΔNp63表达和上皮主调节因子GATA6的缺失。我们研究了驱动PDAC进展和基础程序出现的精确分子事件。我们使用一种新的双重组酶小鼠模型，将患者来源的转录组学数据集和组织样本的分析与机制实验相结合，以研究krasg12d驱动的胰腺肿瘤发生晚期Gata6缺失（Gata6LateKO）。这项从人到小鼠的综合研究表明，对于患者和小鼠中ΔNp63和基础程序的表达，GATA6的缺失是必要的，但不是充分的。HNF1A和HNF4A的同时缺失（可能是通过表观遗传沉默）是完全表型转换所必需的。此外，小鼠的Gata6缺失显著增加了转移率，并倾向于肺转移。通过对小鼠肿瘤原代细胞的RNA-Seq分析，我们发现Gata6抑制肿瘤细胞的可塑性和免疫逃避，这与患者来源的数据一致，表明Gata6是获得完全发育的基础和转移表型的屏障。我们的工作提供了基础表型和转移之间的机制分子联系，以及研究PDAC最具侵袭性亚型的有价值的临床前工具。因此，这些数据对于理解小鼠和人类胰腺癌异质性的病理生物学特征是重要的。
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 ΔNp63 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. 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 KRasG12D-driven pancreatic tumorigenesis (Gata6LateKO). This comprehensive human-to-mouse approach showed that GATA6 loss is necessary, but not sufficient, for the expression of ΔNp63 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. 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.
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影响因子：
82.9
作者：
Noll EM;Eisen C;Stenzinger A;Espinet E;Muckenhuber A;Klein C;Vogel V;Klaus B;Nadler W;Rösli C;Lutz C;Kulke M;Engelhardt J;Zickgraf FM;Espinosa O;Schlesner M;Jiang X;Kopp-Schneider A;Neuhaus P;Bahra M;Sinn BV;Eils R;Giese NA;Hackert T;Strobel O;Werner J;Büchler MW;Weichert W;Trumpp A;Sprick MR
通讯作者：
Sprick MR
影响因子：
64.8
作者：
Manguso RT;Pope HW;Zimmer MD;Brown FD;Yates KB;Miller BC;Collins NB;Bi K;LaFleur MW;Juneja VR;Weiss SA;Lo J;Fisher DE;Miao D;Van Allen E;Root DE;Sharpe AH;Doench JG;Haining WN
通讯作者：
Haining WN
EMT亚型影响上皮可塑性和细胞迁移模式。
影响因子：
11.8
作者：
Aiello NM;Maddipati R;Norgard RJ;Balli D;Li J;Yuan S;Yamazoe T;Black T;Sahmoud A;Furth EE;Bar-Sagi D;Stanger BZ
通讯作者：
Stanger BZ
影响因子：
24.5
作者：
Martinelli P;Carrillo-de Santa Pau E;Cox T;Sainz B Jr;Dusetti N;Greenhalf W;Rinaldi L;Costello E;Ghaneh P;Malats N;Büchler M;Pajic M;Biankin AV;Iovanna J;Neoptolemos J;Real FX
通讯作者：
Real FX
影响因子：
30.8
作者：
Chan-Seng-Yue, Michelle;Kim, Jaeseung C.;Notta, Faiyaz
通讯作者：
Notta, Faiyaz