The EMT-activator Zeb1 is crucial for cellular plasticity and drives metastasis in pancreatic cancer

Depletion of Zeb1 in a KPC-model for pancreatic cancer affected strongly the formation of precursor lesions, tumour grading, invasion and notably metastasis during PDAC progression. In this context, EMT is important for metastasis, but there is variability and specificity (and not redundancy) in the role and function of different EMT-inducing transcription factors. Primary Tumor cell lines were derived in replicates from pancreatic cancer driven by Pdx1-cre-mediated activation of mutant Kras and p53 (KPC-model) and also from Pdx1-Cre;Zeb1fl/fl with KrasLSL.G12D/+;Tp53LSL.R172H/+;Zeb1fl/fl mice (KPCZ, Zeb1 knockout). The tumor cell lines displayed phenotypes from mesenchymal and epithelial (designated as KPC_E, KPCZ_E or KPC_M). Two epithelial KPC cell lines and two KPCZ cell lines were treated with 5ng/ml TGFβ (KPC_E+TGFβ or KPCZ_E+TGFβ)

在胰腺导管腺癌（Pancreatic Ductal Adenocarcinoma，PDAC）的KPC小鼠模型（KPC-model）中，锌指E盒结合同源框1（Zeb1）的敲除会显著影响PDAC进展过程中的癌前病变形成、肿瘤分级、侵袭行为，以及尤为关键的转移进程。在此背景下，上皮间质转化（Epithelial-Mesenchymal Transition，EMT）对肿瘤转移至关重要，但不同EMT诱导转录因子的作用与功能存在异质性与特异性，且不存在功能冗余性。本研究从两种基因工程小鼠中重复分离建立原代肿瘤细胞系：一种是通过Pdx1-cre介导激活突变型Kras与p53构建的胰腺癌小鼠（即KPC模型小鼠），另一种是Pdx1-Cre;Zeb1fl/fl;KrasLSL.G12D/+;Tp53LSL.R172H/+;Zeb1fl/fl小鼠（记为KPCZ，即Zeb1敲除小鼠）。所获得的肿瘤细胞系呈现上皮样与间质样两种表型，分别命名为KPC_E、KPCZ_E与KPC_M。研究选取两株上皮样KPC细胞系与两株上皮样KPCZ细胞系，分别用5ng/ml的转化生长因子β（Transforming Growth Factor β，TGFβ）进行处理，对应组别记为KPC_E+TGFβ与KPCZ_E+TGFβ。