ROR2 regulates cellular plasticity in pancreatic neoplasia and adenocarcinoma [RNA-seq siROR2 ]

Cellular plasticity is a hallmark of pancreatic ductal adenocarcinoma (PDAC) starting from the conversion of normal cells to precancerous lesions to the progression of carcinoma subtypes associated with aggressiveness and therapeutic response. We found that normal acinar cell differentiation, maintained by the transcription factor Pdx1, suppresses a broad gastric cell identity that is maintained in metaplasia, neoplasia, and the classical subtype of PDAC in mouse and human. We have identified the receptor tyrosine kinase Ror2 as marker of a gastric metaplasia (SPEM)-like identity in the pancreas. Ablation of Ror2 in a mouse model of pancreatic tumorigenesis promoted a switch to a gastric pit cell identity that largely persisted through progression to carcinoma. In both human and mouse pancreatic cancer, ROR2 activity continued to antagonize the gastric pit cell identity, strongly promoting an epithelial to mesenchymal transition, conferring resistance to KRAS inhibition, and vulnerability to AKT inhibition. This dataset includes control and ROR2 siRNA-treated human pancreatic cancer cell lines PANC1 and UM5 (n=3).

细胞可塑性是胰腺导管腺癌（pancreatic ductal adenocarcinoma, PDAC）的标志性特征，其进程始于正常细胞向癌前病变的转化，最终进展为与侵袭性及治疗应答相关的癌亚型。我们发现，由转录因子Pdx1维持的正常腺泡细胞分化，可抑制广泛的胃细胞表型；该表型在小鼠和人类的化生、瘤变以及PDAC经典亚型中均得以维持。我们已鉴定出受体酪氨酸激酶Ror2可作为胰腺内胃化生（SPEM）样表型的标志物。在胰腺肿瘤发生的小鼠模型中敲除Ror2，可促进向胃小凹细胞表型的转化，且该表型在肿瘤进展至癌阶段的过程中基本持续存在。在人类和小鼠胰腺癌中，ROR2的活性持续拮抗胃小凹细胞表型，可强力促进上皮间质转化，赋予癌细胞对KRAS抑制的抗性，同时使其对AKT抑制具有易感性。本数据集包含经对照及Ror2小干扰RNA（siRNA）处理的人类胰腺癌细胞系PANC1与UM5（n=3）。