细胞可塑性是胰腺导管腺癌 (PDAC) 的一个标志，从正常细胞转化为癌前病变，到与侵袭性和治疗反应相关的癌症亚型的进展。我们发现，由转录因子 Pdx1 维持的正常腺泡细胞分化抑制了小鼠和人类化生、肿瘤和 PDAC 经典亚型中维持的广泛胃细胞特征。我们已经鉴定出受体酪氨酸激酶 Ror2 作为胰腺肿瘤中胃化生样特征的标记。在胰腺肿瘤发生的小鼠模型中，Ror2 的消除促进了向胃凹细胞特征的转变，这种特征在很大程度上持续到 PDAC 的经典亚型的发展过程中。在人和小鼠胰腺癌中，ROR2 活性持续拮抗胃凹细胞特性，强烈促进上皮细胞向间质细胞的转变，赋予对 KRAS 抑制的抵抗力，并易受 AKT 抑制的影响。

Cellular plasticity is a hallmark of pancreatic ductal adenocarcinoma (PDAC) starting from the conversion of normal cells into precancerous lesions, to the progression of carcinoma subtypes associated with aggressiveness and therapeutic response. We discovered 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-like identity in pancreas neoplasms. 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 the classical subtype of PDAC. 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.