背景：胰导管腺癌（PDAC）是一种侵袭性实体肿瘤，存活率极低。确定推动PDAC进展的关键信号通路对于开发改善患者反应率的疗法至关重要。Kindlin-2是一种多功能蛋白质，参与许多生物过程，包括细胞增殖、凋亡和迁移。然而，关于Kindlin-2在胰腺癌进展中的功能知之甚少。方法：在本研究中，我们采用体内PDAC小鼠模型直接研究Kindlin-2在PDAC进展中的作用。然后，我们利用RNA测序、分子和细胞试验来确定Kindlin-2促进PDAC进展的分子机制。结果：我们发现Kindlin-2的丧失显著抑制了KrasG12D驱动的胰腺癌的体内和体外进展。此外，我们提供了Kindlin-2在这一过程中的新的机制洞察。部分Kindlin-2定位在内质网并与RNA解旋酶DDX3X相联系，后者是mRNA翻译的关键调节因子。Kindlin-2的丧失阻止DDX3X与c-Myc的5'非翻译区结合，抑制DDX3X介导的c-Myc翻译，导致c-Myc介导的葡萄糖代谢和肿瘤生长减少。重要的是，在Kindlin-2缺陷的PDAC细胞中恢复完整的Kindlin-2或c-Myc的表达，而不是DDX3X结合缺陷突变体Kindlin-2的表达，可以逆转由于Kindlin-2丧失引起的糖酵解抑制和胰腺癌进展。结论：我们的研究揭示了PDAC进展中一种新的Kindlin-2-DDX3X-c-Myc信号通路，并暗示该信号通路的抑制可能提供一种有前景的治疗方法来缓解PDAC的进展。©作者（们）。

Rationale: Pancreatic ductal adenocarcinoma (PDAC) is an aggressive solid tumor, with extremely low survival rates. Identifying key signaling pathways driving PDAC progression is crucial for the development of therapies to improve patient response rates. Kindlin-2, a multi-functional protein, is involved in numerous biological processes including cell proliferation, apoptosis and migration. However, little is known about the functions of Kindlin-2 in pancreatic cancer progression in vivo. Methods: In this study, we employ an in vivo PDAC mouse model to directly investigate the role of Kindlin-2 in PDAC progression. Then, we utilized RNA-sequencing, the molecular and cellular assays to determine the molecular mechanisms by which Kindlin-2 promotes PDAC progression. Results: We show that loss of Kindlin-2 markedly inhibits KrasG12D-driven pancreatic cancer progression in vivo as well as in vitro. Furthermore, we provide new mechanistic insight into how Kindlin-2 functions in this process, A fraction of Kindlin-2 was localized to the endoplasmic reticulum and associated with the RNA helicase DDX3X, a key regulator of mRNA translation. Loss of Kindlin-2 blocked DDX3X from binding to the 5'-untranslated region of c-Myc and inhibited DDX3X-mediated c-Myc translation, leading to reduced c-Myc-mediated glucose metabolism and tumor growth. Importantly, restoration of the expression of either the full-length Kindlin-2 or c-Myc, but not that of a DDX3X-binding-defective mutant of Kindlin-2, in Kindlin-2 deficient PDAC cells, reversed the inhibition of glycolysis and pancreatic cancer progression induced by the loss of Kindlin-2. Conclusion: Our studies reveal a novel Kindlin-2-DDX3X-c-Myc signaling axis in PDAC progression and suggest that inhibition of this signaling axis may provide a promising therapeutic approach to alleviate PDAC progression.© The author(s).