Department of General Surgery, The Second Affiliated Hospital of Soochow University, Suzhou, China.
Department of General Surgery, Haian People's Hospital, Haian, China.
Mol Carcinog. 2024 Oct;63(10):1953-1966. doi: 10.1002/mc.23785. Epub 2024 Jul 17.
Pancreatic ductal adenocarcinoma (PDAC) is one of the most aggressive tumors with poor prognosis and inadequate response to treatment, such as gemcitabine (Gem), the first-line chemotherapeutic drug. Understanding the molecular determinants that control drug resistance to Gem is critical to predict potentially responsive patients and improve the benefits of Gem therapy. Emerging evidence suggests that certain developmental pathways, such as Hippo signaling, are aberrated and play important roles in Gem resistance in cancers. Although Hippo signaling has been reported to play a role in chemoresistance in cancers, it has not been clarified which specific target gene(s) functionally mediates the effect. In the present study, we found that YAP serves as a potent barrier for the cellular sensitivity of PDAC cells to Gem. We then identified and characterized laminin subunit beta 3 (LAMB3) as a bona fide target of YAP-TEAD4 to amplify YAP signaling via a feedback loop. Such a YAP-LAMB3 axis is critical to induce epithelial-mesenchymal transition and mediate Gem resistance. Taken together, we uncovered that YAP-LAMB3 axis is an important regulator of Gem, thus providing potential therapeutic targets for overcoming Gem resistance in PDAC.
胰腺导管腺癌 (PDAC) 是一种侵袭性极强的肿瘤，预后不良，对治疗（如吉西他滨 (Gem)，一线化疗药物）反应不足。了解控制 Gem 耐药的分子决定因素对于预测潜在的反应性患者和提高 Gem 治疗的获益至关重要。新出现的证据表明，某些发育途径，如 Hippo 信号通路，在癌症的 Gem 耐药中失调并发挥重要作用。尽管 Hippo 信号通路已被报道在癌症的化疗耐药中发挥作用，但尚未阐明哪个特定的靶基因（s）在功能上介导了这种作用。在本研究中，我们发现 YAP 作为 PDAC 细胞对 Gem 敏感性的强大屏障。然后，我们确定并表征了层粘连蛋白亚单位β 3 (LAMB3) 作为 YAP-TEAD4 的真正靶点，通过反馈环放大 YAP 信号。这种 YAP-LAMB3 轴对于诱导上皮-间充质转化和介导 Gem 耐药至关重要。总之，我们揭示了 YAP-LAMB3 轴是 Gem 的重要调节剂，从而为克服 PDAC 中的 Gem 耐药提供了潜在的治疗靶点。
