TGF-β & Pancreatic Cancer Lab, Centre de Recherche en Cancérologie de Lyon (CRCL), Centre Léon Bérard, INSERM 1052, CNRS 5286, Université de Lyon, Université Claude Bernard Lyon 1, Lyon, France.
Hospices Civils de Lyon, Institute of Pathology, Groupement Hospitalier Est, Bron, France.
Commun Biol. 2022 Oct 7;5(1):1068. doi: 10.1038/s42003-022-03994-6.
TGF-β signaling is involved in pancreatic ductal adenocarcinoma (PDAC) tumorigenesis, representing one of the four major pathways genetically altered in 100% of PDAC cases. TGF-β exerts complex and pleiotropic effects in cancers, notably via the activation of SMAD pathways, predominantly SMAD2/3/4. Though SMAD2 and 3 are rarely mutated in cancers, SMAD4 is lost in about 50% of PDAC, and the role of SMAD2/3 in a SMAD4-null context remains understudied. We herein provide evidence of a SMAD2/3 oncogenic effect in response to TGF-β1 in SMAD4-null human PDAC cancer cells. We report that inactivation of SMAD2/3 in SMAD4-negative PDAC cells compromises TGF-β-driven collective migration mediated by FAK and Rho/Rac signaling. Moreover, RNA-sequencing analyses highlight a TGF-β gene signature related to aggressiveness mediated by SMAD2/3 in the absence of SMAD4. Using a PDAC patient cohort, we reveal that SMAD4-negative tumors with high levels of phospho-SMAD2 are more aggressive and have a poorer prognosis. Thus, loss of SMAD4 tumor suppressive activity in PDAC leads to an oncogenic gain-of-function of SMAD2/3, and to the onset of associated deleterious effects.
TGF-β 信号通路参与胰腺导管腺癌（PDAC）的肿瘤发生，这是 100%的 PDAC 病例中发生遗传改变的四大主要通路之一。TGF-β 在癌症中发挥复杂而多效的作用，特别是通过激活 SMAD 通路，主要是 SMAD2/3/4。尽管 SMAD2 和 3 在癌症中很少发生突变，但 SMAD4 在大约 50%的 PDAC 中丢失，并且在 SMAD4 缺失的情况下 SMAD2/3 的作用仍未得到充分研究。我们在此提供了在 SMAD4 缺失的人类 PDAC 癌细胞中 TGF-β1 反应中 SMAD2/3 致癌作用的证据。我们报告称，SMAD4 阴性 PDAC 细胞中 SMAD2/3 的失活会损害由 FAK 和 Rho/Rac 信号介导的 TGF-β 驱动的集体迁移。此外，RNA 测序分析突出了 TGF-β 基因特征，该特征与 SMAD4 缺失时由 SMAD2/3 介导的侵袭性相关。使用 PDAC 患者队列，我们揭示了具有高水平磷酸化 SMAD2 的 SMAD4 阴性肿瘤更具侵袭性，预后更差。因此，SMAD4 缺失导致 PDAC 中 SMAD2/3 的致癌功能获得，并导致相关有害作用的发生。
