Colon cancer is the third most prominent cancer and second leading cause of cancer-related deaths in the United States. Up to 20% of colon cancers follow the serrated tumor pathway driven by mutations in the MAPK pathway. Loss of SMAD4 function occurs in the majority of late-stage colon cancers and is associated with aggressive cancer progression. Therefore, it is important to develop technology to accurately model and better understand the genetic mechanisms behind cancer invasion. Organoids derived from tumors found in theSmad4KOBRAFV600E/+mouse model present multiple phenotypes characteristic of invasion both in ex vivo and in vivo systems.Smad4KOBRAFV600E/+tumor organoids can migrate through 3D culture and infiltrate through transwell membranes. This invasive behavior can be suppressed when SMAD4 is re-expressed in the tumor organoids. RNA-Seq analysis reveals that SMAD4 expression in organoids rapidly regulates transcripts associated with extracellular matrix and secreted proteins, suggesting that the mechanisms employed by SMAD4 to inhibit invasion are associated with regulation of extracellular matrix and secretory pathways. These findings indicate new models to study SMAD4 regulation of tumor invasion and an additional layer of complexity in the tumor-suppressive function of the SMAD4/Tgfβ pathway.
结肠癌是美国第三大常见癌症，也是癌症相关死亡的第二大主要原因。高达20%的结肠癌遵循由MAPK通路突变驱动的锯齿状肿瘤发展途径。SMAD4功能丧失在大多数晚期结肠癌中发生，并与侵袭性癌症进展相关。因此，开发技术以精确模拟并更好地理解癌症侵袭背后的遗传机制至关重要。源自Smad4KOBRAFV600E/+小鼠模型肿瘤的类器官在离体和体内系统中均表现出多种侵袭特征表型。Smad4KOBRAFV600E/+肿瘤类器官能够通过3D培养迁移并穿透transwell膜。当在肿瘤类器官中重新表达SMAD4时，这种侵袭行为可被抑制。RNA-Seq分析显示，类器官中SMAD4的表达能快速调控与细胞外基质和分泌蛋白相关的转录本，表明SMAD4抑制侵袭的机制与细胞外基质和分泌通路的调控相关。这些发现为研究SMAD4对肿瘤侵袭的调控提供了新模型，并揭示了SMAD4/Tgfβ通路抑癌功能的又一复杂层面。
肿瘤(癌症)患者之家