Abstract：
SMAD4 is a tumor suppressor mutated or silenced in multiple cancers, including oral cavity squamous cell carcinoma (OSCC). Human clinical samples and cell lines, mouse models and organoid culture were used to investigate the role that SMAD4 plays in progression from benign disease to invasive OSCC. Human OSCC lost detectable SMAD4 protein within tumor epithelium in 24% of cases, and this loss correlated with worse progression-free survival independent of other major clinical and pathological features. A mouse model engineered for KrasG12D expression in the adult oral epithelium induced benign papillomas, however the combination of KrasG12D with loss of epithelial Smad4 expression resulted in rapid development of invasive carcinoma with features of human OSCC. Examination of regulatory pathways in 3D organoid cultures of SMAD4+ and SMAD4- mouse tumors with Kras mutation found that either loss of SMAD4 or inhibition of TGFβ signaling upregulated the WNT pathway and altered the extracellular matrix. The gene signature of the mouse tumor organoids lacking SMAD4 was highly similar to the gene signature of human head and neck squamous cell carcinoma. In summary, this work has uncovered novel mechanisms by which SMAD4 acts as a tumor suppressor in OSCC. © 2024 The Author(s). The Journal of Pathology published by John Wiley & Sons Ltd on behalf of The Pathological Society of Great Britain and Ireland.
摘要：
SMAD4是一种在多种癌症中突变或沉默的肿瘤抑制因子，包括口腔鳞状细胞癌（OSCC）。人类临床样本和细胞系，小鼠模型和类器官培养用于研究SMAD4在良性疾病发展为侵袭性OSCC中的作用.在24%的病例中，人OSCC在肿瘤上皮内丢失了可检测的SMAD4蛋白，与其他主要临床和病理特征无关,这种损失与更差的无进展生存期相关.在成人口腔上皮诱导的良性乳头状瘤中设计了KrasG12D表达的小鼠模型，然而，KrasG12D与上皮Smad4表达缺失的组合导致具有人类OSCC特征的浸润性癌的快速发展。检查具有Kras突变的SMAD4和SMAD4-小鼠肿瘤的3D类器官培养物中的调节途径发现，SMAD4的丢失或TGFβ信号传导的抑制上调了WNT途径并改变了细胞外基质。缺乏SMAD4的小鼠肿瘤类器官的基因签名与人头颈部鳞状细胞癌的基因签名高度相似。总之,这项工作揭示了SMAD4在OSCC中作为肿瘤抑制因子的新机制。©2024作者（S）。由JohnWiley＆SonsLtd代表英国和爱尔兰病理学会出版的病理学杂志。
