Concomitant Loss of Smad4 and Activation of Wnt Signaling Triggers Enterocyte De-differentiation and Adenoma Formation

In the current work, we add to the understanding of differentiated-cell-derived tumorigenesis by demonstrating that simultaneous loss of SMAD4 and activation of the WNT pathway triggers stem cell properties and adenoma formation in the differentiated epithelium. Under normal conditions, SMAD4 loss does not immediately affect the normal tissue homeostasis in the intestine. However, after approximately 6 months, adenomas will develop and feature elevated WNT signaling, suggesting that SMAD4 loss predisposes to WNT-driven tumors. Interestingly, ectopic elevation of WNT in the context of a SMAD4 mutant background triggers stem cell activity and adenoma formation in the differentiated epithelium. Thus Smad4 functions to suppress villus cells from re-entering the cell cycle and functioning as stem cells upon exposure to high levels of WNT. Thus, we report a new mechanism through which differentiated cells can contribute to tumor formation.

本研究通过证实SMAD4缺失联合WNT通路（WNT pathway）激活可在分化上皮中诱导干细胞特性与腺瘤形成，加深了学界对分化细胞来源肿瘤发生机制的认知。正常生理状态下，SMAD4缺失并不会立即影响肠道组织的稳态平衡；但在约6个月后，可形成腺瘤并伴随WNT信号通路激活上调，提示SMAD4缺失会使机体易患WNT通路驱动的肿瘤。有趣的是，在SMAD4突变背景下，WNT的异位高表达可在分化上皮中诱导干细胞活性与腺瘤形成。由此可见，SMAD4的功能是抑制肠绒毛细胞在高WNT信号刺激下重新进入细胞周期并行使干细胞功能。综上，本研究揭示了一种分化细胞参与肿瘤形成的全新机制。