The transcription factor Prdm16 functions as a potent suppressor of transforming growth factor-beta (TGF-β) signaling, whose inactivation is deemed essential to the progression of pancreatic ductal adenocarcinoma (PDAC). Using the KrasG12D-based mouse model of human PDAC, we surprisingly found that ablating Prdm16 did not block but instead accelerated PDAC formation and progression, suggesting that Prdm16 might function as a tumor suppressor in this malignancy. Subsequent genetic experiments showed that ablating Prdm16 along with Smad4 resulted in a shift from a well-differentiated and confined neoplasm to a highly aggressive and metastatic disease, which was associated with a striking deviation in the trajectory of the premalignant lesions. Mechanistically, we found that Smad4 interacted with and recruited Prdm16 to repress its own expression, therefore pinpointing a model in which Prdm16 functions downstream of Smad4 to constrain the PDAC malignant phenotype. Collectively, these findings unveil an unprecedented antagonistic interaction between the tumor suppressors Smad4 and Prdm16 that functions to restrict PDAC progression and metastasis.

中文翻译：

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Prdm16 和 Smad4 之间的拮抗作用决定了胰腺癌的轨迹和进展


转录因子 Prdm16 是转化生长因子-β (TGF-β) 信号传导的有效抑制剂，其失活被认为对胰腺导管腺癌 (PDAC) 的进展至关重要。使用基于 KrasG12D 的人类 PDAC 小鼠模型，我们令人惊讶地发现消除 Prdm16 并没有阻断而是加速了 PDAC 的形成和进展，这表明 Prdm16 可能在这种恶性肿瘤中发挥肿瘤抑制作用。随后的基因实验表明，消除 Prdm16 和 Smad4 会导致从分化良好的局限性肿瘤转变为高度侵袭性和转移性疾病，这与癌前病变轨迹的显着偏差有关。从机制上讲，我们发现 Smad4 与 Prdm16 相互作用并招募 Prdm16 来抑制其自身表达，因此确定了 Prdm16 在 Smad4 下游发挥作用以限制 PDAC 恶性表型的模型。总的来说，这些发现揭示了肿瘤抑制因子 Smad4 和 Prdm16 之间前所未有的拮抗相互作用，其作用是限制 PDAC 进展和转移。