Lipids, either endogenously synthesized or exogenous, have been linked to human cancer. Here we found that PML is frequently co-deleted with PTEN in metastatic human prostate cancer (CaP). We demonstrated that conditional inactivation of Pml in the mouse prostate morphs indolent Pten-null tumors into lethal metastatic disease. We identified MAPK reactivation, subsequent hyperactivation of an aberrant SREBP prometastatic lipogenic program, and a distinctive lipidomic profile as key characteristic features of metastatic Pml and Pten double-null CaP. Furthermore, targeting SREBP in vivo by fatostatin blocked both tumor growth and distant metastasis. Importantly, a high-fat diet (HFD) induced lipid accumulation in prostate tumors and was sufficient to drive metastasis in a nonmetastatic Pten-null mouse model of CaP, and an SREBP signature was highly enriched in metastatic human CaP. Thus, our findings uncover a prometastatic lipogenic program and lend direct genetic and experimental support to the notion that a Western HFD can promote metastasis.

中文翻译：

---

异常的依赖于SREBP的脂肪生成程序会促进转移性前列腺癌。

内源性合成或外源性脂质都与人类癌症有关。在这里，我们发现PML在转移性人类前列腺癌（CaP）中经常与PTEN共同缺失。我们证明了小鼠前列腺中Pml的条件失活将惰性的Pten-null肿瘤变成致命的转移性疾病。我们确定了MAPK重新激活，异常SREBP转移性脂肪生成程序的后续超活化，以及独特的脂质组学特征，作为转移性Pml和Pten双无效CaP的关键特征。此外，通过脂肪抑制素在体内靶向SREBP可以阻止肿瘤生长和远处转移。重要的是，高脂饮食（HFD）会引起前列腺肿瘤中脂质的蓄积，并且足以在非转移性Pten-null的CaP小鼠模型中驱动转移，SREBP签名在转移性人类CaP中高度富集。因此，我们的发现揭示了一种促转移的脂肪生成程序，并为西方HFD可以促进转移的观念提供了直接的遗传和实验支持。