Effects of mitochondrial stress on intestinal tumor development depends on Apc status

Mitochondrial stress triggers both metabolic and transcriptomic reprogramming but its effects on tumor development remains unclear. It is also unknown whether the genetic status has any influence on the capacity of mitochondrial stress to control tumor development. To explore these issues, we generated a mouse model lacking the lipid transfer protein Stard7 in intestinal epithelial cells (IECs) and assessed tumor development in both Wnt-dependent tumor initiation and in inflammation-driven tumor development. The loss of Stard7 in both models of intestinal tumors impaired mitochondrial Complex I activity, led to a severe metabolic and lipidomic reprogramming and potentiated mTORC1 activation. As a result, levels of enzymes involved in serine biosynthesis were enhanced in Stard7-deficient IECs showing or not constitutive Wnt signaling. Strikingly, despite similar molecular signatures upon Stard7 deficiency in intestinal crypts showing or not constitutive Wnt signaling, Stard7 contributed to tumor development in AOM/DSS-treated mice but inhibits Wnt-driven cancer initiation in the intestine. Apc+/Min mice lacking Stard7 in IECs developed more tumors in the distal colon. Collectively, our results suggest that the Apc genetic status critically controls the effects of mitochondrial stress on intestinal tumor development.

线粒体应激可同时引发代谢与转录组重编程，但其对肿瘤发生发展的影响仍不明确。目前亦尚不明确遗传状态是否会影响线粒体应激调控肿瘤发生发展的能力。为探究上述问题，我们构建了肠上皮细胞（intestinal epithelial cells, IECs）中脂质转运蛋白Stard7缺失的小鼠模型，并分别在Wnt依赖型肿瘤发生模型与炎症驱动型肿瘤发生模型中评估肿瘤发展情况。在两种肠道肿瘤模型中，Stard7的缺失均会损伤线粒体复合物I活性，引发严重的代谢与脂质组重编程，并增强mTORC1激活。在存在或不存在组成型Wnt信号通路的情况下，Stard7缺陷型肠上皮细胞中参与丝氨酸生物合成的酶水平均有所升高。值得注意的是，尽管在携带或不携带组成型Wnt信号通路的肠隐窝中，Stard7缺失引发的分子特征相似，但Stard7在经偶氮甲烷（azoxymethane, AOM）/葡聚糖硫酸钠（dextran sulfate sodium, DSS）处理的小鼠中可促进肿瘤发生，却会抑制肠道内Wnt驱动的癌症起始。肠上皮细胞缺失Stard7的Apc+/Min小鼠，其远端结肠肿瘤数量更多。综上，我们的研究结果表明，Apc遗传状态可显著调控线粒体应激对肠道肿瘤发生发展的影响。