Department of Cell Biology, Johns Hopkins University School of Medicine, Baltimore, Maryland.
Department of Molecular and Comparative Pathobiology, Johns Hopkins University School of Medicine, Baltimore, Maryland.
Cancer Res Commun. 2024 Sep 1;4(9):2539-2552. doi: 10.1158/2767-9764.CRC-24-0120.
Solid tumors undergo metabolic reprogramming when growth outstrips local nutrient supply. Lipids such as cholesterol and fatty acids are required for continued tumor cell proliferation, and oncogenic mutations stimulate de novo lipogenesis to support tumor growth. Sterol regulatory element-binding protein (SREBP) transcription factors control lipid homeostasis by activating genes required for lipid synthesis and uptake. SREBPs have been implicated in the progression of brain, breast, colon, liver, and prostate cancers. However, the role of the SREBP pathway and its central regulator SREBP cleavage activating protein (SCAP) in pancreatic ductal adenocarcinoma (PDAC) has not been studied in detail. Here, we demonstrated that pancreas-specific knockout of Scap has no effect on mouse pancreas development or function, allowing for examination of the role of Scap in the murine KPC model of PDAC. Notably, heterozygous loss of Scap prolonged survival in KPC mice, and homozygous loss of Scap impaired PDAC tumor progression. Using xenograft models, we showed that SCAP is required for human PDAC tumor growth. Mechanistically, chemical or genetic inhibition of the SREBP pathway prevented PDAC cell growth under low-serum conditions because of a lack of lipid supply. Highlighting its clinical importance, the SREBP pathway is broadly required across cancer cell lines, target genes are upregulated in human PDAC tumors, and increased expression of SREBP targets is associated with poor survival in patients with PDAC. Collectively, these results demonstrate that SCAP and SREBP pathway activity are required for PDAC cell and tumor growth, identifying SCAP as a potential therapeutic target for PDAC.
Our findings demonstrate that SREBP pathway activation is a critical part of the metabolic reprogramming that occurs in PDAC development and progression. Therefore, targeting the SREBP pathway has significant therapeutic potential.
当肿瘤生长超过局部营养供应时，实体瘤会经历代谢重编程。胆固醇和脂肪酸等脂质是肿瘤细胞持续增殖所必需的，致癌突变会刺激从头合成脂质以支持肿瘤生长。固醇调节元件结合蛋白 (SREBP) 转录因子通过激活脂质合成和摄取所需的基因来控制脂质稳态。SREBPs 被认为与脑、乳腺、结肠、肝和前列腺癌的进展有关。然而，SREBP 途径及其核心调节因子 SREBP 切割激活蛋白 (SCAP) 在胰腺导管腺癌 (PDAC) 中的作用尚未得到详细研究。在这里，我们证明了胰腺特异性 Scap 敲除对小鼠胰腺发育或功能没有影响，从而可以研究 Scap 在 KPC 小鼠 PDAC 模型中的作用。值得注意的是，Scap 的杂合缺失延长了 KPC 小鼠的存活时间，而 Scap 的纯合缺失则损害了 PDAC 肿瘤的进展。通过异种移植模型，我们表明 SCAP 是人类 PDAC 肿瘤生长所必需的。从机制上讲，在低血清条件下，化学或遗传抑制 SREBP 途径会阻止 PDAC 细胞生长，因为缺乏脂质供应。突出其临床重要性，SREBP 途径广泛存在于癌细胞系中，靶基因在人类 PDAC 肿瘤中上调，并且 SREBP 靶基因的表达增加与 PDAC 患者的不良生存相关。总之，这些结果表明 SCAP 和 SREBP 途径活性是 PDAC 细胞和肿瘤生长所必需的，鉴定 SCAP 为 PDAC 的潜在治疗靶点。
我们的研究结果表明，SREBP 途径的激活是 PDAC 发生和发展中代谢重编程的关键部分。因此，靶向 SREBP 途径具有重要的治疗潜力。
