Pancreatic ductal adenocarcinoma tumor growth requires SREBP pathway activity. Pancreatic ductal adenocarcinoma tumor growth requires SREBP pathway activity

Tumor growth outstrips local nutrient supply, making metabolic reprogramming a necessary component of oncogenesis and cancer progression. The supply of lipids such as cholesterol and fatty acids is required for continued tumor cell division. Sterol regulatory element-binding protein (SREBP) transcription factors control cellular lipid homeostasis by activating genes required for cholesterol and fatty acid synthesis and uptake. SREBPs have been implicated in the progression of multiple cancers, including glioblastoma, breast, colon, liver and prostate. However, the role 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 demonstrate that SREBP target genes are upregulated in PDAC tumors, and SREBPs are upregulated in patient-derived PDAC cell lines under low serum conditions that mimic the tumor microenvironment. Chemical or genetic inhibition of the SREBP pathway prevented PDAC cell growth under low serum conditions due to a lack of lipid supply. Using subcutaneous and orthotopic xenograft models, we showed that SCAP is required for PDAC tumor growth. Pancreas-specific knockout of Scap had no effect on mouse pancreas development or function, allowing examination of the role for Scap in the murine KPC model of PDAC. Notably, heterozygous loss of Scap significantly prolonged survival in KPC mice, and homozygous loss of Scap impaired PDAC tumor inception. Collectively, these results demonstrate that SCAP and SREBP pathway activity are essential for PDAC cell and tumor growth in vitro and in vivo, identifying SCAP as a potential therapeutic target for PDAC. Overall design: Total RNA isolated from patient derived pancreatic adenocarcinoma cells cultured in 0.5% FBS compared to same cells cultured in 10% FBS.

肿瘤生长速度超过局部营养供给能力，使得代谢重编程（metabolic reprogramming）成为肿瘤发生与进展的必要环节。
胆固醇、脂肪酸等脂质的供给是肿瘤细胞持续分裂所必需的。
固醇调节元件结合蛋白（Sterol Regulatory Element-Binding Protein, SREBP）转录因子通过激活胆固醇与脂肪酸合成、摄取相关基因，调控细胞脂质稳态。
已有研究表明SREBPs参与多种癌症的进展过程，包括胶质母细胞瘤、乳腺癌、结肠癌、肝癌与前列腺癌。
然而，SREBP通路及其核心调控因子SREBP裂解激活蛋白（SREBP Cleavage Activating Protein, SCAP）在胰腺导管腺癌（Pancreatic Ductal Adenocarcinoma, PDAC）中的具体作用尚未得到深入研究。
本研究证实，PDAC肿瘤中SREBP靶基因表达上调；在模拟肿瘤微环境的低血清培养条件下，患者来源的PDAC细胞系中SREBPs的表达同样上调。
由于脂质供给不足，对SREBP通路进行化学或遗传学抑制，可阻断低血清培养条件下PDAC细胞的生长。
通过皮下移植瘤与原位移植瘤模型，本研究证实SCAP是PDAC肿瘤生长所必需的调控因子。
对小鼠进行胰腺特异性Scap基因敲除，不会影响小鼠胰腺的发育与功能，这为研究Scap在PDAC小鼠KPC模型中的作用提供了可行条件。
值得注意的是，Scap杂合缺失可显著延长KPC小鼠的存活期，而Scap纯合缺失则会阻碍PDAC肿瘤的发生。
综上，本研究结果证实，SCAP与SREBP通路活性是PDAC细胞及肿瘤在体外与体内生长的必要条件，由此确定SCAP可作为PDAC潜在的治疗靶点。
实验整体设计：将患者来源的胰腺腺癌细胞分别置于0.5%胎牛血清（Fetal Bovine Serum, FBS）培养基中培养，并与相同细胞在10% FBS培养基中培养的样本进行总RNA提取与对比分析。