Department of Anatomy and Stem Cells and Metabolism Research Program, Faculty of Medicine, University of Helsinki, Helsinki, Finland.
Minerva Foundation Institute for Medical Research, Helsinki, Finland.
Cancer Res. 2022 Nov 2;82(21):3932-3949. doi: 10.1158/0008-5472.CAN-22-0396.
Pancreatic ductal adenocarcinoma (PDAC) is among the deadliest malignancies and potentially curable only with radical surgical resection at early stages. The tumor microenvironment has been shown to be central to the development and progression of PDAC. A better understanding of how early human PDAC metabolically communicates with its environment and differs from healthy pancreas could help improve PDAC diagnosis and treatment. Here we performed deep proteomic analyses from diagnostic specimens of operable, treatment-naïve PDAC patients (n = 14), isolating four tissue compartments by laser-capture microdissection: PDAC lesions, tumor-adjacent but morphologically benign exocrine glands, and connective tissues neighboring each of these compartments. Protein and pathway levels were compared between compartments and with control pancreatic proteomes. Selected targets were studied immunohistochemically in the 14 patients and in additional tumor microarrays, and lipid deposition was assessed by nonlinear label-free imaging (n = 16). Widespread downregulation of pancreatic secretory functions was observed, which was paralleled by high cholesterol biosynthetic activity without prominent lipid storage in the neoplastic cells. Stromal compartments harbored ample blood apolipoproteins, indicating abundant microvasculature at the time of tumor removal. The features best differentiating the tumor-adjacent exocrine tissue from healthy control pancreas were defined by upregulation of proteins related to lipid transport. Importantly, histologically benign exocrine regions harbored the most significant prognostic pathways, with proteins involved in lipid transport and metabolism, such as neutral cholesteryl ester hydrolase 1, associating with shorter survival. In conclusion, this study reveals prognostic molecular changes in the exocrine tissue neighboring pancreatic cancer and identifies enhanced lipid transport and metabolism as its defining features.
In clinically operable pancreatic cancer, regions distant from malignant cells already display proteomic changes related to lipid transport and metabolism that affect prognosis and may be pharmacologically targeted.
胰腺导管腺癌（PDAC）是最致命的恶性肿瘤之一，只有在早期阶段通过根治性手术切除才能治愈。肿瘤微环境已被证明是 PDAC 发展和进展的核心。更好地了解早期人类 PDAC 如何与环境进行代谢交流以及与健康胰腺的不同之处，可能有助于改善 PDAC 的诊断和治疗。在这里，我们对可手术治疗、未经治疗的 PDAC 患者的诊断标本（n = 14）进行了深度蛋白质组学分析，通过激光捕获显微切割分离出四个组织区室：PDAC 病变、肿瘤附近但形态良性的外分泌腺和每个这些区室相邻的结缔组织。比较了区室之间以及与对照胰腺蛋白质组之间的蛋白质和途径水平。在 14 名患者和另外的肿瘤微阵列中对选定的靶标进行了免疫组织化学研究，并通过非线性无标记成像（n = 16）评估了脂质沉积。观察到胰腺分泌功能广泛下调，同时伴有高胆固醇生物合成活性，而肿瘤细胞中没有明显的脂质储存。基质区室含有丰富的血液载脂蛋白，表明在肿瘤切除时存在丰富的微血管。将肿瘤相邻外分泌组织与健康对照胰腺区分开来的最佳特征是与脂质转运相关的蛋白质上调。重要的是，组织学良性的外分泌区含有最显著的预后途径，涉及脂质转运和代谢的蛋白质，如中性胆固醇酯水解酶 1，与较短的生存期相关。总之，这项研究揭示了胰腺癌相邻外分泌组织中的预后分子变化，并确定了增强的脂质转运和代谢是其特征。
在临床上可手术的胰腺癌中，远离恶性细胞的区域已经显示出与脂质转运和代谢相关的蛋白质组变化，这些变化会影响预后，并且可能成为药物治疗的靶点。
