The paradoxical roles of beta hydroxy butyrate in the liver pro-metastatic niche

项目总结/摘要 肝转移是癌症治疗的一大障碍。几种癌症，包括前列腺（PCa）， 结直肠癌（CRC）和胰腺导管腺癌（PDAC）通常转移到该部位。数据显示 肝转移是由原发肿瘤的内分泌信号促进的， 微环境尽管如此，这种转移前到转移后的小生境转化也可以是 受到治疗和饮食的影响。生酮饮食（KD）是一种高脂肪的碳水化合物限制饮食， 使脂肪酸成为能量的主要来源，并促进β-羟基丁酸（βHB）的合成（酮症）。 KD已成功用于帮助患有神经退行性疾病的患者。此外， 提出通过诱导反向Warburg效应和使细胞对 检查点抑制剂。然而，有报道表明βHB能够使癌症干细胞适应营养应激， 前列腺癌的发生与肿瘤的进展和分期有关。然而，βHB也是一种 据报道，肿瘤抑制因子是已知的HDAC抑制剂和通过烟酸受体的信号分子， GPR 109 a，在结肠癌和乳腺癌细胞中。了解到肝脏是βHB合成的主要器官， 本研究旨在阐明生酮代谢对肝转移前小生境的影响， PCa和CRC在其独特的代谢重编程中的矛盾作用。

Project Summary/Abstract Liver metastasis is a steep obstacle for curative cancer treatment. Several cancers including prostate (PCa), colorectal (CRC) and pancreatic ductal adenocarcinoma (PDAC) commonly metastasize to this site. Data shows that liver metastasis is promoted by endocrine signaling from the primary tumor which can transform the liver microenvironment. Nonetheless, this pre-metastatic to post-metastatic niche transformation can also be influenced by therapy and diet. The ketogenic diet (KD) is a high-fat carb-restrictive diet that mimics fasting by making fatty acids the main source of energy and promoting beta hydroxy butyrate (βHB) synthesis (ketosis). KD has been successfully used to aid patients with neurodegenerative diseases. Additionally, it has been proposed to ameliorate different types of cancer by inducing a reverse-Warburg effect and sensitizing cells to checkpoint inhibitors. However, reports show that βHB enables adaptability to nutritional stress in cancer stem cells and is associated with tumor progression and staging of prostate cancer. Nevertheless, βHB is also a reported tumor suppressor being a known HDAC inhibitor and a signaling molecule through the niacin receptor, GPR109a, in colon and breast cancer cells. Understanding that the liver is the main βHB synthesis organ, in this study we aim to elucidate the effects of a ketogenic metabolism affecting the liver premetastatic niche and its paradoxical roles with PCa and CRC in their distinct metabolic reprogramming.