Molecular mechanisms of GI Tumor cell reprogramming governed by lactate metabolism

乳酸代谢控制胃肠道肿瘤细胞重编程的分子机制

• 批准号: 398809650
• 负责人: Professor Dr. Heiner Schäfer
• 金额: --
• 依托单位: Institut für Experimentelle Tumorforschung
• 依托单位国家: 德国
• 项目类别: Research Grants
• 财政年份: 2018
• 资助国家: 德国
• 起止时间: 2017-12-31 至 2021-12-31
• 项目状态: 已结题
• 来源: https://gepris.dfg.de/gepris/projekt/398809650?language=en
• 关键词: Molecular; mechanisms; GI; Tumor; cell

Representing an important determinant of the cellular phenotype, cell metabolism has an essential role in tumorigenesis, A particular condition that greatly impacts on phenotype manifestation and clonal diversity is the metabolic compartmentalization and symbiosis that characterizes the ecosystem and heterogeneity in many soild and stroma-rich tumors (including pancreatic and colorectal cancer). This is controlled by extrinsic effectors like glucose and oxygen supply or by oxidative stress involving mediating transcription factors such as HIF1α, Nrf2 and ATF3. An important manifestation of metabolic compartmentalization/ symbiosis is the aerobe-glycolytic (Warburg) metabolism and the lactate dependent/OxPhos (reverse Warburg) metabolism. Here, not only biomass and energy is transferred bewteen distinct cell types, but also metabolites exerting fundamental effects on the cellular phenotype. This mainly includes direct effects on histone- and DNA-modifications, thereby greatly affecting the epigenome. Depending on these alterations, cellular traits manifest that contribute to tumor malignancy (such as resistance, metastasis formation) and that particulary favour the emergence of clonal entities with stem cell-like properties or a phenotype of cellular dormancy. Given the fact that the reverse Warburg metabolism associates with the advancement and poor prognosis in many types of solid tumors, a better understanding of these metabolite mediated effects is certainly of great relevance. The present project therefore aims at elucidating the modalities and cellular events relating to the reverse Warburg metabolism in colorectal and pancreatic cancer. The working plan will address the following issues: 1) By means of cell culture based models the association between reverse Warburg metabolites, epigenome and phenotype alterations will be elucidated; 2.) Immunohistochemical analyses of tumor tissues from pancreatic (PDAC)- and colorectal cancer (CRC) patients will validate the clinico-pathological role of the reverse Warburg metabolism; 3.) Employing the Pdx1-Flp;FSF-KrasG12D/+;Trp53frt/+ (KPF) PDAC-mouse model, which particularly allows the assessment of desmoplastic mechanisms and the temporal tumorigenesis sequence, the impact of the reverse Warburg metabolism on pancreatic carcinogenesis and metastasis will be studied in vivo.

细胞代谢是细胞表型的重要决定因素，在肿瘤发生中起着重要作用。对表型表现和克隆多样性有很大影响的一个特殊条件是代谢区室化和共生，其表征了许多固体和基质丰富的肿瘤（包括胰腺癌和结直肠癌）中的生态系统和异质性。这是由外部效应物如葡萄糖和氧气供应或氧化应激控制的，涉及介导转录因子如HIF 1 α，Nrf 2和ATF 3。代谢区室化/共生的一个重要表现是需氧-糖酵解（瓦尔堡）代谢和乳酸依赖性/OxPhos（反向瓦尔堡）代谢。在这里，不仅生物量和能量在不同的细胞类型之间转移，而且代谢产物对细胞表型产生根本影响。这主要包括对组蛋白和DNA修饰的直接影响，从而极大地影响表观基因组。取决于这些改变，细胞性状表现出有助于肿瘤恶性（如抗性、转移形成），并且特别有利于具有干细胞样特性或细胞休眠表型的克隆实体的出现。鉴于逆向瓦尔堡代谢与许多类型实体瘤的进展和不良预后相关，更好地理解这些代谢物介导的作用肯定具有重要意义。因此，本项目旨在阐明结肠直肠癌和胰腺癌中与反向瓦尔堡代谢相关的模式和细胞事件。工作计划将解决以下问题：1）通过基于细胞培养的模型，将阐明反向瓦尔堡代谢物、表观基因组和表型改变之间的关联; 2）来自胰腺癌（PDAC）和结直肠癌（CRC）患者的肿瘤组织的免疫组织化学分析将验证反向瓦尔堡代谢的临床病理学作用; 3.）使用Pdx 1-Flp; FSF-KrasG12D/+; Trp 53 frt/+（KPF）PDAC-小鼠模型，其特别允许评估促结缔组织增生机制和时间肿瘤发生顺序，将在体内研究反向瓦尔堡代谢对胰腺癌发生和转移的影响。