Annotating the Role of Dysregulated Inositol Phosphate Metabolism in Malignant Ca

描述（由申请人提供）：癌细胞从根本上改变了细胞代谢，为肿瘤的病因发展提供了生化基础。这些改变包括糖酵解成瘾（“Warburg效应”）、谷氨酰胺依赖性过敏症和新生脂质生物合成，它们是支持致瘤性的代谢平台。尽管这些因素在细胞从非癌性状态到癌性状态的转化中很重要，但对肿瘤进展过程中赋予恶性肿瘤的代谢途径了解甚少。由于大多数癌症死亡与癌症恶性和转移有关，因此了解导致这些癌症致病特征的代谢途径对于诊断和治疗都至关重要。我们对多种类型的侵袭性和非侵袭性人类癌细胞的基因表达进行了分析，发现了过多的代谢酶失调，其表达与恶性肿瘤高度相关。这些数据指向了一组代谢酶和途径，这些酶和途径可能在癌细胞中产生关键的生化变化，从而支持它们向高恶性状态发展。通过筛选确定基因敲低后表现出癌细胞侵袭性受损的酶，我们发现肌醇多磷酸磷酸酶1 （INPP1）的失活导致癌细胞迁移和侵袭性的显著缺陷。从我们对INPP1失活细胞的代谢组学分析的初步结果来看，有趣的是，我们发现INPP1释放肌醇磷酸，它为糖酵解中间体提供了重要的贡献，而这些中间体反过来又转向甘油磷脂的生物合成。这些令人兴奋的结果表明，糖酵解中间体不是主要由外源性葡萄糖产生，而是由内源性肌醇磷酸代谢产生，这使我们假设INPP1失活可能通过使癌细胞缺乏结构和致癌信号脂质所需的糖酵解中间体来抑制恶性肿瘤。该提案将研究肌醇磷酸代谢失调和INPP1在驱动人类癌症恶性发展中的作用，并确定INPP1失活是否可能是阻止癌症进展的一种有吸引力的策略。！

DESCRIPTION (provided by applicant): Cancer cells have fundamentally altered cellular metabolism that provide a biochemical foundation for tumors to progress in their etiology. These alterations include glycolytic addiction ("Warburg effect"), glutamine-dependent anaplerosis, and de novo lipid biosynthesis, which serve as metabolic platforms for supporting tumorigenicity. Although these factors are important in the transformation of cells from a non-cancerous to a cancerous state, much less is understood about the metabolic pathways that confer malignancy during tumor progression. Since most cancer deaths are related to cancer malignancy and metastasis, understanding metabolic pathways that contribute to these pathogenic features of cancer is critical for both diagnosis and treatment. Our efforts to profile the gene expression of broad panel of aggressive versus non-aggressive human cancer cells of multiple types have revealed a plethora of dysregulated metabolic enzymes whose expression is highly associated with cancer malignancy. These data point to a set of metabolic enzymes and pathways that may create key biochemical changes in cancer cells that support their progression to a high-malignancy state. Upon screening efforts to identify enzymes that, upon genetic knockdown, exhibit impaired cancer cell aggressiveness, we found that inactivation of inositol polyphosphate phosphatase 1 (INPP1) led to significant defects in cancer cell migration and invasiveness. From our preliminary results from metabolomic analyses of INPP1 inactivated cells, we interestingly find that INPP1 releases inositol phosphate, which then provides significant contributions to glycolytic intermediates, which are in-turn diverted towards biosynthesis of glycerophospholipids. These provocative results showing that glycolytic intermediates, instead of arising primarily from exogenous glucose, are generated from endogenous inositol phosphate metabolism, lead us to hypothesize that INPP1 inactivation may curb cancer malignancy by starving the cancer cell of glycolytic intermediates required for structural and oncogenic signaling lipids. This proposal will investigate the role of dysregulated inositol phosphate metabolism and INPP1 in driving the malignancy of human cancers and ascertain whether INPP1 inactivation may be an attractive strategy towards thwarting cancer progression. !