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，为肿瘤的病因学进展提供了生物化学基础。这些改变包括糖酵解成瘾（“瓦尔堡效应”）、谷氨酰胺依赖性回补和从头脂质生物合成，其作为支持致瘤性的代谢平台。虽然这些因素在细胞从非癌性转化为癌性状态中很重要，但对肿瘤进展期间赋予恶性的代谢途径了解得少得多。由于大多数癌症死亡与癌症恶性程度和转移有关，因此了解导致癌症这些致病特征的代谢途径对于诊断和治疗至关重要。我们对多种类型的侵袭性与非侵袭性人类癌细胞的基因表达谱分析的努力揭示了过多的失调的代谢酶，其表达与癌症恶性程度高度相关。这些数据指向一组代谢酶和途径，这些代谢酶和途径可能在癌细胞中产生关键的生化变化，从而支持癌细胞向高度恶性状态的进展。在筛选鉴定基因敲低后表现出癌细胞侵袭性受损的酶时，我们发现肌醇多磷酸磷酸酶1（INPP 1）的失活导致癌细胞迁移和侵袭性的显著缺陷。从我们对INPP 1失活细胞的代谢组学分析的初步结果中，我们有趣地发现INPP 1释放肌醇磷酸，然后为糖酵解中间体提供重要贡献，糖酵解中间体又转向甘油磷脂的生物合成。这些挑衅性的结果表明，糖酵解中间体，而不是产生主要来自外源性葡萄糖，是由内源性磷酸肌醇代谢，导致我们假设，INPP 1失活可能遏制癌症恶性肿瘤的饥饿所需的结构和致癌信号脂质的糖酵解中间体的癌细胞。该提案将研究磷酸肌醇代谢失调和INPP 1在驱动人类癌症恶性肿瘤中的作用，并确定INPP 1失活是否可能是阻碍癌症进展的有吸引力的策略。!

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. !