Gene expression programs of lactic acidosis in human cancers

描述（由申请人提供）：由于各种各样的遗传改变和微环境压力，人类癌症的极端异质性给有效治疗带来了重大挑战。强健的有氧糖酵解和显著的灌注缺陷导致乳酸的积累，称为乳酸酸中毒，在许多实体人肿瘤中。越来越多的证据表明，乳酸性酸中毒在影响肿瘤表型、治疗反应和临床结果方面发挥着积极作用。虽然乳酸酸中毒抑制肿瘤生长和糖酵解，但长期暴露于乳酸酸中毒的癌细胞通常会转移并抵抗放射和化疗。因此，特异性靶向乳酸酸中毒下的癌细胞将有助于降低治疗耐药性，改善临床结果。尽管针对缺氧状态下的细胞进行了大量的研究，但针对乳酸酸中毒状态下的细胞的研究相对较少。为了填补这一空白，我们提出了一种系统的方法，通过应用“合成致死性”的概念来发现特异性靶向乳酸酸中毒细胞的策略-基因的破坏，虽然通常是耐受的，但在乳酸酸中毒下赋予致死性。首先，我们将整合人类癌细胞的代谢组学和转录谱，以确定乳酸酸中毒造成的代谢不灵活性和生物能量限制。其次，我们将进行全基因组合成致死RNAi筛选，以鉴定仅在乳酸酸中毒情况下对生存至关重要的基因。然后，通过遗传和化学抑制，我们将评估针对乳酸酸中毒细胞的关键途径和基因的策略。此外，我们将测试上下文必需基因的DNA扩增是否赋予乳酸酸中毒下的任何生存优势，并使细胞独特地易受其靶向。该建议提出了一种创新和综合的方法，以确定新的策略来根除乳酸酸中毒下的癌细胞，从而对患者的预后产生切实和积极的影响。

DESCRIPTION (provided by applicant): The extreme heterogeneity of human cancers, due to a wide variety of genetic alterations and microenvironmental stresses, presents significant challenges for effective treatments. Robust aerobic glycolysis and significant perfusion defects cause an accumulation of lactic acid, termed lactic acidosis, in many solid human tumors. Evidence is accumulating for an active role of lactic acidosis in affecting tumor phenotypes, treatment responses and clinical outcomes. While lactic acidosis inhibits tumor growth and glycolysis, cancer cells that survive exposure to lactic acidosis for an extended period of time often metastasize and resist radio- and chemotherapeutics. Therefore, specifically targeting cancer cells under lactic acidosis will help reduce treatment resistance and improve clinical outcomes. Although significant efforts have been mead to target cells under hypoxia, relatively little attention has been paid to targeting cells under lactic acidosis. To fill this gap, we propoe a systematic approach to discover strategies to specifically target cells under lactic acidosis by applying the concept of "synthetic lethality" - genes whose disruptions, while normally tolerated, confer lethality under lactic acidosis. First, we will integrate metabolomic and transcriptional profiling of human cancer cells to identify the metabolic inflexibilities and bioenergetic restrictions imposed by lactic acidosis. Second, we will perform genome-wide, synthetic lethal RNAi screens to identify genes which are essential for survival only under lactic acidosis. Then through both genetic and chemical inhibition, we will evaluate strategies for targeting the identified pathways and genes that are critical for cells under lactic acidosis. In addition, we wil test whether the DNA amplification of the contextually- essential genes confers any survival advantage under lactic acidosis and renders cells uniquely susceptible to their targeting. This proposal presents an innovative and integrative approach to identify novel strategies to eradicate cancer cells under lactic acidosis to achieve a tangible and positive impact on patients' outcomes.