Gene expression programs of lactic acidosis in human cancers

描述(申请人提供)：人类癌症的极端异质性，由于各种各样的基因改变和微环境压力，对有效的治疗提出了巨大的挑战。在许多实体人类肿瘤中，强健的有氧糖酵解和显著的血流灌注缺陷会导致乳酸积聚，称为乳酸酸中毒。越来越多的证据表明，乳酸酸中毒在影响肿瘤表型、治疗反应和临床结果方面发挥了积极作用。虽然乳酸酸中毒抑制了肿瘤生长和糖酵解，但长期暴露在乳酸酸中毒中存活的癌细胞通常会转移，并对放、化疗药物产生抵抗。因此，针对乳酸酸中毒条件下的肿瘤细胞进行靶向治疗将有助于降低治疗耐药性，改善临床疗效。尽管在低氧条件下靶向细胞的研究已经取得了很大的进展，但在乳酸酸中毒条件下靶向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来发现策略，通过应用“合成致死性”的概念来特定地针对乳酸酸中毒下的细胞--这些基因的中断，虽然通常是可以容忍的，但在乳酸酸中毒下会赋予致命性。首先，我们将整合人类癌细胞的代谢和转录图谱，以确定乳酸酸中毒造成的代谢不灵活和生物能量限制。其次，我们将进行全基因组、人工合成的致命性RNAi筛选，以确定仅在乳酸酸中毒情况下生存所必需的基因。然后，通过基因和化学抑制，我们将评估针对乳酸酸中毒下对细胞至关重要的已识别途径和基因的策略。此外，我们还将测试在乳酸酸中毒的情况下，相关必需基因的DNA扩增是否具有任何生存优势，并使细胞对其靶向具有独特的易感性。这项建议提出了一种创新和综合的方法，以确定新的战略，以根除乳酸酸中毒下的癌细胞，以实现对患者预后的切实和积极的影响。

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.