Gene expression programs of lactic acidosis in human cancers

描述（由申请人提供）：由于各种遗传改变和微环境压力，人类癌症的极端异质性对有效治疗提出了重大挑战。在许多实体肿瘤中，强有氧糖酵解和显著的灌注缺陷引起乳酸的积累，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、治疗反应和临床结局方面具有积极作用。虽然乳酸酸中毒抑制肿瘤生长和糖酵解，但在长时间暴露于乳酸酸中毒后存活的癌细胞通常会转移并抵抗放射治疗和化疗。因此，特异性靶向乳酸酸中毒下的癌细胞将有助于减少治疗抵抗并改善临床结果。尽管在缺氧条件下靶向细胞已经做出了显著的努力，但相对较少关注乳酸酸中毒条件下的靶向细胞。为了填补这一空白，我们提出了一个系统的方法来发现战略，特别是目标细胞下乳酸酸中毒的概念，应用“合成致死性”-基因的破坏，而正常耐受，赋予致死性下乳酸酸中毒。首先，我们将整合人类癌细胞的代谢组学和转录谱分析，以确定乳酸酸中毒引起的代谢能力和生物能量限制。第二，我们将进行全基因组的合成致死性RNAi筛选，以鉴定仅在乳酸酸中毒下生存所必需的基因。然后，通过遗传和化学抑制，我们将评估针对已确定的通路和基因的策略，这些通路和基因对乳酸酸中毒下的细胞至关重要。此外，我们将测试背景必需基因的DNA扩增是否赋予乳酸酸中毒下的任何存活优势，并使细胞独特地对其靶向敏感。该提案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，从而对患者的结果产生切实和积极的影响。 公共卫生相关性：癌症是一种重要的公共卫生风险。由于乳酸性酸中毒是大多数实体瘤的突出特征，我们关于识别新策略的建议 靶向乳酸酸中毒下的细胞可以改善治疗结果，并改善实体瘤患者的健康状况。

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. PUBLIC HEALTH RELEVANCE: Cancer is an important public health risk. Since lactic acidosis is a prominent feature in most solid tumors, our proposal on the identification of novel strategies to target cells under lactic acidosis can improve the treatment outcomes and improve the health of patients who suffer from solid tumors.