Role of a Novel Stress Response Mechanism-Genetic Buffering-in Tumor Evolution

描述（由申请人提供） 翻译后摘要：癌症是第二个最常见的死亡原因在美国;每年有50多万美国人死于癌症。尽管在过去的三十年里，癌症研究和治疗工作取得了巨大的进展，但进展却令人沮丧地缓慢。迫切需要对基础肿瘤生物学和创新思维有更深入的了解。在这个建议中，我们专注于理解一种新的肿瘤发生的范式-压力表型和压力反应成瘾，这可能代表了癌症生物学的一个基本方面，同时也是癌症的主要脆弱性。我们之前的研究结果表明，已知可以保护细胞免受压力的压力反应也是肿瘤发生的多方面因素。在我们最初发现的一个重大进展中，该提案旨在询问应激反应的开创性机制-“遗传缓冲”-在肿瘤演变中的作用，以及应激表型的潜在临床应用，这是癌症的一个新兴标志。具体来说，我们将解决两个关键问题：1）压力反应是否可以通过遗传缓冲促进肿瘤的演变？2)应激表型能否如实反映肿瘤的恶性潜能？除了概念上的进步，这种新的范式可能具有广泛的临床意义。癌症的应激表型可用作肿瘤恶性程度的通用指标和实现肿瘤分子成像的创新方法的机制。此外，由于癌症的应激反应成瘾性，应激反应可以作为癌症预防和治疗的新靶点。从广义上讲，这些概念可以为未来的癌症治疗提供一个统一的框架。这项拟议的研究非常适合这种独特的资助机制，因为它测试了癌症生物学中一个新兴的高度创新的概念，如果成功，可能会对癌症研究和治疗产生重大影响。 公共卫生相关性：这项研究检查了通常保护细胞免受环境侵害的应激反应是否真的能够，并且实际上可能是人类肿瘤中癌症起始和进展所普遍需要的。这些开创性的研究可能最终导致应激反应作为人类癌症新诊断、预防和治疗方法的一般标志物和靶标的发展。

DESCRIPTION (Provided by the applicant) Abstract: Cancer is the second most common cause of death in the U.S.; over half a million Americans die from cancer each year. Despite the tremendous cancer research and treatment efforts over the past three decades, progress has been frustratingly slow. A deeper understanding of fundamental tumor biology and innovative thinking are urgently needed. In this proposal, we focus on understanding a novel paradigm of tumorigenesis-the stress phenotype and stress-response addiction, which may represent a fundamental aspect of cancer biology and at the same time a principal vulnerability of cancer. Our previous findings reveal that the stress response, known to protect cells from stress, is also a multifaceted enabler of tumorigenesis. In a major advance from our original findings, this proposal aims to interrogate the role of a pioneering mechanism of the stress response- "genetic buffering" -in tumor evolution, and the potential clinical applications of the stress phenotype, an emerging hallmark of cancer. Specifically, we will address two key questions: 1) Can the stress response advance tumor evolution by genetic buffering? 2) Can the stress phenotype faithfully indicate tumor malignant potential? In addition to conceptual advances, this new paradigm could have broad clinical implications. The stress phenotype of cancer may be utilized as a generic indicator of tumor malignancy and a mechanism enabling an innovative approach for tumor molecular imaging. Further, because of the stress-response addiction of cancer, the stress response may serve as a novel target for both cancer prevention and therapy. In a broad sense, these concepts could provide a unifying framework for future cancer therapies. This proposed research is well suited to this unique funding mechanism, as it tests a newly emerging and highly innovative concept in cancer biology, which, if successful, could have major impacts on cancer research and treatment. Public Health Relevance: This research examines whether the stress response, which normally protects cells from environmental insults, actually enables, and may in fact be universally required for, cancer initiation and progression in human tumors. These pioneering studies may ultimately lead to development of the stress response as a general marker and target for novel diagnosis, prevention and treatment methods for human cancer.