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

描述(由申请人提供) 摘要：癌症是美国第二大常见死因；每年有超过50万美国人死于癌症。尽管在过去的30年里，癌症研究和治疗做出了巨大的努力，但进展缓慢得令人沮丧。迫切需要对基础肿瘤生物学有更深入的了解和创新思维。在这个提议中，我们专注于理解肿瘤发生的一个新范式--应激表型和应激反应成瘾，这可能代表了癌症生物学的一个基本方面，同时也是癌症的一个主要脆弱性。我们以前的发现表明，应激反应，众所周知，保护细胞免受应激，也是一个多方面的肿瘤发生的启动因素。在我们最初发现的一个重大进展中，这项提议旨在询问应激反应的开创性机制--“遗传缓冲”--在肿瘤进化中的作用，以及应激表型的潜在临床应用，应激表型是癌症的一个新标志。具体地说，我们将解决两个关键问题：1)应激反应能否通过遗传缓冲促进肿瘤的进化？2)应激表型能否忠实地指示肿瘤的恶性潜能？除了概念上的进步，这一新的范例可能具有广泛的临床意义。癌症的应激表型可能被用作肿瘤恶性程度的通用指标，并可能成为肿瘤分子成像的一种创新方法。此外，由于癌症的应激反应成瘾，应激反应可能成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一独特的资助机制，因为它测试了癌症生物学中一个新出现的高度创新的概念，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：这项研究考察了通常保护细胞免受环境侮辱的应激反应是否实际上启动了人类肿瘤的癌症启动和发展，而且实际上可能是普遍需要的。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的诊断、预防和治疗方法的一般标志和靶点的发展。

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.