Studying metabolic stress signaling in renal cancer

描述（由申请人提供）：肿瘤生长需要高能量和营养供应。因此，癌细胞通常会经历各种类型的代谢应激。克服代谢压力是癌症发展的关键一步。然而，癌细胞如何参与代谢适应策略以在代谢应激下生存和生长尚不清楚。我们的长期目标是研究癌症发展过程中代谢应激反应的关键信号通路，使医学界能够在治疗人类癌症时合理靶向这些通路。本应用程序的目的是研究FoxO转录因子（FoxOs）在肾细胞癌（RCC）的能量应激反应和肿瘤抑制中的作用。我们广泛的初步数据支持了我们提出的中心假设，即FoxO-BNIP3轴在能量应激下抑制细胞生长（细胞大小增加）和细胞存活方面起双重作用，FoxOs或BNIP3的缺失是肾癌细胞在肿瘤发展过程中适应能量应激的重要策略。本研究的基本原理是研究FoxO信号在能量应激反应和肾肿瘤抑制中的作用，将促进我们对肾癌细胞如何绕过能量应激生存和生长的理解，并将为开发针对肾癌治疗代谢应激的新治疗策略或预后标志物提供重要见解。为了验证我们的假设，我们将追求以下具体目标：探讨FoxO信号在肾癌细胞能量应激反应中的调控作用及其机制。具体目标2。探讨FoxOs和BNIP3在体内mTORC1抑制和肾肿瘤抑制中的作用。就预期结果而言，我们提出的研究将确定能量应激途径的新机制，阐明FoxO和BNIP3在肾癌中的抑瘤功能，并为FoxO/BNIP3表达在肾癌患者预后分层中的应用提供重要见解。我们的建议是高度创新的，因为它专注于一个以前未被探索的途径，填补了目前将能量应激与肾肿瘤发展联系起来的空白。我们提出的研究将对理解能量应激信号的基本机制和在临床上操纵能量应激途径在人类癌症患者的分层和治疗中产生重大影响。

DESCRIPTION (provided by applicant): Tumor growth requires high energy and nutrient supplies. As a result, cancer cells usually undergo various types of metabolic stress. Overcoming metabolic stress is a critical step in cancer development. However, how cancer cells engage strategies of metabolic adaptation to survive and grow under metabolic stress is not well understood. Our long-term goal is to study key signaling pathways in metabolic stress response in the context of cancer development, so as to enable the medical community to rationally target such pathways in the treatment of human cancers. The objective of this application is to study the roles of FoxO transcription factors (FoxOs) in energy stress response and tumor suppression in renal cell carcinoma (RCC). Our extensive preliminary data support the central hypothesis of our proposal that FoxO-BNIP3 axis plays a dual role in inhibiting both cell growth (cell size increase) and cell survival in response to energy stress, and loss of FoxOs or BNIP3 is one important strategy renal cancer cells adapt to energy stress during tumor development. The rationale for the proposed research is that studying the roles of FoxO signaling in energy stress response and renal tumor suppression will advance our understanding of how renal cancer cells bypass energy stress to survive and grow, and will provide important insights on the development of novel therapeutic strategies or prognostic markers targeting metabolic stress in renal cancer treatment. To test our hypothesis, we will pursue the following specific aims: Specific Aim 1. To determine the regulation and mechanisms of FoxO signaling in energy stress response in renal cancer cells. Specific Aim 2. To determine the roles of FoxOs and BNIP3 in mTORC1 inhibition and renal tumor suppression in vivo. With respect to expected outcomes, our proposed studies will identify novel mechanisms of energy stress pathways, clarify the tumor suppression function of FoxO and BNIP3 in renal cancer, and provide important insights on the use of FoxO/BNIP3 expression in prognostic stratification of renal cancer patients. Our proposal is highly innovative, because it focuses on a previously unexplored pathway that fills in the current gap to link energy stress to renal tumor development. Our proposed studies will have significant impact on both understanding the fundamental mechanisms of energy stress signaling and manipulating energy stress pathways clinically in the stratification and treatment of human cancer patients.