Metabolic Regulation of Tumor Progression, Metastasis and Chemoresistance by SIRT5/ELK3 signaling in Pancreatic Cancer

胰腺导管腺癌（PDAC）是最致命的癌症之一，因为 它们广泛侵入周围组织并转移到远处器官，即使在早期阶段也是如此。 肿瘤进展。这种恶性肿瘤的预后差也反映了对目前治疗的反应普遍较差。 治疗因此，了解这些肿瘤的生物学和促进其侵袭的机制， 转移将为开发新的诊断和治疗方法提供基础。 肿瘤细胞表现出代谢改变，导致肿瘤生长或转移增强。具体地说， 代谢重编程促进肿瘤细胞在运输到远处的苛刻条件下存活， 一旦肿瘤细胞建立转移位点，则诱导增殖。谷氨酰胺代谢异常与 与Kras驱动的胰腺癌的肿瘤生长有关。同样，我们的初步数据显示， 转移病灶对谷氨酰胺代谢的依赖性。此外，我们证明谷氨酰胺 代谢通过调节嘧啶生物合成的通量来调节对吉西他滨的反应性 通路我们确定SIRT 5是谷氨酰胺代谢的一个关键负调节因子， 胰腺癌细胞的摄取和依赖性。SIRT 5减少原位肿瘤生长和转移 模型我们还观察到SIRT 5负调节Elk-3的表达，Elk-3促进谷氨酰胺的表达。 代谢、胰腺癌细胞存活和侵袭性。对该提案特别重要的是，ELK 3 在晚期原发性和转移性胰腺肿瘤病变中显著过表达，因此ELK 3- 诱导的代谢重编程预期是抑制胰腺肿瘤进展的靶点， 转移 我们的长期目标是确定SIRT 5/ELK 3介导的代谢改变的分子基础 促进胰腺癌的进展和转移。在这里，我们假设SIRT 5/ELK 3- 介导的谷氨酰胺代谢调节有助于肿瘤进展、转移和 PDAC中的化学抗性。此外，我们假设靶向谷氨酰胺代谢可以提供 一种治疗策略，以对抗PDAC中的肿瘤进展、转移和化疗耐药性。在这里， 我们提出在SIRT 5缺陷的胰腺肿瘤模型中表征代谢表型（目的1）， 研究Elk 3介导的转录和代谢重编程是否有助于SIRT 5介导的 代谢表型（Aim 2）。此外，我们建议阐明ELK 3在调节肿瘤中的作用， PDAC中的进展、转移和吉西他滨耐药（目的3）。这些研究将阐明代谢 SIRT 5/ELK 3介导的肿瘤进展和转移方面，并强烈期望揭示 治疗胰腺癌的其他治疗策略。

Pancreatic ductal adenocarcinomas (PDAC) are among the most lethal cancers because of their extensive invasion into surrounding tissues and metastasis to distant organs, even during early stages of tumor progression. The poor prognosis for this malignancy also reflects a generally poor response to current therapies. Thus, understanding the biology of these tumors and the mechanisms that promote their invasion and metastasis will provide a basis for developing new methods for diagnosis and treatment. Tumor cells display metabolic alterations that result in enhanced tumor growth or metastasis. Specifically, metabolic reprogramming promotes tumor cell survival under harsh conditions during transit to distant sites and induces proliferation once the tumor cells establish metastatic loci. Aberrant glutamine metabolism is associated with tumor growth in Kras-driven pancreatic cancer. Likewise, our preliminary data demonstrate increased dependence of metastatic lesions on glutamine metabolism. Additionally, we demonstrate that glutamine metabolism regulates responsiveness against gemcitabine by regulating flux through the pyrimidine biosynthesis pathway. We identify SIRT5 as a key negative regulator of glutamine metabolism that diminishes glutamine uptake and dependence in pancreatic cancer cells. SIRT5 diminishes tumor growth and metastasis in orthotopic models. We also observe that SIRT5 negatively regulates the expression of Elk-3, which promotes glutamine metabolism, pancreatic cancer cell survival, and invasiveness. Of particular significance to the proposal, ELK3 is significantly overexpressed by advanced primary and metastatic pancreatic tumor lesions, and hence ELK3- induced metabolic reprogramming is expected to be a target for suppressing pancreatic tumor progression and metastasis. Our long-term goal is to determine the molecular basis of SIRT5/ELK3-mediated metabolic alterations that facilitate progression and metastasis in pancreatic cancer. Here, we hypothesize that SIRT5/ELK3- mediated regulation of glutamine metabolism contributes to tumor progression, metastasis, and chemoresistance in PDAC. Furthermore, we hypothesize that targeting glutamine metabolism can provide a therapeutic strategy to combat tumor progression, metastasis, and chemoresistance in PDAC. Here, we propose to characterize the metabolic phenotype in SIRT5-deficient pancreatic tumor models (Aim 1) and investigate if Elk3-mediated transcriptional and metabolic reprogramming contributes to SIRT5-mediated metabolic phenotype (Aim 2). Furthermore, we propose to elucidate the role of ELK3 in regulating tumor progression, metastasis, and gemcitabine resistance in PDAC (Aim 3). These studies will elucidate the metabolic aspects of SIRT5/ELK3-mediated tumor progression and metastasis and are strongly expected to uncover additional therapeutic strategies for the treatment of pancreatic cancer.