The role of ceramide kinase in metastasis growth from aggressive breast cancer

神经酰胺激酶在侵袭性乳腺癌转移生长中的作用

• 批准号: 10652894
• 负责人: Nitai Hait
• 金额: $ 8.68万
• 依托单位: ROSWELL PARK CANCER INSTITUTE CORP
• 依托单位国家: 美国
• 财政年份: 2023
• 资助国家: 美国
• 起止时间: 2023-05-01 至 2025-04-30
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10652894
• 关键词: 3-Dimensional; Applications Grants; Attention; Biological Markers; Brain; Breast Cancer Cell; Breast Cancer Patient; Breast Epithelial Cells; Breast cancer metastasis; CRISPR/Cas technology; Cell Nucleus; Cell Survival; Cell surface; Cessation of life; Clinical; DNA Sequence Alteration; Data; Development; Disease; Disease Progression; Distant Metastasis; ERBB2 gene; Environmental Risk Factor; Enzymes; Epidermal Growth Factor Receptor; FRAP1 gene; Freezing; Funding Mechanisms; Future; G-Protein-Coupled Receptors; Genetic Transcription; Goals; Golgi Apparatus; Growth; Inflammation; Inflammation Mediators; Knowledge; Link; Lipids; Liver; Lung; Lung Adenocarcinoma; Malignant Neoplasms; Malignant neoplasm of pancreas; Mammary Neoplasms; Mediating; Messenger RNA; Metabolic; Metabolism; Metastatic Neoplasm to the Bone; Modeling; Neoplasm Metastasis; Nuclear; Organoids; Outcome; PI3K/AKT; Patients; Play; Primary Neoplasm; Recording of previous events; Relapse; Research Project Grants; Resistance; Role; Signal Transduction; Specimen; Sphingolipids; Surface; Testing; Tumor Tissue; Work; aggressive breast cancer; bone; breast cancer progression; cancer cell; ceramide 1-phosphate; ceramide kinase; chemotherapy; clinically significant; cohort; extracellular; genetic approach; kinase inhibitor; lipid metabolism; malignant breast neoplasm; migration; mouse model; novel; novel therapeutics; overexpression; pharmacologic; power analysis; predictive marker; progression marker; protein expression; response; sphingosine 1-phosphate; targeted treatment; transcriptome sequencing; triple-negative invasive breast carcinoma; tumor; tumor progression; wound healing

ABSTRACT Sphingolipid metabolites and their metabolic enzymes, often dysregulated in cancer, may present a novel but exploitable target for therapeutics against aggressive diseases such as triple -negative breast cancer (TNBC) and epidermal growth factor receptor 2 (HER2+) breast cancers, where new therapy is desperately needed. A growing body of evidence implicates the cellular bioactive sphingolipid metabolite, ceramide -1- phosphate (C1P), and ceramide kinase (CERK), the only mammalian enzyme known to produce cellul ar C1P, as essential signaling mediators of inflammation and cancer progression. However, the function of C1P and CERK remains enigmatic. Nevertheless, CERK is prominently associated with cancer, including lung adenocarcinoma, pancreatic cancer, and breast cancer. Excessive tumor CERK expression correlates with greater aggressiveness and poorer clinical outcome. A Cancer CERK is linked with activation of Ras/ERK, PI3K/AKT/mTOR, and resistance to chemotherapy. It is commonly thought that Golgi-resident CERK generates C1P that is released into the extracellular milieu and that signals through unknowncell surface G -protein coupled receptors to regulate inflammation and cancer cell survival, migration and wound healing. Challenging the notion of Golgi-resident CERK, our Preliminary Results showed enzymatically active CERK is enriched in the nucleus of normal breast epithelial cells and highly overexpressed in aggressive breast cancer cells. The presence of nuclear CERK and intracellular C1P implicate an undocumented underlying mechanism in aggressive breast cancer. Moreover, our Preliminary Data point to a previously uncharacterized role of CERK in aggressive diseases. 1.) Analysis of breast cancer metastases cohort (GSE2034, n=286) data revealed higher expression levels of CERK mRNA are linked to poor relapse-free survival (RFS). 2.) Our RNA-Seq data showed that CERK expression is elevated in primary breast tumors in patients with a history of breast cancer bone metastasis. 3.) As a proof-of-principle, an existing CERK inhibitor, NVP-231, drastically reduced the 3D invasive growth of aggressive breast cancer cells. 4.) NVP-231 also reduces aggressive type tumor progression and metastasis in mouse models. The overarching hypothesis is that CERK and C1P in the nucleus play a key role in aggressive breast cancer progression and metastasis. The immediate goal of this proposal is to gather more robust preliminary data to understand the functions, a) clinical utility and significance, and b) characterization of CERK and C1P in aggressive breast cancers. Two Specific Aims are proposed, 1) Clinical significance of ceramide kinase and C1P and 2) Functional role of ceramide kinase and C1P in aggressive breast cancers. The scope of the proposed work explores a previously unknown novel mechanism by which CERK and C1P function in the nucleus. This work will demonstrate whether nuclear C1P and CERK are critical for aggressive diseases for developing novel therapeutics, which can be tested for R01/DoD grant application.

抽象的鞘脂代谢物及其代谢酶（通常在癌症中失调）可能存在 一种针对侵略性疾病（例如三重阴性乳腺癌）的新型但可利用的靶标 （TNBC）和表皮生长因子受体2（HER2+）乳腺癌，新的疗法拼命为 需要。越来越多的证据表明细胞生物活性鞘脂代谢物，神经酰胺-1- 磷酸盐（C1P）和神经酰胺激酶（CERK），这是唯一已知会产生蜂窝AR C1P的哺乳动物酶 作为炎症和癌症进展的基本信号传导介体。但是，C1P和 塞克仍然神秘。尽管如此，Cerk还是与癌症的重要相关的，包括肺 腺癌，胰腺癌和乳腺癌。过度肿瘤CERK表达与 更大的侵略性和较差的临床结果。癌症Cerk与Ras/Erk的激活有关 PI3K/AKT/MTOR，以及对化学疗法的抗性。通常认为Golgi居民Cerk会产生 C1P被释放到细胞外环境中，并通过未知细胞表面G-蛋白耦合发出信号 受体调节炎症和癌细胞存活，迁移和伤口愈合。挑战这个概念 在Golgi居住的Cerk中，我们的初步结果表明，酶促活性的CERK富含核 正常的乳腺上皮细胞和在侵袭性乳腺癌细胞中高度表达的。存在 核Cerk和细胞内C1P暗示了一种无证件的基本机制 癌症。此外，我们的初步数据表明，Cerk在侵略性中的先前未表征的作用 疾病。 1.）分析乳腺癌转移队列（GSE2034，n = 286）数据显示较高的表达 CERK mRNA的水平与无复发生存期（RFS）相关。 2.）我们的RNA-seq数据显示Cerk 乳腺癌骨转移史的患者原发性乳腺肿瘤的表达升高。 3.） 作为原理证明，现有的CERK抑制剂NVP-231大大降低了3D侵入性生长 侵略性乳腺癌细胞。 4.）NVP-231还降低了侵袭性的肿瘤进展和转移 鼠标模型。总体假设是核中的Cerk和C1P在侵略性中起着关键作用 乳腺癌的进展和转移。该提议的直接目标是收集更强大的 初步数据了解功能，a）临床实用性和意义，b）Cerk的表征 和侵略性乳腺癌中的C1P。提出了两个具体目的，1）神经酰胺的临床意义 激酶和C1P以及2）神经酰胺激酶和C1P在侵袭性乳腺癌中的功能作用。范围 拟议的工作探讨了一种以前未知的新型机制，CERK和C1P在该机制中起作用 核。这项工作将证明核C1P和Cerk对于侵略性疾病至关重要 开发新型治疗剂，可以针对R01/DOD赠款应用进行测试。