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.

摘要鞘磷脂代谢物及其代谢酶在癌症中常表现为失调。 治疗三阴性乳腺癌等侵袭性疾病的新靶点 (TNBC)和表皮生长因子受体2(HER2+)乳腺癌，新的治疗方法正处于绝望之中 需要的。越来越多的证据表明，细胞内具有生物活性的鞘磷脂代谢物神经酰胺-1- 磷酸盐(C1P)和神经酰胺酶(CERK)，这是已知的唯一能产生细胞内C1P的哺乳动物酶， 作为炎症和癌症进展的重要信号介质。然而，C1P和C1P的功能 Cerk仍然是个谜。然而，Cerk与包括肺癌在内的癌症密切相关。 腺癌、胰腺癌和乳腺癌。肿瘤CEK的过度表达与 更大的侵袭性和更差的临床结果。癌变与RAS/ERK的激活有关， PI3K/AKT/mTOR与化疗耐药。人们普遍认为，居住在高尔基山脉的Cerk会产生 C1P被释放到细胞外环境中，通过未知的细胞表面G蛋白偶联来传递信号 受体调节炎症和癌细胞的存活、迁移和伤口愈合。挑战这一观念 对于驻留在高尔基体内的Cerk，我们的初步结果显示，具有酶活性的Cerk在细胞核中丰富。 在正常乳腺上皮细胞中有表达，在侵袭性乳腺癌细胞中高度过度表达。.的存在 核CEK和细胞内C1P在侵袭性乳腺中的潜在机制未见文献报道 癌症。此外，我们的初步数据表明，Cerk在攻击性过程中扮演了一个以前没有描述过的角色。 疾病。1)对乳腺癌转移队列(GSE2034，n=286)数据的分析显示高表达 Cerk基因的表达水平与无复发生存率(RFS)差有关。2.)我们的RNA-Seq数据显示CERK 在有乳腺癌骨转移病史的患者的原发乳腺肿瘤中，其表达水平升高。3.) 作为一项原则证明，现有的CERK抑制剂NVP-231显著减少了血管内皮细胞的3D侵袭性生长 侵袭性的乳腺癌细胞。4.)NVP-231还可以减少侵袭型肿瘤的进展和转移 老鼠模型。最重要的假设是核内的Cerk和C1P在攻击性中起关键作用 乳腺癌的进展和转移。这项提议的直接目标是聚集更强大的 了解CERK功能的初步数据，a)临床应用和意义，b)CEK的特征 和C1P在侵袭性乳腺癌中的表达。提出了两个具体目标：1)神经酰胺的临床意义 2)神经酰胺酶和C1P在侵袭性乳腺癌中的功能作用。的范围 这项拟议的工作探索了一种以前未知的新机制，通过这种机制，Cerk和C1P在 原子核。这项工作将证明核C1P和Cerk是否是侵袭性疾病的关键 开发新的治疗药物，可用于R01/DoD补助金申请。