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 鞘脂代谢物及其代谢酶在癌症中经常失调，可能会出现 一种新颖但可利用的治疗侵袭性疾病（例如三阴性乳腺癌）的靶点 (TNBC) 和表皮生长因子受体 2 (HER2+) 乳腺癌，迫切需要新的治疗方法 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)，这是唯一已知产生细胞 C1P 的哺乳动物酶， 作为炎症和癌症进展的重要信号传导介质。然而，C1P 的功能和 CERK 仍然是个谜。然而，CERK 与癌症（包括肺癌）显着相关 腺癌、胰腺癌和乳腺癌。肿瘤 CERK 过度表达与 更大的侵袭性和更差的临床结果。癌症 CERK 与 Ras/ERK 的激活有关， PI3K/AKT/mTOR，以及化疗耐药。人们普遍认为驻留在高尔基体的 CERK 产生 C1P 被释放到细胞外环境并通过未知细胞表面 G 蛋白偶联发出信号 调节炎症和癌细胞存活、迁移和伤口愈合的受体。挑战观念 的高尔基驻留 CERK，我们的初步结果表明酶活性 CERK 在细胞核中富集 正常乳腺上皮细胞的表达，并在侵袭性乳腺癌细胞中高度过表达。的存在 核CERK和细胞内C1P暗示侵袭性乳腺中未记录的潜在机制 癌症。此外，我们的初步数据表明，CERK 在攻击性攻击中发挥着先前未表征的作用。 疾病。 1.) 乳腺癌转移队列（GSE2034，n=286）数据分析显示较高的表达 CERK mRNA 水平与较差的无复发生存期 (RFS) 相关。 2.) 我们的 RNA-Seq 数据表明 CERK 有乳腺癌骨转移史的患者的原发性乳腺肿瘤中表达升高。 3.) 作为原理验证，现有的 CERK 抑制剂 NVP-231 大大减少了 3D 侵袭性生长 侵袭性乳腺癌细胞。 4.) NVP-231 还可以减少侵袭性肿瘤的进展和转移 鼠标模型。总体假设是细胞核中的 CERK 和 C1P 在攻击性行为中发挥着关键作用。 乳腺癌进展和转移。该提案的近期目标是聚集更强大的 了解 CERK 功能的初步数据，a) 临床实用性和意义，以及 b) 表征 和 C1P 在侵袭性乳腺癌中的作用。提出了两个具体目标，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 这项工作探索了一种以前未知的新机制，CERK 和 C1P 通过该机制在 核。这项工作将证明核 C1P 和 CERK 是否对于侵袭性疾病至关重要 开发新疗法，可以针对 R01/DoD 拨款申请进行测试。