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， 一种新的但可开发的靶点，用于治疗侵袭性疾病，如三阴性乳腺癌 （TNBC）和表皮生长因子受体2（HER 2+）乳腺癌，其中新的治疗方法是绝望的 needed.越来越多的证据表明，细胞的生物活性鞘脂代谢产物神经酰胺-1- 磷酸（C1 P）和神经酰胺激酶（CERK），已知唯一产生细胞C1 P的哺乳动物酶， 作为炎症和癌症进展的重要信号介质。然而，C1 P和 CERK仍然是个谜。然而，CERK与癌症，包括肺癌， 腺癌、胰腺癌和乳腺癌。过度的肿瘤CERK表达与 更大的侵略性和更差的临床结果。癌症CERK与Ras/ERK的激活有关， PI 3 K/AKT/mTOR与化疗耐药的关系。通常认为，高尔基体的CERK产生 C1 P被释放到细胞外环境中，并通过未知的细胞表面G蛋白偶联 受体来调节炎症和癌细胞存活、迁移和伤口愈合。放弃这个概念 我们的初步结果表明，酶活性的CERK在细胞核中富集， 在侵袭性乳腺癌细胞中高度过表达。的存在 细胞核CERK和细胞内C1 P与侵袭性乳腺癌的潜在机制有关 癌此外，我们的初步数据表明，CERK在侵袭性神经元损伤中的作用是以前未描述的。 疾病1.）的人。乳腺癌转移队列（GSE 2034，n=286）数据分析显示， CERK mRNA水平与无复发生存期（RFS）较差有关。2.）的情况。我们的RNA-Seq数据显示， 在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.）第三章 作为原理证明，现有的CERK抑制剂NVP-231大大减少了肿瘤的3D侵入性生长。 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。 小鼠模型。最重要的假设是，细胞核中的CERK和C1 P在攻击性神经元中起着关键作用。 乳腺癌进展和转移。该提案的直接目标是收集更强大的 了解功能的初步数据，a）临床效用和意义，以及B）CERK的表征 和C1 P在侵袭性乳腺癌中的作用提出两个具体目的：1）神经酰胺的临床意义 2）神经酰胺激酶和C1 P在侵袭性乳腺癌中的功能作用。的范围 这项工作探索了一种以前未知的新机制，CERK和C1 P在神经细胞中发挥作用， 原子核这项工作将证明核C1 P和CERK是否对侵袭性疾病至关重要， 开发新的治疗方法，可以测试R 01/DoD拨款申请。