Fatty acids and their receptors-mediated tumor metastasis and progression

脂肪酸及其受体介导的肿瘤转移和进展

基本信息

批准号：
9916932
负责人：
David K Ann
金额：
$ 40.26万
依托单位：
BECKMAN RESEARCH INSTITUTE/CITY OF HOPE
依托单位国家：
美国
项目类别：
财政年份：
2020
资助国家：
美国
起止时间：
2020-02-14 至 2025-01-31
项目状态：
未结题

来源：
https://reporter.nih.gov/project-details/9916932
关键词：
ABCB1 gene Acetyl Coenzyme A Acetylation Acyl Coenzyme A Adipocytes Anabolism Apoptosis BRAF gene Biogenesis CD36 gene CD44 gene Catabolism Cell Survival Cells Clinical Coenzyme A Ligases Colorectal Cancer DNA Sequence Alteration Data Diet Drug resistance Event Family member Fatty Acids Fatty acid glycerol esters Goals Lead Lipids Malignant Neoplasms Mediating Membrane Membrane Potentials Metabolic Metabolism Mitochondria Molecular Multi-Drug Resistance Mus Mutate Mutation Nature Neoplasm Metastasis Obesity Oncogenic Outcome Pathway interactions Patients Peptides Pharmaceutical Preparations Phospholipids Play Publishing Pump Refractory Resistance Role STAT3 gene Site Testing Therapeutic Intervention Tissues Treatment Efficacy Tumor-Derived Xenograft Model Xenograft procedure cancer cell chemotherapy clinical translation colon cancer patients colorectal cancer metastasis colorectal cancer prevention colorectal cancer progression fatty acid oxidation in vivo evaluation inhibitor/antagonist insight lipid transport long chain fatty acid metastatic colorectal mitochondrial membrane neoplastic cell novel novel strategies outcome forecast receptor stemness targeted treatment therapy resistant triple-negative invasive breast carcinoma tumor tumor microenvironment tumor progression tumor xenograft uptake

项目摘要

Overcoming metastasis and resistance to chemotherapy remains a major unmet need for colorectal cancer (CRC), despite significant progress made in the molecular characterization and understanding of metastatic CRC. RAS and BRAF mutations (occur in 50% and 10% of CRC patients, respectively) are known to have worse overall prognosis and/or clinical outcome. However, no inhibitors, including those against RAS pathway and BRAF mutation, are able to overcome CRC progression. Increased adipocytes and lipids associated with obesity/diet that accumulate at tumor sites as in CRC are recognized as critical for cancer metastasis and resistance to therapy. Although CD36 is well-documented as a lipid transporter that plays an important role in initiating metastasis and therapy resistance, our preliminary studies indicate that CD36 is only partially responsible for lipid uptake in CRC tumor cells. Moreover, MDR1, known for its function in pumping out drugs, co-expresses with CD36 and plays a role in lipid uptake into metastatic initiating/chemo-resistant CRC cells. The nature of lipid species transported by CD36 and MDR1 critical for initiating metastasis and resistance to apoptosis is unknown. We therefore propose to (1) determine the specific roles of MDR1 and CD36 as fatty acid receptors and elucidate the oncogenic lipids they transport in mediating tumor metastasis in CRC; (2) investigate how excess lipids fail to cause lipotoxicity while promoting metastasis and resistance to apoptosis of CRC cells with RAS and BRAF mutations. Our published data demonstrate that STAT3 upregulates fatty acid oxidation (FAO), leading to increased cancer cell stemness, which is important for metastasis and drug resistance. We further demonstrated in preliminary data that extra acetyl-CoAs, generated by increased FAO, activate STAT3 by acetylation, which in turn upregulates Acyl-CoA synthetases (ACSL), supporting lipid catabolism and phospholipid biogenesis. We will test the hypothesis that the fatty acid receptors, CD36 and MDR1, mitigate lipotoxicity and resist apoptosis through enhanced phospholipid biosynthesis and heightened mitochondrial integrity. Our preliminary data are indicative that acetylated STAT3 is critical for metabolizing excess lipids and for fatty acids-mediated resistance of CD36+MDR1+ CRC cells to apoptosis by increasing mitochondrial membrane potential, which will be further validated in Aim 2. We therefore propose to (3) validate acetylated-STAT3 as a target for controlling CRC metastasis and chemo-resistance in highly metastatic CRC xenografts and in metastatic patient-derived xenografts (contain either RAS or BRAF mutations). To this effect we will utilize our newly developed cell-penetrating acetylated-STAT3 decoy peptide that effectively and specifically targets activated (acetylated) STAT3. Our proposed studies will provide mechanistic insights into tumor progression mediated by increased lipids in the tumor microenvironment. They may also lead to more effective therapeutic interventions for CRC with various genetic mutations.

克服转移和化疗耐药仍然是结直肠癌未满足的主要需求（CRC），尽管在转移性的分子特征和理解方面取得了重大进展 CRC。已知 RAS 和 BRAF 突变（分别发生在 50% 和 10% 的 CRC 患者中）总体预后和/或临床结果更差。然而，没有抑制剂，包括针对 RAS 通路的抑制剂和 BRAF 突变，能够克服 CRC 进展。与相关的脂肪细胞和脂质增加肥胖/饮食在肿瘤部位积累（如结直肠癌），被认为对癌症转移至关重要对治疗的抵抗。尽管 CD36 已被充分证明是一种脂质转运蛋白，在启动转移和治疗抵抗，我们的初步研究表明 CD36 仅部分参与负责 CRC 肿瘤细胞的脂质摄取。此外，MDR1以其泵出药物的功能而闻名，与 CD36 共表达，并在转移起始/化疗耐药 CRC 细胞的脂质摄取中发挥作用。 CD36 和 MDR1 转运的脂质种类的性质对于启动转移和耐药性至关重要细胞凋亡未知。因此，我们建议（1）确定 MDR1 和 CD36 作为脂肪的具体作用。酸受体并阐明它们在介导结直肠癌肿瘤转移中转运的致癌脂质； (2) 研究过量的脂质如何在促进转移和抵抗细胞凋亡的同时不会引起脂毒性具有 RAS 和 BRAF 突变的 CRC 细胞。我们发表的数据表明 STAT3 上调脂肪酸氧化（FAO），导致癌细胞干性增加，这对转移和药物很重要反抗。我们在初步数据中进一步证明，FAO 增加产生的额外乙酰辅酶A，通过乙酰化激活 STAT3，进而上调酰基辅酶 A 合成酶 (ACSL)，支持脂质分解代谢和磷脂生物发生。我们将检验脂肪酸受体 CD36 和 MDR1，通过增强磷脂生物合成和提高，减轻脂毒性并抵抗细胞凋亡线粒体完整性。我们的初步数据表明乙酰化 STAT3 对于代谢至关重要过量脂质和脂肪酸介导的 CD36+MDR1+ CRC 细胞对细胞凋亡的抵抗力线粒体膜电位，这将在目标 2 中进一步验证。因此，我们建议 (3) 验证乙酰化-STAT3 作为控制 CRC 转移和高度化疗耐药的靶标转移性 CRC 异种移植物和转移性患者来源的异种移植物（包含 RAS 或 BRAF 突变）。为此，我们将利用我们新开发的细胞穿透性乙酰化 STAT3 诱饵肽有效且特异性地针对激活（乙酰化）的 STAT3。我们提出的研究将提供对肿瘤微环境中脂质增加介导的肿瘤进展的机制见解。他们还可能为具有各种基因突变的结直肠癌带来更有效的治疗干预措施。