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

• 批准号: 10549362
• 负责人: David K Ann
• 金额: $ 39.45万
• 依托单位: BECKMAN RESEARCH INSTITUTE/CITY OF HOPE
• 依托单位国家: 美国
• 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/10549362
• 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; Chemoresistance; Clinical; Coenzyme A Ligases; Colorectal Cancer; DNA Sequence Alteration; Data; Diet; Drug resistance; Event; Family member; Fatty Acids; Fatty acid glycerol esters; Goals; Lipids; Malignant Neoplasms; Mediating; Membrane Potentials; Metabolic; Metabolism; Mitochondria; Molecular; Multi-Drug Resistance; Mus; Mutate; Mutation; Nature; Neoplasm Metastasis; Obesity; Oncogenic; Outcome; Pathway interactions; Patients; Penetration; Peptides; Pharmaceutical Preparations; Phospholipids; Play; Prognosis; Publishing; Pump; Refractory; Resistance; Role; STAT3 gene; Site; Testing; Therapeutic; Therapeutic Intervention; Tissues; Tumor Promotion; 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; insight; lipid transport; long chain fatty acid; metastatic colorectal; mitochondrial membrane; neoplastic cell; novel; novel strategies; oxidation; patient derived xenograft model; receptor; stemness; therapeutically effective; therapy resistant; triple-negative invasive breast carcinoma; tumor; tumor initiation; tumor microenvironment; tumor progression; tumor xenograft; uptake

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.

克服转移和对化学疗法的抵抗力仍然是对结直肠癌的主要需求 （CRC），尽管在分子表征和对转移性的理解方面取得了重大进展 CRC。 RAS和BRAF突变（分别发生在50％和10％的CRC患者中） 总体预后和/或临床结果较差。但是，没有抑制剂，包括针对RAS途径的抑制剂 和BRAF突变，能够克服CRC的进展。与之相关的脂肪细胞和脂质增加 在CRC中，积累在肿瘤部位积累的肥胖/饮食对癌症转移至关重要 抵抗治疗。尽管CD36有充分记录为脂质转运蛋白，在 我们的初步研究引发转移和耐药性，表明CD36仅部分是 负责CRC肿瘤细胞中的脂质摄取。此外，MDR1以其在泵出药物方面的功能而闻名， 与CD36共表达，并在脂质吸收中起作用，从而进入转移性/耐化学CRC细胞。 CD36和MDR1传输的脂质物种的性质对于引发转移和抗性至关重要 凋亡是未知的。因此，我们建议（1）确定MDR1和CD36作为脂肪的特定作用 酸受体并阐明了它们在CRC中介导肿瘤转移中转运的致癌脂质； （2） 研究过量脂质如何在促进转移和对凋亡的抗性的同时导致脂肪毒性 带有RAS和BRAF突变的CRC细胞。我们已发布的数据表明STAT3上调了脂肪 酸性氧化（FAO），导致癌细胞干的增加，这对于转移和药物很重要 反抗。我们在初步数据中进一步证明了粮农组织增加的额外的乙酰基-COA， 通过乙酰化激活STAT3，乙酰化又上调酰基辅酶A合成酶（ACSL） 分解代谢和磷脂生物发生。我们将检验以下假设：脂肪酸受体CD36和 MDR1，通过增强的磷脂生物合成并增强，减轻脂肪毒性并抵抗凋亡 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 过量的脂质和脂肪酸介导的CD36+ MDR1+ CRC细胞对细胞凋亡的抗性 线粒体膜电位将在AIM 2中得到进一步验证。因此，我们建议（3） 验证乙酰化-STAT3作为控制高度CRC转移和化学抗性的靶标 转移性CRC异种移植物和转移性患者衍生的异种移植物（包含RAS或BRAF） 突变）。为此，我们将利用我们新开发的细胞穿透乙酰化乙酰化 - STAT3诱饵肽 这有效，专门针对激活（乙酰化）STAT3。我们提出的研究将提供 肿瘤微环境中脂质增加介导的对肿瘤进展的机械洞察力。他们 还可能导致对具有各种遗传突变的CRC进行更有效的治疗干预措施。