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.

克服转移和化疗耐药性仍然是结直肠癌的主要未满足需求 (CRC)尽管在转移性乳腺癌的分子表征和理解方面取得了重大进展， 《儿童权利公约》。RAS和BRAF突变（分别发生在50%和10%的CRC患者中）已知具有 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。脂肪细胞和脂质增加与 如CRC中在肿瘤部位积累的肥胖/饮食被认为是癌症转移的关键， 对治疗的抵抗虽然CD 36作为脂质转运蛋白在肿瘤的发生发展中起着重要作用， 启动转移和治疗耐药性，我们的初步研究表明，CD 36只是部分 负责CRC肿瘤细胞的脂质摄入。此外，MDR 1以其泵出药物的功能而闻名， 与CD 36共表达，并在转移起始/化学抗性CRC细胞的脂质摄取中起作用。 由CD 36和MDR 1转运的脂质种类的性质对于启动转移和耐药至关重要。 凋亡是未知的。因此，我们建议（1）确定MDR 1和CD 36作为脂肪细胞的特定作用， 酸受体并阐明它们在介导CRC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抗凋亡的同时不引起脂毒性 RAS和BRAF突变的CRC细胞。我们发表的数据表明，STAT 3上调脂肪 酸氧化（FAO），导致癌细胞干细胞性增加，这对转移和药物治疗很重要。 阻力我们在初步数据中进一步证明，增加FAO产生的额外乙酰辅酶A， 通过乙酰化激活STAT 3，这反过来又上调酰基辅酶A合成酶（ACSL），支持脂质 钙通道和磷脂生物合成。我们将检验脂肪酸受体CD 36和 MDR 1，通过增强磷脂生物合成和增强细胞凋亡来减轻脂毒性和抵抗细胞凋亡。 线粒体完整性我们的初步数据表明，乙酰化的STAT 3是代谢的关键， 过量脂质和脂肪酸介导的CD 36 + MDR 1 + CRC细胞对凋亡的抵抗， 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STAT 3作为控制CRC转移和化疗耐药性的靶标， 转移性CRC异种移植物和转移性患者来源的异种移植物（含有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STAT 3诱饵肽 有效和特异性靶向激活的（乙酰化的）STAT 3。我们建议的研究将提供 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 也可能导致对具有各种基因突变的CRC的更有效的治疗干预。