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仍然是结直肠癌尚未满足的主要需求 (CRC)，尽管在分子特征和对转移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)已知具有 总体预后和/或临床结果较差。然而，没有任何抑制剂，包括那些针对RAS途径的抑制剂 和BRAF突变，均能克服CRC进展。与以下疾病相关的脂肪细胞和血脂增加 在结直肠癌等肿瘤部位堆积的肥胖/饮食被认为是癌症转移和 对治疗的抗拒。尽管CD36作为一种脂类转运蛋白已经得到了很好的证明，它在 启动转移和治疗耐药，我们的初步研究表明CD36只是部分 负责结直肠癌肿瘤细胞的脂质摄取。此外，以排出药物而闻名的mdr1， CD36与CD36共表达，并在转移起始/耐药的CRC细胞的脂质摄取中发挥作用。 CD36和MDR1转运的脂类物种的性质对启动转移和耐药至关重要 细胞凋亡尚不清楚。因此，我们建议：(1)确定MDR1和CD36在脂肪中的具体作用 酸性受体并阐明其在介导结直肠癌肿瘤转移中的致癌脂质转运；(2) 研究过多的脂类如何在促进转移和抵抗细胞凋亡的同时没有引起脂毒性 具有RAS和BRAF突变的CRC细胞。我们公布的数据表明，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 抵抗。我们在初步数据中进一步证明，粮农组织增加产生的额外乙酰-COAs， 通过乙酰化激活STAT3，进而上调酰辅酶A合成酶(ACSL)，支持脂质 分解代谢与磷脂生物发生。我们将检验这样一种假设，即脂肪酸受体CD36和 Mdr1，通过增强磷脂生物合成和增强 线粒体的完整性。我们的初步数据表明，乙酰化的STAT3对新陈代谢至关重要 CD36+MDR1+结直肠癌细胞过氧化脂质和脂肪酸介导的抗凋亡作用 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作为控制大肠癌转移和高度耐药的靶点 转移性结直肠癌异种移植和转移性患者来源的异种移植(含有RAS或BRAF 突变)。为此，我们将利用我们新开发的穿透细胞的乙酰化STAT3诱骗多肽 有效和特定地针对激活的(乙酰化的)STAT3。我们建议的研究将提供 肿瘤微环境中脂质增加对肿瘤进展的机械性洞察。他们 也可能导致对具有各种基因突变的CRC进行更有效的治疗干预。