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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：
10330011
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
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/10330011
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 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 Prognosis Publishing Pump Refractory Resistance Role STAT3 gene Site Testing Therapeutic Intervention Tissues 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 insight lipid transport long chain fatty acid metastatic colorectal mitochondrial membrane neoplastic cell novel novel strategies patient derived xenograft model receptor stemness targeted treatment therapeutically effective 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的主要未满足需求