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HIF-1alpha and FBP2 in sarcoma metabolism, progression, and metastasis

HIF-1α 和 FBP2 在肉瘤代谢、进展和转移中的作用

基本信息

批准号：
10080711
负责人：
M. CELESTE SIMON
金额：
$ 53.27万
依托单位：
UNIVERSITY OF PENNSYLVANIA
依托单位国家：
美国
项目类别：
财政年份：
2017
资助国家：
美国
起止时间：
2017-02-01 至 2023-01-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/10080711
关键词：
Affect Allografting Attenuated Binding Cell Line Cell Maintenance Cell Proliferation Cell surface Cells Chemoresistance Clear cell renal cell carcinoma Connective Tissue Correlative Study Diagnosis Distant Metastasis Environment Enzymes Epithelial Cells Exhibits Fatty acid glycerol esters Fructose-1,6-Bisphosphatase Genes Genetic Genetic Engineering Genetic Transcription Gluconeogenesis Glutathione Glycolysis HIF1A gene Human Hypoxia Hypoxia Inducible Factor In Vitro KRASG12D Kidney Malignant Epithelial Cell Malignant Fibrous Histiocytoma Malignant Neoplasms Mediating Mesoderm Metabolism Metastatic Neoplasm to the Lung Methods Modeling Mus Muscle Neoplasm Metastasis Nuclear Nutrient Oxidative Phosphorylation Patients Pentosephosphate Pathway Persons Phenotype Play Proliferating Property Reaction Recurrence Reporting Research Proposals Resistance Role Sampling Signal Transduction Soft tissue sarcoma Solid Neoplasm Testing Tissues Tubular formation Tumor Suppressor Proteins United States VEGFA gene Warburg Effect Xenograft procedure aerobic glycolysis angiogenesis beta catenin chemotherapy design macromolecule metabolic abnormality assessment migration mouse model neoplastic cell novel overexpression prevent progenitor restoration sarcoma self-renewal stem cells stem-like cell targeted agent tumor tumor metabolism tumorigenesis

项目摘要

Project Summary/Abstract Sarcomas are a heterogeneous group of malignancies arising from mesoderm-derived tissues such as muscle, fat, and connective tissue. They are diagnosed in nearly 20,000 persons in the United States each year, and approximately 40% of patients die of either loco-regional recurrence or distant metastasis. Sarcomas and other solid tumors typically thrive in hypoxic and nutrient-poor conditions to proliferate and metastasize. To survive in such environments, sarcomas hijack two adaptive mechanisms: (1) activation of hypoxia inducible factor 1α (HIF-1α), which enhances the transcription of over 150 genes mediating tumor metabolism, angiogenesis, and metastasis and (2) utilization of aerobic glycolysis (a.k.a. the Warburg effect), which creates energy by means of glycolysis rather than oxidative phosphorylation. HIF-1α appears to be particularly critical for a subset of tumor cells which we will refer to as “sarcoma stem-like cells” or SSCs, characterized by their ability to self renew and differentiate. In preliminary studies, we have found that SSCs reside preferentially in hypoxic regions of tumors, exhibit elevated levels of HIF-1α, and are likely to promote chemotherapy resistance and metastasis. The reverse reaction of glycolysis is gluconeogenesis, where fructose-1, 6-bisphosphatase (FBP) acts as a rate-limiting enzyme. We also recently determined that FBP2 is consistently downregulated in 8 human sarcoma subtypes compared to normal human mesoderm-derived tissues. The long-term objective of this proposal is to expand the use of agents targeting HIF-1α and FBP2 in patients with sarcomas to reduce recurrence, distant metastasis, and chemotherapy resistance. Consequently, this proposal is designed to test the hypothesis that HIF-1α and FBP2 play critical and inter- related roles in regulating sarcomagenesis, metabolism, metastasis, and chemotherapy resistance. To test this hypothesis, this research proposal will (1) define the role of FBP2 in sarcoma metabolism, progression, and metastasis, and (2) determine the role of HIF-1α in SSC metastasis and chemotherapy resistance. The methods of this proposal include analysis of autochthonous and xenograft mouse models of sarcomas, analysis of sarcoma cell lines in vitro, metabolic studies, and correlative studies of tumor samples from sarcoma patients.

项目总结/文摘

项目成果

期刊论文数量（31）

专著数量（0）

科研奖励数量（0）

会议论文数量（0）

专利数量（0）

KMT2C Mutations in Diffuse-Type Gastric Adenocarcinoma Promote Epithelial-to-Mesenchymal Transition.

DOI：
10.1158/1078-0432.ccr-17-1679
发表时间：
2018-12-15
期刊：
Clinical cancer research : an official journal of the American Association for Cancer Research
影响因子：
0
作者：
Cho SJ;Yoon C;Lee JH;Chang KK;Lin JX;Kim YH;Kook MC;Aksoy BA;Park DJ;Ashktorab H;Smoot DT;Schultz N;Yoon SS
通讯作者：
Yoon SS

Multimodal targeting of tumor vasculature and cancer stem-like cells in sarcomas with VEGF-A inhibition, HIF-1α inhibition, and hypoxia-activated chemotherapy.

DOI：
10.18632/oncotarget.10212
发表时间：
2016-07-12
期刊：
Oncotarget
影响因子：
0
作者：
Yoon C;Chang KK;Lee JH;Tap WD;Hart CP;Simon MC;Yoon SS
通讯作者：
Yoon SS

Platelet-derived growth factor receptor-α and -β promote cancer stem cell phenotypes in sarcomas.

DOI：
10.1038/s41389-018-0059-1
发表时间：
2018-06-19
期刊：
Oncogenesis
影响因子：
6.2
作者：
Chang KK;Yoon C;Yi BC;Tap WD;Simon MC;Yoon SS
通讯作者：
Yoon SS

CD44 expression denotes a subpopulation of gastric cancer cells in which Hedgehog signaling promotes chemotherapy resistance.

DOI：
10.1158/1078-0432.ccr-14-0011
发表时间：
2014-08-01
期刊：
Clinical cancer research : an official journal of the American Association for Cancer Research
影响因子：
0
作者：
Yoon C;Park DJ;Schmidt B;Thomas NJ;Lee HJ;Kim TS;Janjigian YY;Cohen DJ;Yoon SS
通讯作者：
Yoon SS

Hypoxia-Inducible Factors in Cancer.