Role of breast cancer-secreted miRNA in directing a stromal metabolic plasticity

乳腺癌分泌的 miRNA 在指导基质代谢可塑性中的作用

• 批准号: 10221635
• 负责人: Shizhen Emily Wang
• 金额: $ 48.19万
• 依托单位: UNIVERSITY OF CALIFORNIA, SAN DIEGO
• 依托单位国家: 美国
• 财政年份: 2017
• 资助国家: 美国
• 起止时间: 2017-08-01 至 2024-07-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10221635
• 关键词: Ammonia; Bioenergetics; Biological Assay; Blood Circulation; Blood Vessels; Breast Cancer Cell; Cells; Clinical; Clinical Trials; Coculture Techniques; Communication; Coupling; Disease Progression; Drainage procedure; Encapsulated; Environment; Enzymes; Fibroblasts; Future; Gene Expression; Genes; Genetic; Glucose; Glutamine; Glycolysis; Goals; Growth; Human; Lactate Dehydrogenase; Lactic acid; MXI1 gene; Malignant Neoplasms; Mammary Neoplasms; Mass Fragmentography; Mediating; Metabolic; Metabolic stress; Methods; MicroRNAs; Modeling; Modification; Molecular; Mus; Neoplasm Metastasis; Nutrient; Pathway interactions; Patients; Pharmacology; Prevalence; Preventive; Process; Pyruvate; Regulation; Regulator Genes; Reporter; Research; Research Personnel; Resistance; Role; Sampling; Serum; Signal Transduction; Stromal Cells; Symbiosis; Testing; Therapeutic; Therapeutic Intervention; Tissues; Translations; Transplant Recipients; Transplantation; base; breast cancer progression; cancer cell; carcinogenesis; cell type; circulating biomarkers; deprivation; design; extracellular; extracellular vesicles; fitness; genetic manipulation; in vivo; inhibitor/antagonist; innovation; mRNA Transcript Degradation; malignant breast neoplasm; metabolic phenotype; metabolomics; novel; novel therapeutic intervention; patient screening; pre-clinical; prevent; programs; promoter; response; restoration; stable isotope; tumor; tumor growth; tumor metabolism; tumor microenvironment; tumor progression

PROJECT SUMMARY/ABSTRACT The metabolic interactions and coevolution that occur between cancer and stromal cells is an unexplored topic that combines cancer metabolism and tumor microenvironment. The proposed project will investigate this unique aspect of cancer–host crosstalk from the novel perspective of extracellular miRNAs, whose function in transferring cancer-derived signals to various types of niche cells to facilitate cancer growth and metastasis has been recently recognized. MiRNA negatively regulates gene expression through inducing mRNA degradation and/or translation blockade. The goals of this study are to identify the mechanisms by which cancer cell-secreted miRNAs direct a metabolic plasticity in stromal fibroblasts to engage different modes of cancer–stroma interactions under different metabolic conditions, and to examine potential therapeutic interventions targeting this process. In Aim 1, we will determine the acting mechanisms of selected breast cancer (BC)-secreted miRNAs in the metabolic reprogramming of cancer-associated fibroblasts (CAFs), including a mechanism through activation of MYC-directed metabolic program. In Aim 2, we will characterize the metabolic interplays between BC cells and reprogrammed CAFs under different metabolic conditions using stable isotope tracing and cell co-cultures. The specific role of selected miRNAs as well as their target genes will be determined by genetic modifications and pharmacological inhibition. In Aim 3, we will evaluate the in vivo effects of the herein identified miRNA-regulated pathways, as well as their pharmacological inhibition, on tumor growth and progression using models of co-transplanted BC and CAF cells derived from patients. We will also examine the associations among selected miRNAs and metabolic genes/regulators in human BCs, as well as the circulating levels of these miRNAs in the corresponding serum samples. The proposed studies will provide a novel perspective to our understanding of the dynamic communication between cancer and host as well as cancer's response to metabolic therapies, and will establish rationales for novel therapeutic strategies to slow or stop BC progression, which is our long-term objective. Clinical-stage inhibitors will be examined for their effects to block cancer–stroma metabolic interactions and suppress tumor progression, which allows rapid translation into future clinical trials.

项目总结/文摘

项目成果

Modeling the bidirectional glutamine/ammonium conversion between cancer cells and cancer-associated fibroblasts.

• DOI: 10.7717/peerj.10648
• 发表时间: 2021
• 期刊: PeerJ
• 影响因子: 2.7
• 作者: Hinow P;Pinter G;Yan W;Wang SE
• 通讯作者: Wang SE

Extracellular Vesicles and Metastasis.

• DOI: 10.1101/cshperspect.a037275
• 发表时间: 2020-07
• 期刊: Cold Spring Harbor perspectives in medicine
• 影响因子: 5.4
• 作者: Shizhen Emily Wang