Signaling and Targeting of CRTC1-MAML2 Fusion Oncoprotein in Salivary Gland

唾液腺中 CRTC1-MAML2 融合癌蛋白的信号传导和靶向

• 批准号: 10672248
• 负责人: Lizi Wu
• 金额: $ 35.43万
• 依托单位: UNIVERSITY OF FLORIDA
• 依托单位国家: 美国
• 财政年份: 2014
• 资助国家: 美国
• 起止时间: 2014-08-08 至 2024-07-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10672248
• 关键词: Antisense Oligonucleotides; Automobile Driving; Biology; CREB1 gene; Cell Survival; Cells; Chimeric Proteins; Cyclic AMP; Data; Development; Diagnostic; Disease; Dominant-Negative Mutation; Funding; Fusion Oncogene Proteins; Genes; Genetic Transcription; Genetically Engineered Mouse; Growth; Human; Impairment; In Vitro; Investigation; MLL/ELL; Maintenance; Malignant - descriptor; Malignant Epithelial Cell; Malignant Neoplasms; Malignant neoplasm of salivary gland; Metastatic/Recurrent; Modeling; Molecular; Mucoepidermoid Carcinoma; Oncogenes; Oncogenic; Outcome; Pathway interactions; Patients; Pattern; Permeability; Recurrence; Regulator Genes; Research; Role; Salivary Glands; Signal Transduction; Specificity; Testing; Therapeutic; Tissues; Transgenic Mice; Untranslated RNA; Xenograft procedure; cell growth; design; diagnostic biomarker; fusion gene; in vivo; in vivo evaluation; insight; mouse model; novel; novel diagnostics; novel strategies; novel therapeutic intervention; programs; protein protein interaction; prototype; small hairpin RNA; stapled peptide; targeted treatment; therapeutic target; transcription factor; tumor; tumorigenesis

Project Summary/Abstract This proposal focuses on the oncogenic CRTC1-MAML2 fusion that underlies the development of mucoepidermoid carcinomas (MEC), the most common type of salivary gland cancers. Patients with advanced, metastatic and recurrent MECs have poor outcomes and no targeted therapy is currently available. A comprehensive understanding of functions and mechanisms of this oncogenic fusion is essential for uncovering effective diagnostic and therapeutic approaches. We demonstrated that the CRTC1-MAML2 fusion is a major driver for MEC initiation and maintenance. Our investigations into the CRTC1-MAML2-induced oncogenic transcriptional program implicated long noncoding RNAs (lncRNAs) in MEC tumorigenesis and maintenance. LncRNAs belong to a novel class of gene regulators with emerging roles in human cancer and have the potential to serve as diagnostic markers due to their tissue and disease specificity. However, the involvement and mechanistic basis of lncRNAs remain poorly defined in MEC. Moreover, our data revealed the interaction of the CRTC1-MAML2 fusion with the transcription factor CREB is critical for inducing the major oncogenic transcriptional program; thus, targeting this interaction interface will have the advantage of blocking multiple critical fusion target genes/pathways. However, the significance of this fusion interaction as a therapeutic target remains to be tested in vivo. Therefore, the objectives of this proposal are to elucidate the lncRNA aspect of the oncogenic transcriptional program in CRTC1-MAML2- driven MEC and the significance of the critical fusion protein interaction governing the oncogenic transcriptional program in MEC. Two aims are proposed to test the overall hypothesis that the CRTC1-MAM2 fusion induces a unique lncRNA program in promoting MEC and that the CRTC1-MAML2/CREB interaction is critical for inducing the major oncogenic transcriptional program in MEC. Consequently, critical lncRNAs and fusion interaction can be targeted for MEC inhibition. Aim 1 will investigate the mechanisms and targeting of lncRNAs in CRTC1- MAML2 fusion-driven tumorigenesis. Aim 2 will Investigate the significance and targeting of the CRTC1-MAML2 fusion/CREB interaction in MEC. The completion of these proposed studies will uncover new mechanistic and functional insights into lncRNAs and the CRTC1-MAML2 oncogenic fusion and reveal new approaches for blocking MEC. We anticipate that these efforts will enhance our understanding of the CRTC1-MAML2 fusion oncogene and MEC biology and lead to the identification of novel diagnostic and therapeutic strategies.

项目总结/文摘

项目成果

Role of INSL4 Signaling in Sustaining the Growth and Viability of LKB1-Inactivated Lung Cancer.

• DOI: 10.1093/jnci/djy166
• 发表时间: 2018-11
• 期刊: Journal of the National Cancer Institute
• 作者: Rongqiang Yang;Steven W. Li;Zirong Chen;Xin Zhou;W. Ni;Dongtao A. Fu;Jianrong Lu;F. Kaye;Lizi Wu

Targeting Notch and EGFR signaling in human mucoepidermoid carcinoma.

• DOI: 10.1038/s41392-020-00388-0
• 发表时间: 2021-01-21
• 期刊: Signal transduction and targeted therapy
• 影响因子: 39.3
• 作者: Ni W;Chen Z;Zhou X;Yang R;Yu M;Lu J;Kaye FJ;Wu L
• 通讯作者: Wu L

Dependency of human and murine LKB1-inactivated lung cancer on aberrant CRTC-CREB activation.

• DOI: 10.7554/elife.66095
• 发表时间: 2021-06-18
• 期刊: eLife
• 影响因子: 7.7
• 作者: Zhou X;Li JW;Chen Z;Ni W;Li X;Yang R;Shen H;Liu J;DeMayo FJ;Lu J;Kaye FJ;Wu L
• 通讯作者: Wu L

Gene expression profiling analysis of CRTC1-MAML2 fusion oncogene-induced transcriptional program in human mucoepidermoid carcinoma cells.

• DOI: 10.1186/s12885-015-1827-3
• 发表时间: 2015-10-26
• 期刊: BMC cancer
• 影响因子: 3.8
• 作者: Chen J;Li JL;Chen Z;Griffin JD;Wu L
• 通讯作者: Wu L

CRTC1-MAML2 fusion-induced lncRNA LINC00473 expression maintains the growth and survival of human mucoepidermoid carcinoma cells.

• DOI: 10.1038/s41388-017-0104-0
• 发表时间: 2018-04
• 期刊: Oncogene
• 影响因子: 8
• 作者: Chen Z;Lin S;Li JL;Ni W;Guo R;Lu J;Kaye FJ;Wu L
• 通讯作者: Wu L