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You searched for subject:(Metadherin MTDH ). One record found.

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Princeton University

1. Wan, Liling. Dissecting the roles of MTDH/AEG-1 during multiple steps of cancer development .

Degree: PhD, 2014, Princeton University

Growing clinical evidence indicates a strong correlation between MTDH expression and the pathogenesis of many human cancer types, underscoring the potentially broad importance of this molecule in cancer biology. However, fundamental understanding of MTDH in normal development and malignancy is hindered by the lack of physiologically relevant animal models, and the mechanisms of its action remain poorly understood. Here, by generating the first knockout/transgenic mouse models, I dissect Mtdh's function during cancer progression and explore the underlying mechanisms. First, we report that while whole-organism ablation of Mtdh has little effect on normal development in mice, it inhibits mammary tumor formation driven by diverse oncogenes and carcinogen, and this tumorigenic defect in Mtdh-KO mice can be rescued by mammary epithelial cell-specific re-expression of Mtdh. Furthermore, Mtdh is required for oncogene-induced expansion and activities of basal and luminal tumor-initiating cells (TICs) at early tumorigenesis, whereas it is dispensable for normal mammary stem cells. Second, we performed thorough clinical and functional investigation of MTDH in prostate cancer (PCa) progression and metastasis. We found MTDH levels are tightly correlated with human PCa progression, and genomic gain at 8q22, where MTDH resides, is also observed frequently in prostate tumors and is associated with adverse clinical outcome. Functionally, deletion of Mtdh in a PCa mouse model prolongs tumor latency, reduces tumor burden, arrests cancer progression at non-malignant stages, and finally, inhibits systemic metastasis. These clinical and functional data thus establish MTDH as a potential biomarker and therapeutic target for human PCa. Finally, we examined the functional dependency of MTDH on its interacting partner SND1. We solved the crystal structure of MTDH-SND1 complex and uncovered key residues critical for the interaction. Silencing MTDH or SND1 individually, or disrupting their interaction by mutagenesis, impairs the survival and tumorigenenic potential of TICs. Mechanistically, SND1 acts as a survival factor by regulating the expression of pro-survival genes under stress, and MTDH interaction is critical to stabilize SND1 and sustain SND1-dependent survival gene signature. Our study suggests that targeting the MTDH-SND1 interaction may offer an opportunity to control tumor initiation, recurrence and metastasis by regulating cellular survival and TIC activities. Advisors/Committee Members: Kang, Yibin (advisor).

Subjects/Keywords: AEG-1; breast cancer; Metadherin; MTDH; SND1; stem cell

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APA · Chicago · MLA · Vancouver · CSE | Export to Zotero / EndNote / Reference Manager

APA (6th Edition):

Wan, L. (2014). Dissecting the roles of MTDH/AEG-1 during multiple steps of cancer development . (Doctoral Dissertation). Princeton University. Retrieved from http://arks.princeton.edu/ark:/88435/dsp01k930bx182

Chicago Manual of Style (16th Edition):

Wan, Liling. “Dissecting the roles of MTDH/AEG-1 during multiple steps of cancer development .” 2014. Doctoral Dissertation, Princeton University. Accessed December 05, 2020. http://arks.princeton.edu/ark:/88435/dsp01k930bx182.

MLA Handbook (7th Edition):

Wan, Liling. “Dissecting the roles of MTDH/AEG-1 during multiple steps of cancer development .” 2014. Web. 05 Dec 2020.

Vancouver:

Wan L. Dissecting the roles of MTDH/AEG-1 during multiple steps of cancer development . [Internet] [Doctoral dissertation]. Princeton University; 2014. [cited 2020 Dec 05]. Available from: http://arks.princeton.edu/ark:/88435/dsp01k930bx182.

Council of Science Editors:

Wan L. Dissecting the roles of MTDH/AEG-1 during multiple steps of cancer development . [Doctoral Dissertation]. Princeton University; 2014. Available from: http://arks.princeton.edu/ark:/88435/dsp01k930bx182

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