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Regulation of Intratumor Heterogenei...

Liu, Xiaoni.

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Regulation of Intratumor Heterogeneity and Anti- tumor Immunity of Melanoma by Targeting KDM5B.

紀錄類型:	書目-電子資源 : Monograph/item
正題名/作者:	Regulation of Intratumor Heterogeneity and Anti- tumor Immunity of Melanoma by Targeting KDM5B./
作者:	Liu, Xiaoni.
出版者:	Ann Arbor : ProQuest Dissertations & Theses, : 2018,
面頁冊數:	145 p.
附註:	Source: Dissertations Abstracts International, Volume: 80-02, Section: B.
Contained By:	Dissertations Abstracts International80-02B.
標題:	Cellular biology. -
電子資源:	http://pqdd.sinica.edu.tw/twdaoapp/servlet/advanced?query=10927831
ISBN:	9780438194014

Regulation of Intratumor Heterogeneity and Anti- tumor Immunity of Melanoma by Targeting KDM5B.
Liu, Xiaoni.

Regulation of Intratumor Heterogeneity and Anti- tumor Immunity of Melanoma by Targeting KDM5B. - Ann Arbor : ProQuest Dissertations & Theses, 2018 - 145 p.

Source: Dissertations Abstracts International, Volume: 80-02, Section: B.

Thesis (Ph.D.)--Yale University, 2018.

This item must not be added to any third party search indexes.

Melanoma is the deadliest form of skin cancer. In the United States, there will be approximately 91,270 new cases of melanoma and 10,000 deaths due to the disease in 2018. While development of targeted inhibitors and immune therapies has revolutionized the clinical management of melanoma, there remain many obstacles regarding treatment efficacy and resistance. Melanoma is a highly heterogeneous disease and consists of multiple subpopulations of tumor cells that exhibit distinct cellular characteristics. Therefore, many believe that, by advancing our knowledge of intratumor heterogeneity, we could help overcome some of the most urgent challenges in treating melanoma. Previously, the Bosenberg lab identified three tumor subpopulations in murine melanomas based on expression of cell surface markers. Among the p75 - populations, CD34+ and CD34- tumor cells are both "melanoma-propagating cells (MPCs)" but present varying yet critical cellular features. These two subpopulations differ from each other in tumorigenic potential, ability to recapitulate heterogeneity, and chemo-resistance. This thesis dissertation focuses on identifying novel characteristics of MPC subpopulations, particularly in their response to targeted therapies and interaction with the tumor immune system. Furthermore, findings of this thesis shed light on how MPC subpopulations are regulated and the therapeutic potential of modulating intratumor heterogeneity of melanoma. Specifically, this thesis provides evidence that CD34- cells are more resistant to targeted BRAF inhibitor or combined BRAF and MEK inhibitors. By upregulating expression of KDM5B, a member of the lysine-specific histone demethylase family, "drug-sensitive" CD34+ cells shift to become "drug-tolerant" CD34- cells upon exposure to the targeted therapies. Combined treatment with BRAF inhibitor and a pan-KDM5 inhibitor mitigates the "subpopulation shifting" phenotype and leaves more CD34+ cells to respond to BRAF inhibitor. Moreover, we demonstrate that loss of KDM5B in murine melanoma cells significantly delays tumor growth in vivo through increased CD8 + T cell infiltration. Interestingly, the enhanced immune response requires functional interferon-gamma signaling in tumor cells and improves tumor response to immune checkpoint inhibitors. We also present evidence that CD34+ cells harvested from murine melanoma tumors express a higher level of MHC-I, indicating that the two MPC subpopulations may differ from each other in immunogenicity and their ability to interact with the tumor immune system. In summary, this thesis aims to expand our current understanding of the diverse impact of intratumor heterogeneity on melanoma development, progression, and response to treatments. Lastly, by identifying a key regulator that governs the heterogeneous dynamics of melanoma, we highlight the potential to develop novel therapeutic regimens by targeting intratumor heterogeneity and to ultimately improve clinical outcome of patients with this debilitating disease.

ISBN: 9780438194014Subjects--Topical Terms:

3172791
Cellular biology.

Regulation of Intratumor Heterogeneity and Anti- tumor Immunity of Melanoma by Targeting KDM5B.
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