Epigenetic reprogramming in tumor plasticity / Salina Gin-Schuan Yuan.

Format:

Book

Thesis/Dissertation

Author/Creator:

Yuan, Salina Gin-Schuan, author.

Contributor:

University of Pennsylvania. Department of Cell and Molecular Biology, degree granting institution.

Language:

English

Subjects (All):

Molecular biology.

Cellular biology.

Oncology.

Immunology.

Cell and molecular biology--Penn dissertations.

Penn dissertations--Cell and molecular biology.

Local Subjects:

Molecular biology.

Cellular biology.

Oncology.

Immunology.

Cell and molecular biology--Penn dissertations.

Penn dissertations--Cell and molecular biology.

Genre:

Academic theses.

Physical Description:

1 online resource (159 pages)

Contained In:

Dissertations Abstracts International 82-04B.

Place of Publication:

[Philadelphia, Pennsylvania] : University of Pennsylvania ; Ann Arbor : ProQuest Dissertations & Theses, 2020.

Language Note:

English

System Details:

Mode of access: World Wide Web.

text file

Summary:

During cancer progression, tumor cells undergo various molecular and phenotypic changes collectively referred to as "plasticity," leading to both cell autonomous and non-cell autonomous consequences. There is increasing evidence that epigenetic modifiers - enzymes and complexes involved in the removal, deposition, and molecular interpretation of chromatin post-translational modifications--play an important role in regulating tumor plasticity. Still, our understanding of how or even the extent to which chromatin-based mechanisms contribute to tumor biology remains limited. Here we employed CRISPR-based forward genetic screening to unbiasedly address the epigenetic basis of tumor plasticity. Through an in vitro screen, we first identified two histone-modifying enzymes involved in the writing and erasing of H3K36me2 that act reciprocally to regulate epithelial plasticity, a particular form of cellular plasticity whereby cells transition between epithelial and mesenchymal states, as well as tumor differentiation and metastasis. Mechanistically, we found that global changes in H3K36me2 reprogram enhancers associated with master transcriptional regulators of the mesenchymal state. While these results indicate that a large-scale, epigenome-wide mechanism underlies epithelial plasticity in cancer, we subsequently identified focal epigenetic alterations as the basis for microenvironmental plasticity. Specifically, using an in vivo CRISPR-Cas9 screen, we identified the histone demethylase KDM3A as a potent tumor cell-intrinsic epigenetic regulator of the immune microenvironment. Through transcriptomic and epigenomic analyses, we found that KDM3A and its two downstream mediators, KLF5 and SMAD4, transcriptionally converge on EGFR to suppress T cell infiltration, and that loss of any of the components of this molecular axis is sufficient to convert the immune microenvironment from non-T cell-inflamed to T cell-inflamed, thereby sensitizing tumors to combination immunotherapy. Thus, using the power of CRISPR genetic screening, we identified key epigenetic determinants of cellular plasticity, which lead to both cell intrinsic and extrinsic changes. These epigenetic modifiers also represent a promising class of therapeutic targets for some of the most lethal aspects of tumor progression, including metastasis and therapy resistance.

Notes:

Source: Dissertations Abstracts International, Volume: 82-04, Section: B.

Advisors: Stanger, Ben Z.; Committee members: David Feldser; Irfan Asangani; Andy Minn; Kenneth Zaret.

Department: Cell and Molecular Biology.

Ph.D. University of Pennsylvania 2020.

Local Notes:

School code: 0175

ISBN:

9798672129075

Access Restriction:

Restricted for use by site license.

This item must not be sold to any third party vendors.