Mechanical Confinement and Heat as Drivers of Aneuploidy in Cancer Steven Huy Phan

Format:

Book

Thesis/Dissertation

Author/Creator:

Phan, Steven Huy, author.

Contributor:

University of Pennsylvania. Chemical and Biomolecular Engineering., degree granting institution.

Language:

English

Subjects (All):

0307.

0369.

0379.

0786.

0992.

Local Subjects:

0307.

0369.

0379.

0786.

0992.

Physical Description:

1 electronic resource (96 pages)

Contained In:

Dissertations Abstracts International 87-07B

Place of Publication:

Ann Arbor : ProQuest Dissertations and Theses, 2025

Language Note:

English

Summary:

Aneuploidy, defined as an abnormal number of chromosomes, is a hallmark of human cancers and contributes to tumor evolution, heterogeneity, and therapeutic resistance. While classically attributed to chromosome mis-segregation during mitosis, emerging evidence indicates that diverse physical and physiological stresses in the tumor microenvironment also shape genomic stability across the cell cycle. In this dissertation, I primarily investigate how mechanical drive heritable chromosome losses. I also extend these findings to other tumor-relevant stressors, particularly heat shock and lipid accumulation. In Chapter 1, I provide a brief overview of aneuploidy, outlining the role of the cell cycle, its role in cancer progression, and its clinical implications. In Chapter 2, I examine how mechanical confinement, a physiologically relevant feature of solid tumors, perturbs mitotic cells. Using a chromosome reporter system, I show that confinement disrupts prometaphase progression, generates delayed micronuclei, and leads to heritable chromosome losses These effects phenocopy nocodazole, a microtubule inhibitor, and transcriptional analysis identifies confinement-induced dysregulation of mitotic programs. These results introduce the concept of a mitotic memory, in which transient mechanical stress on mitotic cells leaves lasting genetic changes. In Chapter 3, I extend my studies on chromosomal instability to other stressors. Hyperthermia destabilizes the mitotic spindle, induces abnormal spindle morphologies, and produces a linear increase in heritable chromosome losses and micronuclei across multiple cancer cell lines. In contrast, lipid droplet accumulation delays the cell cycle and reduces chromosome losses, yet still perturbs spindle integrity. Both stresses generate co-localized colonies of chromosome losses and gains, with gains consistently lagging behind losses, supporting a model in which micronuclei harbor nascent gains. Overall, by showing how confinement, heat, and fat act through overlapping and distinct mechanisms to affect genome stability, this work expands our understanding of the mechanisms of chromosomal instability

Notes:

Advisors: Discher, Dennis E. Committee members: Jiang, Ning Jenny; Lim, Bomyi; Radhakrishnan, Ravi; Zhang, Nancy R.

Source: Dissertations Abstracts International, Volume: 87-07, Section: B.

Ph.D. University of Pennsylvania 2025

Vendor supplied data

Local Notes:

School code: 0175

ISBN:

9798276001449

Access Restriction:

Restricted for use by site license