Date of Award

8-7-2018

Degree Type

Dissertation

Degree Name

Doctor of Philosophy (PhD)

Department

Biology

First Advisor

Ritu Aneja

Second Advisor

Deborah J Baro

Third Advisor

Zhi-Ren Liu

Fourth Advisor

Emilius Adrianus Maria Janssen

Abstract

Cancer initiation and progression are multistep processes that rely on the generation and accumulation of non-lethal mutations, which deregulate function of tumor suppressor genes and activate oncogenic pathways. Evolving through a landscape of heterogeneous somatic mutations, mutated cells undergo subsequent selection pressures and the one endowed with the greatest fitness advantage survives giving rise to genetically diverse cell populations resulting in intratumor heterogeneity (ITH). Presence of the abnormal number of centrosomes is one of the key factors contributing towards ITH. Clustering of amplified centrosomes allows cancer cells to avoid mitotic spindle multipolarity that could otherwise result in cell death either by mitotic catastrophe or a high-grade multipolar division yielding intolerably severe aneuploidy. Thus, centrosome clustering enables low-grade chromosomal missegregation and their unequal distribution to daughter cells resulting in chromosomal instability (CIN), thus contributing to neoplastic transformation. Owing to the presence of genetically different cells in a tumor, monotargeted therapy spares clones lacking therapy-specific targets giving them the opportunity to repopulate the tumor with immunity toward the applied therapy and propensity to recur. Therefore, ITH poses major challenges to both clinicians and drug developers as it precludes detection of low-level clones, prediction of tumor evolution, development of drugs to target specific clones and evaluation of effective, yet non-toxic combinatorial regimens to combat ITH.

I envision that a comprehensive quantitative analysis of centrosome amplification (CA), which is a bonafide driver of ITH might help better understand clinical behavior and improve therapeutic management of tumors. To this end, my research, presented here, primarily focuses on testing i) the impact of centrosome amplification and centrosome clustering protein (KIFC1) on clinical outcomes in multiple malignancies and ii) the role of tumor hypoxia in inducing centrosome amplification in cancer. Collectively, my findings reveal that CA and KIFC1 are prognostic and predictive in multiple malignancies and that tumor hypoxia plays a crucial role in inducing CA in tumors. This body of work expands our knowledge in causes and clinical implications of CA to help guide treatment decisions and development of precision medicine for multiple malignancies.

DOI

https://doi.org/10.57709/12477393

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