DECIPHERING AND EXPLOITING ANEUPLOIDY IN CANCER
type: CreativeWork
description: Aneuploidy - a state of karyotype imbalance – arises from errors in the process of chromosome segregation and induces a multitude of cellular stresses that are mostly detrimental in untransformed cells. Importantly, aneuploidy is a pervasive feature of tumors, being present in the vast majority of both solid and blood cancers. In the first part of my PhD, I have been focusing on understanding how cancer cells can exploit aneuploidy-associated stresses for their survival and proliferation. My work sheds light on how cancer cells capitalize on aneuploidy-induced genome instability and associated gene copy-number changes caused by aneuploidy to withstand selective pressures, such as chemotherapy. The development of resistance to chemotherapeutic drugs appears to be influenced by the emergence of recurrent karyotypes, suggesting that gene dosage could contribute to chemoresistance. This establishes a direct correlation between aneuploidy-induced gene copy number alterations and chemoresistance, potentially explaining the failure of some chemotherapy treatments. While aneuploidy is recognized as a characteristic of human cancer, the cellular processes that cells employ to manage the resulting stresses are not well understood. These processes may reveal vulnerabilities that could be exploited to target cancer cells. In the second part of my PhD, I generated and characterized several stable clones with varying degrees of chromosome imbalances. Through comprehensive genomic profiling of six isogenic clones via whole-exome and RNA sequencing, along with extensive CRISPR/Cas9 and drug screening, I explored their cellular dependency landscapes. In line with earlier findings, I observed increased DNA damage and p53 pathway activation in aneuploid cells. These cells also showed an increased DNA damage response (DDR), leading to greater resistance against further DNA damage. Notably, aneuploid cells had increased RAF/MEK/ERK pathway activity and were particularly sensitive to dru…
abstract: Aneuploidy - a state of karyotype imbalance – arises from errors in the process of chromosome segregation and induces a multitude of cellular stresses that are mostly detrimental in untransformed cells. Importantly, aneuploidy is a pervasive feature of tumors, being present in the vast majority of both solid and blood cancers. In the first part of my PhD, I have been focusing on understanding how cancer cells can exploit aneuploidy-associated stresses for their survival and proliferation. My work sheds light on how cancer cells capitalize on aneuploidy-induced genome instability and associated gene copy-number changes caused by aneuploidy to withstand selective pressures, such as chemotherapy. The development of resistance to chemotherapeutic drugs appears to be influenced by the emergence of recurrent karyotypes, suggesting that gene dosage could contribute to chemoresistance. This establishes a direct correlation between aneuploidy-induced gene copy number alterations and chemoresistance, potentially explaining the failure of some chemotherapy treatments. While aneuploidy is recognized as a characteristic of human cancer, the cellular processes that cells employ to manage the resulting stresses are not well understood. These processes may reveal vulnerabilities that could be exploited to target cancer cells. In the second part of my PhD, I generated and characterized several stable clones with varying degrees of chromosome imbalances. Through comprehensive genomic profiling of six isogenic clones via whole-exome and RNA sequencing, along with extensive CRISPR/Cas9 and drug screening, I explored their cellular dependency landscapes. In line with earlier findings, I observed increased DNA damage and p53 pathway activation in aneuploid cells. These cells also showed an increased DNA damage response (DDR), leading to greater resistance against further DNA damage. Notably, aneuploid cells had increased RAF/MEK/ERK pathway activity and were particularly sensitive to dru…
author: IPPOLITO, MARICA ROSARIA
language: eng
keywords: aneuploidy, cancer, chemoresistance, DNA damage, UPR, NMD
date published: 2024-04-11
date modified: 2026-07-27T20:18:56Z
provider: Università degli Studi di Milano
publisher: Networked Digital Library of Theses and Dissertations
type: WebPage
source organization: Università degli Studi di Milano

PropertyValue
property ID: Handle
value: https://hdl.handle.net/2434/1040037

PropertyValue
property ID: DOI
value: 10.13130/ippolito-marica-rosaria_phd2024-04-11