Understanding chromosomal instability-induced senescence

[eng] Aneuploidy, defined as a chromosome number that deviates from a multiple of the haploid set, is a common feature in human cancer, and around 70% of human solid tumours are aneuploid. The resulting metabolic imbalance is proposed to play a fundamental role in the compromised fitness of these ce...

ver descrição completa

Detalhes bibliográficos
Autor: Santos Tapia, Celia
Formato: tesis doctoral
Estado:Versión publicada
Fecha de publicación:2019
País:España
Recursos:Universidad de Barcelona
Repositorio:Dipòsit Digital de la UB
OAI Identifier:oai:diposit.ub.edu:2445/178622
Acesso em linha:https://hdl.handle.net/2445/178622
http://hdl.handle.net/10803/671915
Access Level:acceso abierto
Palavra-chave:Mort cel·lular
Cromosomes
Càncer
Cell death
Chromosomes
Cancer
id ES_4dc06772c19fc11143437790f043c634
oai_identifier_str oai:diposit.ub.edu:2445/178622
network_acronym_str ES
network_name_str España
repository_id_str
dc.title.none.fl_str_mv Understanding chromosomal instability-induced senescence
title Understanding chromosomal instability-induced senescence
spellingShingle Understanding chromosomal instability-induced senescence
Santos Tapia, Celia
Mort cel·lular
Cromosomes
Càncer
Cell death
Chromosomes
Cancer
title_short Understanding chromosomal instability-induced senescence
title_full Understanding chromosomal instability-induced senescence
title_fullStr Understanding chromosomal instability-induced senescence
title_full_unstemmed Understanding chromosomal instability-induced senescence
title_sort Understanding chromosomal instability-induced senescence
dc.creator.none.fl_str_mv Santos Tapia, Celia
author Santos Tapia, Celia
author_facet Santos Tapia, Celia
author_role author
dc.contributor.none.fl_str_mv Milán, Marco
Universitat de Barcelona. Facultat de Biologia
dc.subject.none.fl_str_mv Mort cel·lular
Cromosomes
Càncer
Cell death
Chromosomes
Cancer
topic Mort cel·lular
Cromosomes
Càncer
Cell death
Chromosomes
Cancer
description [eng] Aneuploidy, defined as a chromosome number that deviates from a multiple of the haploid set, is a common feature in human cancer, and around 70% of human solid tumours are aneuploid. The resulting metabolic imbalance is proposed to play a fundamental role in the compromised fitness of these cells and lead to malignant transformation by causing proteotoxic stress and affecting cell cycle proliferation and growth. However, most of the molecular pathways and cellular behaviours underlying aneuploid-induced tumorigenesis remain uncharacterized. Drosophila larval epidermal primordia have proved useful model systems to demonstrate the contribution of aneuploidy-induced metabolic stress to tumour growth. By depleting different Spindle Assembly Checkpoint (SAC) genes in the epithelial cells, we induce chromosomal instability and generate aneuploidy. When prevented from undergoing programmed cell death (PCD), these cells give rise to a neoplasic overgrowth. Here we propose that CIN-induced aneuploidy in epithelial cells activates low levels of the c-Jun N-terminal kinase (JNK) and the DNA damage response (DDR). This induces a G1 stall that prevents the accumulation of damage. However, when due to CIN these cells become highly aneuploid, they delaminate from the epithelium and acquire a senescent behaviour. This senescent behaviour is dependent on high levels of JNK and DDR signalling, and induce the secretion of wide variety of factors - also known as the senescence-associated secretory phenotype (SASP) -, and a permanent G2 arrest, among other senescent features. In addition, we have identified two target effectors, Fizzy-related and String, that are miss-regulated and could act downstream JNK and the DDR to induce the G2 arrest. Finally, we were able to explore two different ways to target CIN-aneuploid cells based on their basal levels of replicative stress: genetic (CycE/Dap overexpression) and chemical (Hydroxyurea), which significantly affect tissue growth and impair tumour progression.
publishDate 2019
dc.date.none.fl_str_mv 2019
dc.type.none.fl_str_mv info:eu-repo/semantics/doctoralThesis
info:eu-repo/semantics/publishedVersion
format doctoralThesis
status_str publishedVersion
dc.identifier.none.fl_str_mv https://hdl.handle.net/2445/178622
http://hdl.handle.net/10803/671915
url https://hdl.handle.net/2445/178622
http://hdl.handle.net/10803/671915
dc.language.none.fl_str_mv Inglés
language_invalid_str_mv Inglés
dc.rights.none.fl_str_mv (c) Santos Tapia, Celia, 2021
info:eu-repo/semantics/openAccess
rights_invalid_str_mv (c) Santos Tapia, Celia, 2021
eu_rights_str_mv openAccess
dc.format.none.fl_str_mv application/pdf
dc.publisher.none.fl_str_mv Universitat de Barcelona
publisher.none.fl_str_mv Universitat de Barcelona
dc.source.none.fl_str_mv Tesis Doctorals - Facultat - Biologia
reponame:Dipòsit Digital de la UB
instname:Universidad de Barcelona
instname_str Universidad de Barcelona
reponame_str Dipòsit Digital de la UB
collection Dipòsit Digital de la UB
repository.name.fl_str_mv
repository.mail.fl_str_mv
_version_ 1869407712540884992
spelling Understanding chromosomal instability-induced senescenceSantos Tapia, CeliaMort cel·lularCromosomesCàncerCell deathChromosomesCancer[eng] Aneuploidy, defined as a chromosome number that deviates from a multiple of the haploid set, is a common feature in human cancer, and around 70% of human solid tumours are aneuploid. The resulting metabolic imbalance is proposed to play a fundamental role in the compromised fitness of these cells and lead to malignant transformation by causing proteotoxic stress and affecting cell cycle proliferation and growth. However, most of the molecular pathways and cellular behaviours underlying aneuploid-induced tumorigenesis remain uncharacterized. Drosophila larval epidermal primordia have proved useful model systems to demonstrate the contribution of aneuploidy-induced metabolic stress to tumour growth. By depleting different Spindle Assembly Checkpoint (SAC) genes in the epithelial cells, we induce chromosomal instability and generate aneuploidy. When prevented from undergoing programmed cell death (PCD), these cells give rise to a neoplasic overgrowth. Here we propose that CIN-induced aneuploidy in epithelial cells activates low levels of the c-Jun N-terminal kinase (JNK) and the DNA damage response (DDR). This induces a G1 stall that prevents the accumulation of damage. However, when due to CIN these cells become highly aneuploid, they delaminate from the epithelium and acquire a senescent behaviour. This senescent behaviour is dependent on high levels of JNK and DDR signalling, and induce the secretion of wide variety of factors - also known as the senescence-associated secretory phenotype (SASP) -, and a permanent G2 arrest, among other senescent features. In addition, we have identified two target effectors, Fizzy-related and String, that are miss-regulated and could act downstream JNK and the DDR to induce the G2 arrest. Finally, we were able to explore two different ways to target CIN-aneuploid cells based on their basal levels of replicative stress: genetic (CycE/Dap overexpression) and chemical (Hydroxyurea), which significantly affect tissue growth and impair tumour progression.[spa+ La aneuploidía, que se define como un número de cromosomas diferente al haploide, es una característica muy común en cáncer ya que se encuentra en alrededor de 68% de los tumores sólidos. Esta resulta en un desequilibrio metabólico que compromete la función celular induciendo estrés proteotóxico y afectando el crecimiento celular, dando lugar a así a una transformación maligna de estas células. Sin embargo, muchos de los mecanismos moleculares detrás de esta transformación generada por la aneuploidía son aún desconocidos. En este trabajo, usamos el epitelio del ala de Drosophila como tejido modelo para demostrar la contribución de la aneuploidía al crecimiento tumoral. Mediante la inhibición de genes del checkpoint del huso mitótico, inducimos inestabilidad cromosómica y aneuploidía que, tras bloquear la muerte celular, da lugar a un sobrecrecimiento tumoral. Cuando las células no tienen aún altos niveles de aneuploidía, activan bajos niveles de la quinasa c-Jun N-terminal (JNK) y activan la respuesta a daño en el DNA (DDR). Esto induce un arresto temporal en G1 que previene la acumulación de más daño. Sin embargo, debido a la inestabilidad cromosómica, estas células continúan proliferando y acumulan altos niveles de aneuploidía, delaminan del epitelio y adquieren un comportamiento senescente. Este depende de la activación de altos niveles de JNK y la DDR y tiene como consecuencia la secreción de distintos factores (SASP) y un arresto permanente en G2, entre otras características senescentes. Además, hemos podido identificar dos factores involucrados en el arresto, Tribbles and String, que podrían actuar en respuesta a JNK y a la DDR para hacer efectivo el arresto en G2. Finalmente, exploramos dos maneras distintas de afectar los tumores CIN aprovechando que sufren daño en el DNA: genéticamente (mediante la sobre-expresión de CycE/Dap) y químicamente (mediante el tratamiento con hidroxiurea), afectando ambas el crecimiento del tejido e inhibiendo la progresión tumoral.Universitat de BarcelonaMilán, MarcoUniversitat de Barcelona. Facultat de Biologia2019info:eu-repo/semantics/doctoralThesisinfo:eu-repo/semantics/publishedVersionapplication/pdfhttps://hdl.handle.net/2445/178622http://hdl.handle.net/10803/671915Tesis Doctorals - Facultat - Biologiareponame:Dipòsit Digital de la UBinstname:Universidad de BarcelonaInglés(c) Santos Tapia, Celia, 2021info:eu-repo/semantics/openAccessoai:diposit.ub.edu:2445/1786222026-05-27T06:46:51Z
score 15.300719

Registos relacionados