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Genomic instability and evolution in cancer stromal cells

English title Genomic instability and evolution in cancer stromal cells
Applicant Dotto Gian-Paolo
Number 176404
Funding scheme Project funding (Div. I-III)
Research institution Département de Biochimie Université de Lausanne
Institution of higher education University of Lausanne - LA
Main discipline Physiology : other topics
Start/End 01.10.2017 - 30.09.2020
Approved amount 846'481.00
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All Disciplines (2)

Discipline
Physiology : other topics
Experimental Cancer Research

Keywords (4)

Cancer Associated Fibroblasts; Telomere protection and erosion; Chromosome instability; Notch/CSL

Lay Summary (French)

Lead
SynthèseLe risque de développer un cancer augmente de façon exponentielle avec le vieillissement. Cette étude est focalisée sur le rôle du micro-environnement de la tumeur dans ce contexte, à l'interface entre vieillissement et développement du cancer.ObjectifsNous allons tester un modèle de co-évolution cancer/ stroma avec CSL et p53, comme facteurs de co-détermination et explorer la signification clinique des résultats. Le contexte socio-scientifiqueL’augmentation du cancer dépendant de l’âge et des tumeurs épithéliales récurrentes sont les principales causes de morbidité et de mortalité. Notre travail sur ce sujet est d'une capitale, car il peut conduire à de nouvelles approches préventives et thérapeutiques.
Lay summary

Le domaine de la cancérisation est d’une importance clinique majeure consistant en des altérations tissulaires étendues associées à des tumeurs primaires multiples et récurrentes. L'activation des fibroblastes stromaux dans les fibroblastes associés au cancer (FACs) est le plus souvent considérée comme secondaire pour les modifications de l'épithélium. Cependant, nos travaux précédents ont indiqué qu'elle pouvait jouer un rôle primordial dans le développement du cancer épithélial. Nous étudions actuellement un processus en plusieurs étapes de l’activation et de l’expansion des FACs basées sur une combinaison d'événements génétiques et/ou épigénétiques. Il reste à établir si des changements chromosomiques de signification fonctionnelle se produisent ou non dans ce contexte. Dans nos travaux futurs, nous aborderons cette question en nous concentrant sur le rôle d'une protéine spécifique de liaison à l'ADN, CSL, dans le contrôle de la stabilité des chromosomes et de la maintenance des télomères. L'expression et la fonction de CSL sont impliquées dans les FACs et nous testerons si, comme résultat, ces cellules acquièrent des altérations chromosomiques spécifiques leur conférant un avantage de croissance importante pour l'expansion des cellules stromales cancéreuses.

Direct link to Lay Summary Last update: 20.10.2017

Lay Summary (English)

Lead
SynthesisThe risk of most cancer types increases exponentially with aging. This proposal is focused on the role of the tumor microenvironment in this context, at the interface between aging and cancer development. Subjects and ObjectivesOur main objective is to dissect the function of the CSL protein, the effector of canonical Notch signaling, in stromal cell senescence and Cancer Associated Fibroblast activation. We will be testing a cancer/stromal co-evolution model with CSL and p53 as co-determining factors and explore the clinical significance of the findings.Socio-scientific contextAge-dependent increase of cancer and recurrent epithelial tumors are major causes of morbidity and mortality. Development of epithelial cancer can result from an altered tissue microenvironment. Our work on this topic is of substantial socio-scientific relevance, as it may lead to novel preventive and therapeutic approaches to the cancer problem.
Lay summary

Field cancerization is a condition of major clinical significance consisting of widespread tissue alterations associated with multiple and recurrent primary tumors. Activation of stromal fibroblasts into cancer associated fibroblasts (CAFs) is most frequently viewed as secondary to changes in the epithelium. However, our previous work indicated that it can play a primary role in epithelial cancer development. We are currently exploring a multistep process of CAF activation and expansion based on a combination of genetic and/or epigenetic events. Whether or not chromosomal changes of functional significance occur in this context remain to be established. In our future work, we will address this question focusing on the role of a specific DNA- binding protein, CSL, in control of chromosome stability and telomere maintenance. CSL expression and function are commonly compromised in CAFs and we will test whether, as a result, these cells acquire specific chromosomal alterations that confer a growth advantage important for cancer stromal cell expansion. 

Direct link to Lay Summary Last update: 20.10.2017

Responsible applicant and co-applicants

Employees

Associated projects

Number Title Start Funding scheme
156191 Cancer stromal cell genetic control 01.10.2014 Project funding (Div. I-III)
183398 Deep interrogation of cancer immunotherapy 01.03.2019 R'EQUIP

Abstract

Activation of cancer associated fibroblasts (CAFs) and associated chronic inflammation are most frequently viewed as secondary to changes in the epithelium. However, our previous work indicated that stromal fibroblast alterations can play a primary role in epithelial cancer development and field cancerization, a condition of major clinical significance consisting of widespread tissue alterations associated with multiple and recurrent primary tumors. More recently, we proposed a multistep model CAF activation, whereby concomitant loss of two key genes, CSL, a repressor of transcription and key mediator of Notch signaling, and p53, enhances expression of CAF effector genes and promotes stromal and cancer cell expansion. Chromosome instability is a hallmark of cancer3,4. Whether or not chromosomal changes of functional significance occur also in cancer-associated fibroblasts (CAFs) is a question of debate 5,6,7. These could play an important role in cancer stromal cell evolution. In our future work, we will test the hypotheses that : (i) decreased expression of CSL is a trigger of chromosomal instability in stromal fibroblasts; (ii) CSL plays an essential function in telomere maintenance as part of a complex with proteins with telomere protective / repair functions; (iii) chromosome instability is also a feature of clinically occurring CAFs and specific CNVs (copy number variations) confer upon these cells a growth advantage important for cancer stromal cell expansion.
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