Présentation

Equipe de Recherche Fondamentale  "Telomere Shortening in Cancer and Aging"


Miguel GODINHO FERREIRA, DR2 CNRS, Chef d'Equipe



Résumé


Our main goal is to understand the mechanisms that promote the rise of cancer incidence with age and to understand the role telomeres plays on this phenomenon. We have developed novel vertebrate system to study this question - the zebrafish. Contrary to common mouse models, zebrafish has natural shorter telomeres that decline with age and limit cell proliferation and longevity.

Telomeres protect the ends of chromosomes from inappropriately being recognized as a double strand break and constant DNA erosion. As telomeres shorten throughout life, we lose this protection, leading to cell senescence and, possibly, genome instability.

We are testing an hypothesis that attempts to explain the apparent paradox of cancer arising at this stage of low cell proliferation. Due to telomere shortening, senescent cells accumulate with age. These cells secrete a very distinct set of signaling factors, proteases and other molecules (SASP). SASP promotes both malignant phenotypes in culture and tumor growth and invasiveness in vivo. The “seed-and-soil” theory proposes the importance of the microenvironment for carcinogenesis. With aging, senescent cells with short telomeres may provide the right soil for tumors to arise in a non-cell autonomous manner.



Projet de Recherche

Projet de Recherche


Telomere length is one of the best-studied markers of aging in humans and is correlated with many age-related diseases amongst them cancer. However, it remains unclear whether telomere length has a causative role in the age-related increase in cancer risk. On one hand, telomere shortening is thought to prevent uncontrolled cell growth, but on the other hand, the vast majority of cancers arise when telomeres are the shortest.

We will directly test whether telomere shortening not only correlates, but actually causes increase cancer incidence with age. In recent years, zebrafish emerged as a promising model to address this question because, unlike the laboratory mouse, it has telomeres of a length similar to that of humans.

To this end, we will combine established zebrafish cancer models with our recently described telomerase mutant. Using conditional transgenics, we will manipulate telomere length in both cancer cells and cells of the surrounding microenvironment to modulate rates of tumor formation. Additionally, we will ask whether ectopic telomerase expression (normally thought of as a carcinogen) actually promotes cancer in both young and old individuals. These experiments will finally test deeply entrenched ideas about age-dependent cancer pathogenesis in a model organism that, like humans, relies on telomere shortening as means of controlling cell division.


Figure 1.

Telomeres shorten at different rates anticipating local and systemic dysfunction in zebrafish aging. 

Telomeres shorten naturally over time in specific zebrafish organs regardless of differences in proliferation rates. This shortening, together with the accumulation of local telomere damage, precludes the onset of tissue dysfunction events in aging, including intestinal inflammation and sarcopenia (Carneiro et al. 2016, PMID: 27482813). Critically short telomeres may be sufficient to disrupt homeostasis in other tissues where telomeres do not erode, by generating systemic signals of dysfunction that create a "disease-permissive" environment.

 

Publications


Publications


Telomeres in aging and disease: lessons from zebrafish.

Carneiro MC, de Castro IP, Ferreira MG.

Dis Model Mech. 2016 Jul 1;9(7):737-48. doi: 10.1242/dmm.025130. Review.


TERT promoter mutations in pancreatic endocrine tumours are rare and mainly found in tumours from patients with hereditary syndromes.

Vinagre J, Nabais J, Pinheiro J, Batista R, Oliveira RC, Gonçalves AP, Pestana A, Reis M, Mesquita B, Pinto V, Lyra J, Cipriano MA, Ferreira MG, Lopes JM, Sobrinho-Simões M, Soares P.

Sci Rep. 2016 Jul 14;6:29714.


Short Telomeres in Key Tissues Initiate Local and Systemic Aging in Zebrafish.

Carneiro MC, Henriques CM, Nabais J, Ferreira T, Carvalho T, Ferreira MG.

PLoS Genet. 2016 Jan 20;12(1):e1005798.


Cdk1 restrains NHEJ through phosphorylation of XRCC4-like factor Xlf1.

Hentges P, Waller H, Reis CC, Ferreira MG, Doherty AJ.

Cell Rep. 2014 Dec 24;9(6):2011-7.


Nat Commun. 2013;4:2235.


Telomerase is required for zebrafish lifespan.

Henriques CM, Carneiro MC, Tenente IM, Jacinto A, Ferreira MG.

PLoS Genet. 2013;9(1):e1003214.


Nucleic Acids Res. 2013 Mar 1;41(5):3056-67.


EMBO J. 2012 Dec 12;31(24):4576-86.


Curr Opin Cell Biol. 2012 Dec;24(6):804-8.


Taz1 enforces cell-cycle regulation of telomere synthesis.

Dehé PM, Rog O, Ferreira MG, Greenwood J, Cooper JP.

Mol Cell. 2012 Jun 29;46(6):797-808.




(Mars 2017)