HAL Id: hal-02472505
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Submitted on 2 Dec 2020
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Non-cell autonomous roles of telomere shortening in zebrafish
Gil Mariana, Margarida Figueira, Miguel G. Ferreira, Mariana Gil, Ahmed Maouche, Naz Serifoglu, Margarida Figueira, Miguel Ferreira
To cite this version:
Gil Mariana, Margarida Figueira, Miguel G. Ferreira, Mariana Gil, Ahmed Maouche, et al.. Non-cell autonomous roles of telomere shortening in zebrafish. 4th Labex SIGNALIFE Meeting, Feb 2020, Nice, France. 2020, �10.1073/pnas.1920049117/- /DCSupplemental.www.pnas.org/cgi/doi/10.1073/pnas.1920049117�. �hal-02472505�
Non-cell autonomous roles of telomere shortening in zebrafish
WT
Aspirin
Background:
Cancer incidence increases with age. Due to the end-replicative problem, telomeres shorten with each cell division throughout our lives. Telomere shortening has consequences beyond the cellular level. As we age, cells approach replicative senescence and DNA damage emanating by short telomeres initiate a cascade of events that expands to the extracellular environment. Senescent cells were shown to release a set of molecules including inflammatory cytokines, termed senescence-associated secretory phenotype (SASP). Indeed, an inflammatory environment generates a pro-tumorigenic environment that supports tumor invasiveness.
Aim of the study:
Investigate the causal relation between short telomeres and cancer incidence. Determine whether this effect has a non-cell autonomous component by using zebrafish embryo chimeras and tumor transplants.
Mariana M. GIL
1, Ahmed MAOUCHE
2, Naz SERIFOGLU
2, Margarida FIGUEIRA
1and Miguel GODINHO FERREIRA
1,21
Instituto Gulbenkian de Ciência, 2781-901 Oeiras, Portugal Instituto de Medicina Molecular
2
Institute for Research on Cancer and Aging of Nice (IRCAN), CNRS UMR7284 INSERM U1081 UNS, 06107 Nice, France.
mitfa:HRASG12V ß-actin:GFP
tert+/- incross
Casper (no melanocytes)
Donor Recipient
0 10 20 30
0 50 100
Age (weeks)
Tum or fr e e fis h [ % ]
WT tert-/-
n=45 n=47
*
Percentoftotal
WT
tert-/- 0
50 100
Benign tumors Malignant, non-invasive Malignant, invasive 8
2 4
3 2
Tumor staging
1. Short telomeres induce tumorigenesis in a non-cell autonomous manner
WT recipient tert-/- recipient
2. Melanoma is more invasiveness in an environment with short telomeres
G2 tert-/- WT
WT
G2 tert-/-
G2 tert-/- → WT
SA-ß-Gal
3. Telomerase deficient tissues present higher levels of senescence
Neutrophils Tg(mpx:GFP)
(WT)
WT or
G2 tert-/-
WT → WT Tg(mpx:GFP)
G2 tert-/- → WT Tg(mpx:GFP)
n o n in je c t e d t e r t + / +è m p x t e r t - / -è m p x
0 1 0 0 2 0 0 3 0 0 4 0 0 5 0 0
Nº of neutrophils (mpx), 4dpf
ns **
**
+ Aspirin
+ Aspirin
WT G2tert-/-
6. Increased tumor invasiveness in G2 tert-/- larvae is rescued by inhibiting inflammation.
5. Telomerase deficient tissues present higher level of inflammation
WT
control
Tert control
Tert Aspirin
A)Chimeras generation
A) Chimeras generation
B ) Chimeras generation
C) Measurement of Neutrophis numbers A) Measurement of inflammatory cytokine (TNF)
Tânia Carvalho, iMM Portugal
Short Telomeres ≈ Aged tissues
Tert -/- More tumor invasiveness environment & Progression
non-cell autonomous
4. Short telomeres influences neighbour tissues 7. Conclusion
G2 tert -/- WT
B) Control
SA-ß-Gal
SA-ß-Gal
systemic inflammation
+ Aspirin
WT recipient
tert-/- recipient Tumor
Tumor
Lex et al ., 2019
Lex et al ., 2019
Lex et al ., 2019
Lex et al ., 2019 Lex et al ., 2019
Wildtype ≈ normal telomeres
B) Measurement of melanoma occurrence in chimeric fish
