Biology subjects

Lopes-Bastos, B.

Publications and source records attributed to Lopes-Bastos, B..

3 recordsLinked to original sources

bioRxiv2025

Telomeric antisense oligonucleotides reduce premature aging phenotypes in telomerase mutant zebrafish

Telomerase activity is restricted in somatic cells, resulting in progressive telomere shortening. Telomere erosion eventually activates the DNA damage response (DDR), inducing cell-cycle arrest and cellular senescence or apoptosis. We previously reported that telomere dysfunction induces the transcription of telomeric non-coding RNAs (tncRNAs) which are critical mediators of DDR activation. Blocking tncRNAs with telomeric antisense oligonucleotides (tASOs) suppresses in vivo DDR signaling and its downstream effects. Here, we show that tASO-mediated inhibition of telomeric DDR in second-generation tert-/- zebrafish embryos with critically short telomeres leads to improved developmental outcomes and rescues premature aging phenotypes, including enhanced survival. Notably, a single tASO treatment administered at the one-cell stage of first-generation tert-/- embryos leads to enhanced fertility observed in 6-month-old adults. Overall, these findings demonstrate that tASO-based inhibition of telomeric DDR is sufficient to effectively rescue premature aging phenotypes in zebrafish.

pathology↗

bioRxiv2023

Absence of Telomerase Leads to Immune Response and Tumor Regression in Zebrafish Melanoma

Most cancers reactivate telomerase to maintain telomere length to acquire immortality. The importance of this process is well illustrated by the fact that telomerase promoter mutations are found at a high frequency in many cancer types, including melanoma. However, it is unclear when and if telomerase is strictly required during tumorigenesis. Here, we show that melanoma can occur in the absence of telomerase but is required to sustain later growth and to avoid tumor regression. We combined telomerase mutant zebrafish (tert-/-) with two established melanoma models and found equal melanoma incidence and invasiveness as tumors became visible. Later, however, while tert+/+ fish develop increasing larger tumors, tert-/- tumors stagnate growth and regress. tert-/- tumors showed lower cell proliferation, higher apoptosis and melanocyte differentiation. We also detected an immune response directed at tert-/- tumors. tert-/- tumors exhibited increased immune cell infiltrates and resume growth when transplanted into immunocompromised hosts. We propose that telomerase is required for melanoma in zebrafish, albeit at later stages of progression, to sustain growth while avoiding immune rejection and regression. Thus, absence of telomerase restricts melanoma through tumor-autonomous mechanisms (cell cycle arrest, apoptosis and melanocyte differentiation) and a non-tumor-autonomous mechanisms (immune rejection).

cancer biology↗

bioRxiv2019

Telomere shortening produces an inflammatory environment that promotes tumor invasiveness in zebrafish

Cancer incidence increases exponentially with age, when human telomeres are shorter. Similarly, telomerase mutant zebrafish (tert) have premature short telomeres and anticipate cancer incidence to younger ages. However, because short telomeres constitute a road block to cell proliferation, telomere shortening is currently viewed as a tumor suppressor mechanism and should protect from cancer. This conundrum is not fully understood. In our current study, we report that telomere shortening promotes cancer in a non-cell autonomous manner. Using zebrafish chimeras, we show increased incidence of invasive melanoma when WT tumors are generated in tert mutant zebrafish. tert zebrafish show increased levels of senescence (cdkn2a and ink4a/b) and inflammation (TNF-). In addition, we transferred second generation tert blastula cells into WT to produce embryo chimeras. Cells with very short telomeres induced senescence and increased neutrophil numbers in surrounding larval tissues in a non-cell autonomous manner, creating an inflammatory environment. Considering that inflammation is pro-tumorigenic, we transplanted melanoma-derived cells into second generation tert zebrafish embryos and observed that tissue environment with short telomeres leads to increased micrometastasis. To test if inflammation was necessary for this effect, we treated melanoma transplants with non-steroid anti-inflammatory drugs and show that higher melanoma invasiveness can be averted. Thus, apart from the cell autonomous role of short telomeres in contributing to genome instability, we propose that telomere shortening with age causes systemic chronic inflammation leading to increased tumor incidence. Significance StatementCancer incidence increases exponentially in human midlife. Even though mutation accumulation in somatic tissues results in increased tumorigenesis, it is currently not understood how aging contributes to cancer. Telomeres, the ends of eukaryotic linear chromosomes, shorten with each cell division. Here we show that telomere shortening contributes to cancer in a non-cell autonomous manner. Using embryo chimeras of telomerase deficient zebrafish generated from melanoma-prone fish, we show that tumors arise more frequently and become more invasive in animals with shorter telomeres. Telomere shortening gives rise to increased senescence and systemic inflammation. We observed increased melanoma metastasis dissemination in zebrafish larvae with very short telomeres. Thus, telomere shortening similar to human aging, generates a chronic inflammatory environment that increases cancer incidence.

cancer biology↗