Developments in zebrafish avatars as radiotherapy sensitivity reporters - towards personalized medicine

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Developments in zebrafish avatars as radiotherapy sensitivity reporters - towards personalized medicine

Terça, 17.11.2020

Authors and Affiliations:

Bruna Costa: Champalimaud Centre for the Unknown, Champalimaud Foundation, 1400-038 Lisbon, Portugal

Susana Ferreira: Champalimaud Centre for the Unknown, Champalimaud Foundation, 1400-038 Lisbon, Portugal

Vanda Póvoa: Champalimaud Centre for the Unknown, Champalimaud Foundation, 1400-038 Lisbon, Portugal

Oriol Parés: Radiation Oncology Department, Champalimaud Clinical Centre, Champalimaud Foundation, 1400-038 Lisbon, Portugal

Maria João Cardoso: Radiation Oncology Department, Champalimaud Clinical Centre, Champalimaud Foundation, 1400-038 Lisbon, Portugal

Sandra Vieira: Radiation Oncology Department, Champalimaud Clinical Centre, Champalimaud Foundation, 1400-038 Lisbon, Portugal

Joep Stroom: Radiation Oncology Department, Champalimaud Clinical Centre, Champalimaud Foundation, 1400-038 Lisbon, Portugal

Paulo Fidalgo: Digestive Unit, Champalimaud Clinical Centre, Champalimaud Foundation, 1400-038 Lisbon, Portugal

Ricardo Rio-Tinto: Digestive Unit, Champalimaud Clinical Centre, Champalimaud Foundation, 1400-038 Lisbon, Portugal

Nuno Figueiredo: Digestive Unit, Champalimaud Clinical Centre, Champalimaud Foundation, 1400-038 Lisbon, Portugal

Carlo Greco: Radiation Oncology Department, Champalimaud Clinical Centre, Champalimaud Foundation, 1400-038 Lisbon, Portugal

Miguel Godinho Ferreira: Université Côte d'Azur, Institute for Research on Cancer and Aging of Nice (IRCAN), CNRS UMR7284 INSERM U1081, 06107 Nice, France.

Rita Fior: Champalimaud Centre for the Unknown, Champalimaud Foundation, 1400-038 Lisbon, Portugal

 

Abstract

Background: Whereas the role of neoadjuvant radiotherapy in rectal cancer is well-established, the ability to discriminate between radioresistant and radiosensitive tumors before starting treatment is still a crucial unmet need. Here we aimed to develop an in vivo test to directly challenge living cancer cells to radiotherapy, using zebrafish xenografts.

Methods: We generated zebrafish xenografts using colorectal cancer cell lines and patient biopsies without in vitro passaging, and developed a fast radiotherapy protocol consisting of a single dose of 25 Gy. As readouts of the impact of radiotherapy we analyzed proliferation, apoptosis, tumor size and DNA damage.

Findings: By directly comparing isogenic cells that only differ in the KRASG13D allele, we show that it is possible to distinguish radiosensitive from radioresistant tumors in zebrafish xenografts, even in polyclonal tumors, in just 4 days. Most importantly, we performed proof-of-concept experiments using primary rectum biopsies, where clinical response to neoadjuvant chemoradiotherapy correlates with induction of apoptosis in their matching zebrafish Patient-Derived Xenografts-Avatars.

Interpretation: Our work opens the possibility to predict tumor responses to radiotherapy using the zebrafish Avatar model, sparing valuable therapeutic time and unnecessary toxicity.

 

Journal: EBiomedicine

 

Linkhttps://www.thelancet.com/article/S2352-3964(19)30788-1/fulltext