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Zebrafish avatars to forecast hormone therapy response in breast cancer
Publication . Ferreira, Salvador Saldanha da Gama Loura; Mendes, Raquel; Fior, Rita; Barral, Duarte
Breast cancer (BC) stands as one of the most prevalent cancers and a leading cause of mortality among women. Approximately 70% of all BC cases are characterized as hormone-receptor-positive (HR+). For these patients, treatment mainly comprises endocrine therapies (ET), inhibiting estrogen signaling by blocking receptors or hindering estrogen production [84, 85, 86]. Consequently, the growth and spread of hormone-sensitive cancer cells become compromised. The use of ET has significantly reduced BC-related mortality. However, despite its effectiveness, 15-20% of tumors are intrinsically resistant to treatment [87] and 30-50% eventually develop resistance [88]. Moreover, these cancers can lie dormant, and metastasis may emerge many years after diagnosis [88].
Thus, a test that could anticipate which patients are resistant to ET could help guide treatment decisions, sparing patients from unnecessary toxicities.
My host Lab has been developing the zebrafish xenograft model (zAvatars), as a quick in-vivo screening platform for drug testing and personalized therapy. zAvatars are generated by injecting human tumor cells obtained from surgery or biopsies, into zebrafish embryos [89, 90, 91]. zAvatars offer speed (10 days assay), cellular resolution, and the ability to perform numerous transplants simultaneously. Most importantly, they can be used to detect changes in cell mortality, proliferation rate, and even some cancer hallmarks like angiogenesis and metastasis formation.
Our laboratory has shown that the zebrafish xenograft model has resolution to distinguish sensitivity/resistance towards multiple chemotherapies in the context of different cancer types. However, it is important to note that most of these therapies targeted molecular pathways within the tumor cells (i.e. cell-autonomous). While this is the case for two ETs, Tamoxifen and Fulvestrant, Letrozole on the other hand also acts systemically, by inhibiting the production of estrogen not only by tumor cells but also throughout the patient’s tissues.
The primary goal of this project was to validate zebrafish xenografts for BC within the context of ET.
We started by developing, characterizing, and optimizing our model of HR+ BC zebrafish xenografts. These xenografts were generated with the T47-D cell line, a Luminal A type, HR+ BC cell line, therefore being representative of the most common type of BC. We found that these cells implanted more efficiently in the brain than in the PVS, the most usual injection site.
By treating T47-D xenografts with these 3 ETs, we found that all ETs were able to significantly induce Act.Caspase-3 expression, a marker for apoptosis. We also registered a decrease in cell proliferation upon Letrozole administration.
Subsequently, we were also able to generate patient-derived xenografts or zAvatars with a sample from a stage IV metastatic BC patient with the Luminal B subtype. The zAvatars were sensitive to the 3 ETs. Overall, my work suggests that the zebrafish xenograft model has the resolution necessary to screen sensitivity to ET, including Letrozole, as long as the cancer cells tested express the aromatase-coding gene CYP19A1.
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Fundação para a Ciência e a Tecnologia
Programa de financiamento
Concurso de Projetos IC&DT em Todos os Domínios Científicos
Número da atribuição
PTDC/BTM-SAL/3796/2021