Dissecting intra-tumour clonal dynamics and its cross-talk with the microenvironment in a zebrafish xenograft model

Financiador

Organização

Publicações

Dissecting intra-tumor clonal dynamics and its crosstalk with the microenvironment in a zebrafish xenograft model

Publication . Póvoa, V.; Fior, Rita

Colorectal cancer represents one of the major leading causes for cancer-related death worldwide. Despite several efforts to improve cancer patient survival, recurrence and disease progression rates remain unacceptably high. The current colorectal cancer (CRC) classification, prognosis prediction and therapeutic decision-making are based on histopathological features – the tumor, lymph node, metastasis (TNM) staging. Therefore, patients are treated using a one-size-fits all strategy based on tumor stage and some predictive indications (prognostic molecular markers) of therapeutic response. The major hurdle of this approach is that it fails to identify and predict which patients will benefit from treatment and which will not. As a result, some patients benefit from treatment while others are inadequately treated, or overtreated with chemotherapeutics that come with substantial side effects.

2022-05-09Tese de doutoramento

Acesso aberto

Ver mais

Innate immune evasion revealed in a colorectal zebrafish xenograft model

Publication . Póvoa, Vanda; Rebelo de Almeida, Cátia; Maia-Gil, Mariana; Sobral, Daniel; Domingues, Micaela; Martinez-Lopez, Mayra; de Almeida Fuzeta, Miguel; Silva, Carlos; Grosso, Ana Rita; Fior, Rita; DCV - Departamento de Ciências da Vida; UCIBIO - Applied Molecular Biosciences Unit; Nature Portfolio

Cancer immunoediting is a dynamic process of crosstalk between tumor cells and the immune system. Herein, we explore the fast zebrafish xenograft model to investigate the innate immune contribution to this process. Using multiple breast and colorectal cancer cell lines and zAvatars, we find that some are cleared (regressors) while others engraft (progressors) in zebrafish xenografts. We focus on two human colorectal cancer cells derived from the same patient that show contrasting engraftment/clearance profiles. Using polyclonal xenografts to mimic intra-tumor heterogeneity, we demonstrate that SW620_progressors can block clearance of SW480_regressors. SW480_regressors recruit macrophages and neutrophils more efficiently than SW620_progressors; SW620_progressors however, modulate macrophages towards a pro-tumoral phenotype. Genetic and chemical suppression of myeloid cells indicates that macrophages and neutrophils play a crucial role in clearance. Single-cell-transcriptome analysis shows a fast subclonal selection, with clearance of regressor subclones associated with IFN/Notch signaling and escaper-expanded subclones with enrichment of IL10 pathway. Overall, our work opens the possibility of using zebrafish xenografts as living biomarkers of the tumor microenvironment.

2021-12Artigo científico

Acesso aberto

Ver mais

Entidade financiadora

Fundação para a Ciência e a Tecnologia

Número da atribuição

SFRH/BD/118252/2016