Zebrafish as a model to assess cancer heterogeneity, progression and relapse

Abstract

Clonal evolution is the process by which genetic and epigenetic diversity is created within malignant tumor cells. This process culminates in a heterogeneous tumor, consisting of multiple subpopulations of cancer cells that often do not contain the same underlying mutations. Continuous selective pressure permits outgrowth of clones that harbor lesions that are capable of enhancing disease progression, including those that contribute to therapy resistance, metastasis and relapse. Clonal evolution and the resulting intratumoral heterogeneity pose a substantial challenge to biomarker identification, personalized cancer therapies and the discovery of underlying driver mutations in cancer. The purpose of this Review is to highlight the unique strengths of zebrafish cancer models in assessing the roles that intratumoral heterogeneity and clonal evolution play in cancer, including transgenesis, imaging technologies, high-throughput cell transplantation approaches and in vivo single-cell functional assays.

Neutrophils in the Tumor Microenvironment

“…Many studies have taken advantage of easy and rapid genetic manipulations to drive oncogenic transformation of various cell types or to create mutants in tumor suppressor genes and generate cancer models. In addition, xenografts of human tumor cells into an immunocompetent zebrafish larval host may also be performed due to the delayed development of the zebrafish adaptive immune system (the use of zebrafish as a cancer model is further reviewed here [104, 105]). Xenografted cells can be labeled and tracked within a zebrafish larva over long periods of time allowing for visualization of tumor cell invasion [71, 106].…”

Uncovering metabolism in rhabdomyosarcoma

“…Once they have established a new tumor site, the less differentiated myf5-positive cells migrate into the newly forming tumor, ultimately driving tumor expansion and progression. 125,126 This implicates that the less differentiated RMSpropagating cells may take advantage of specific nutrients produced by the neighboring more differentiated cells during tumor dissemination, a process that might be even influenced by the proportion of fast or slow twitch muscle fibers potentially releasing specific metabolites around the tumor niche (at least when the tumor arises in muscle beds). This scenario seemingly resembles the so-called reverse Warburg effect, in which epithelial cancer cells were found to corrupt the stroma associated fibroblasts undergoing myo-fibroblastic differentiation to release micronutrients in the milieu, such as lactate and pyruvate, which are then taken up by cancer cells to produce energy in the mitochondria.…”

Untitled

“…Diversity is not unique to normal lymphocytes; lymphoid cancers also contain heterogeneous populations, as previously shown in D. rerio mMyc-driven T-ALL [15,40,45,48]. To assess tumor heterogeneity in hMYCinduced ALL and begin to define its extent, we analyzed mRNA expression in single cells from B-or T-ALL from hMYC fish (Figure 4).…”