Unveiling Tumor Microenvironment Interactions Using Zebrafish Models

Abstract

The tumor microenvironment (TME) is a rich and active arena that is strategically evolved overtime by tumors to promote their survival and dissemination. Over the years, attention has been focused to characterize and identify the tumor-supporting roles and subsequent targeting potentials of TME components. Nevertheless, recapitulating the human TME has proved inherently challenging, leaving much to be explored. In this regard, in vivo model systems like zebrafish, with its optical clarity, ease of genetic manipulation, and high engraftment, have proven to be indispensable for TME modeling and investigation. In this review, we discuss the recent ways by which zebrafish models have lent their utility to provide new insights into the various cellular and molecular mechanisms driving TME dynamics and tumor support. Specifically, we report on innate immune cell interactions, cytokine signaling, metastatic plasticity, and other processes within the metastatic cascade. In addition, we reflect on the arrival of adult zebrafish models and the potential of patient-derived xenografts.

The application of zebrafish patient‐derived xenograft tumor models in the development of antitumor agents

“…The zPDX model is gradually widely used to study the tumor microenvironment 11,18 . The optical clarity of embryos or larvae makes it possible to visualize the tumor microenvironment with single‐cell resolution 140,141 . In addition, the apparent development and differentiation characteristics of zebrafish embryos can provide a variety of injection location options for patient‐derived tumor cells, thereby providing different tumor microenvironments 18 .…”

“…11,18 The optical clarity of embryos or larvae makes it possible to visualize the tumor microenvironment with single-cell resolution. 140,141 In addition, the apparent development and differentiation characteristics of zebrafish embryos can provide a variety of injection location options for patient-derived tumor cells, thereby providing different tumor microenvironments. 18 Importantly, recent progress demonstrated zPDX as a living biomarker to probe the dynamic communication between tumor cells and the immune system.…”

Shifting the focus of zebrafish toward a model of the tumor microenvironment

“…The smaller size makes it possible for an entire zebrafish embryo/larvae to be placed on a confocal and multi-photon microscope. The ability to image an entire animal at single-cell resolution enables investigation of not just local microenvironmental interactions but also distant ‘whole body’ interactions ( Loveless et al, 2020 ). This is particularly important for understanding the contribution of the TME to metastasis, which is classically separated into at least four steps: intravasation from the primary site, circulation in blood stream, extravasation at distant sites, and outgrowth at those sites ( Gupta and Massagué, 2006 ).…”

“…In contrast, the zebrafish can be used to image and quantify each of these steps in a single animal, since it is highly amenable to standard epifluorescence microscopy (for many cells), confocal microscopy (for single cells), and lightsheet microscopy (even now including whole embryo and adult animals). Given their small size and transparency, most questions related to cell-cell interactions can be captured using epifluorescence and confocal microscopy, although more specialized methods, such as two photon, second harmonic generation, light sheet, and micro-CT, are also possible, and their applications and technical advantages have been summarized by Loveless et al, 2020 .…”