# Dissecting the Ecology of Metastasis in a Zebrafish Model: Trade-Offs of Size and Diversity in Circulating Tumor Cell Clusters

> **NIH NIH F30** · WEILL MEDICAL COLL OF CORNELL UNIV · 2020 · $17,176

## Abstract

PROJECT SUMMARY
Metastasis is a defining feature of advanced cancer, often representing a transition from curable to incurable
disease. It is largely driven by stochastic processes, and remains challenging to predict when it will occur. We
undertake an investigation into the mechanisms driving the increased metastatic potential of circulating tumor
cell (CTC) clusters through a combination of systems biology, in vivo experiments in zebrafish, and theoretical
ecology. Melanoma, the most lethal of skin cancers, shows a particularly stark difference between the
outcomes of patients with local versus metastatic disease. CTC clusters have been isolated from the blood of
patients with melanoma, among other cancer types, and portend a poor clinical prognosis. CTC clusters are
important in metastases, but despite their importance many key mechanisms underlying their formation,
increased metastatic capacity, and potential for therapeutic targeting remain largely unexplored, particularly in
melanoma. Our study takes advantage of the zebrafish model of metastatic melanoma, including zebrafish
melanoma cell lines capable of transplantation into transparent Casper zebrafish, providing a powerful tool for
investigating the cellular processes driving the increased metastatic potential of CTC clusters. For this
fellowship, we will address two properties of CTC clusters and how they relate to metastatic fitness. (Aim 1)
We hypothesize that the trade-off between group size and number—integral to ecological dispersal—is key in
metastasis formation by CTC clusters. We will test this hypothesis by applying quantitative statistical analysis
to melanoma clusters of varying size transplanted into zebrafish, characterizing the metastatic fitness
landscape of melanoma CTC clusters. We will then introduce genetic perturbations specifically targeting
hypothesized mechanisms of cluster cooperation in order to elucidate the mechanisms underlying CTC cluster
fitness. (Aim 2) We hypothesize that high intra-cluster diversity promotes overall metastatic fitness despite the
presence of some cells with lower individual fitness. We will test this hypothesis by engineering clusters with
melanoma-specific forms of genetic heterogeneity. We will apply quantitative statistical analysis comparing
high- and low-diversity clusters transplanted into zebrafish, evaluating the role of compositional heterogeneity
in CTC cluster metastatic fitness. These two approaches, combined with validation in mammalian models, will
generate new insights into the size and compositional trade-offs underlying CTC cluster fitness that can inform
the development of new diagnostic, prognostic and therapeutic strategies in melanoma and more broadly.

## Key facts

- **NIH application ID:** 9867712
- **Project number:** 5F30CA220954-03
- **Recipient organization:** WEILL MEDICAL COLL OF CORNELL UNIV
- **Principal Investigator:** Nathaniel R Campbell
- **Activity code:** F30 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2020
- **Award amount:** $17,176
- **Award type:** 5
- **Project period:** 2018-03-01 → 2020-07-01

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/9867712

## Citation

> US National Institutes of Health, RePORTER application 9867712, Dissecting the Ecology of Metastasis in a Zebrafish Model: Trade-Offs of Size and Diversity in Circulating Tumor Cell Clusters (5F30CA220954-03). Retrieved via AI Analytics 2026-05-22 from https://api.ai-analytics.org/grant/nih/9867712. Licensed CC0.

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