# Role of tumor cell cluster-induced signaling in breast cancer metastasis

> **NIH NIH R37** · FRED HUTCHINSON CANCER CENTER · 2022 · $260,589

## Abstract

The root cause of most breast cancer deaths is metastasis. By dissecting the molecular events driving it, the
research community can develop new therapeutic approaches to eradicate and prevent metastatic disease.
One promising avenue of research involves the cooperative behavior of tumor cells. Conventionally,
metastasis is conceptualized as the dissemination of individual tumor cells to distant organs. However, recent
studies by the Cheung research group and others have established that clusters of tumor cells metastasize to
distant organs more efficiently than single cells in mouse models, and that circulating tumor cell clusters are
associated with poor patient outcomes and therapy resistance in humans. The molecular mechanisms
responsible for aggression in tumor cell clusters and the optimal therapeutic strategies to eliminate clusters
have remained obscure. Recently, the Cheung laboratory has found that clustered tumor cells display
heightened levels of apoptosis resistance, cell proliferation, and changes in molecular expression that indicate
that the cells are cooperating with one another. These studies reveal that the tyrosine kinase EGFR is
activated at cell-cell contacts in clustered tumor cells, and they establish that EGFR and the low-affinity EGFR
ligand Epigen are necessary for cluster-dependent proliferation and metastatic colonization. The proposed
project will test the hypothesis that tumor cell clusters are highly metastatic because they contain a private
signaling environment involving EGFR, Epigen, and the transcription factor Fra-1, and that disrupting this
signaling environment will neutralize clusters’ metastatic potential. The Cheung lab has already developed
technically innovative organoid and murine models to study cluster-based signaling and its impact on
metastasis in vivo. Using these models, the lab will first determine whether cluster-induced metastatic
efficiency depends specifically on local activation by Epigen. Second, the lab will determine the impact of Fra-1
transcriptional programs and signaling feedback loops on metastatic processes specific to tumor cell clusters,
as well as whether this program depends on the presence of Epigen. Third, the lab will supplement its
experimental findings by studying the association between EGFR, Epigen, and long-term recurrence and
mortality data from human breast cancer datasets. Through this integrated approach, the Cheung lab will
develop an understanding of the cooperative molecular mechanisms that underlie the propensity of tumor cell
clusters to metastasize. As described in the proposal, this understanding is likely to reveal molecular
vulnerabilities that can be exploited to develop new anti-metastatic therapies. Although the work proposed here
focuses on uncovering therapeutic strategies to target tumor cell clusters in breast cancer, the findings will
potentially be relevant to a wide range of tumor types.

## Key facts

- **NIH application ID:** 10601469
- **Project number:** 6R37CA234488-04
- **Recipient organization:** FRED HUTCHINSON CANCER CENTER
- **Principal Investigator:** Kevin Jon Cheung
- **Activity code:** R37 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2022
- **Award amount:** $260,589
- **Award type:** 6
- **Project period:** 2019-12-01 → 2024-11-30

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10601469

## Citation

> US National Institutes of Health, RePORTER application 10601469, Role of tumor cell cluster-induced signaling in breast cancer metastasis (6R37CA234488-04). Retrieved via AI Analytics 2026-05-23 from https://api.ai-analytics.org/grant/nih/10601469. Licensed CC0.

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