# Role of CX3CR1 in breast cancer metastasis

> **NIH NIH R01** · DREXEL UNIVERSITY · 2020 · $357,994

## Abstract

Breast cancer patients die from metastatic disease. Primary breast adenocarcinoma spreads to distant organs
by shedding circulating tumor cells (CTCs) in the blood. When these cells leave the systemic circulation, they
convert into Disseminated Tumor Cells (DTCs), which are the seeds of secondary tumors. Mounting evidence
indicates that existing metastases can mobilize cancer cells back into the blood, thus leading to further
spreading that precipitates clinical progression. Thus, strategies aimed to impair tumor seeding have the
potential to arrest or significantly decelerating the extension of the disease. Chemokine receptors have been
implicated in dissemination, proliferation and survival of cancer cells. Our recent work indicates that the
chemokine receptor CX3CR1 is over-expressed in both primary breast tumors and metastatic lesions and
plays a role in the lodging of breast cancer cells to the skeleton of animal models. Furthermore, studies form
others have shown that this receptor is expressed by cells with tumor-forming abilities and can transactivate
growth factor receptors regulating proliferation and survival. Thus, based on the existing literature and our
preliminary data, we hypothesize that CX3CR1 is implicated in both early and late stages of metastasis and
that its blockade can both deter breast cancer cells from seeding multiple organs and counter their tumor-
initiating properties. To test this hypothesis, we will use a combination of CRISPR interference (CRISPRi) and
a novel small-molecule antagonist to delineate the time-frame for CX3CR1 involvement in metastatic
progression and the effects of pharmacologic targeting of CX3CR1 in tertiary spreading from existing
metastases. Finally, we intend to gain a mechanistic understanding of CX3CR1 signaling and determine the
molecular pathways associated with tumor-initiation properties activated by this receptor in breast cancer cells.
This proposal is structured into three specific aims: AIM 1. To delineate the temporal involvement of
CX3CR1 in metastatic progression; AIM 2. To define the effects of CX3CR1 blockade on tumor re-
seeding from existing metastases; AIM 3. To elucidate the mechanistic details of CX3CR1 involvement
in the metastatic behavior of breast cancer cells.
This proposal will define how CX3CR1 influences breast cancer metastatic behavior, reveal important
mechanistic details of its activity in cancer cells and provide pre-clinical support for the pharmacologic targeting
of this receptor, which presents a high therapeutic potential from several standpoints. From a drug-safety
perspective, transgenic mice knockout for CX3CR1 are viable and exhibit no impairment of their immune
response under unchallenged conditions, overt behavioral abnormalities or macroscopic anatomical alterations.
Thus, if successful our work should pave the way to a novel series of therapeutics and promote multifaceted
strategies to counteract the metastatic progression of breast cancer.

## Key facts

- **NIH application ID:** 9965760
- **Project number:** 5R01CA202929-05
- **Recipient organization:** DREXEL UNIVERSITY
- **Principal Investigator:** Alessandro Fatatis
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2020
- **Award amount:** $357,994
- **Award type:** 5
- **Project period:** 2019-07-01 → 2023-06-30

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/9965760

## Citation

> US National Institutes of Health, RePORTER application 9965760, Role of CX3CR1 in breast cancer metastasis (5R01CA202929-05). Retrieved via AI Analytics 2026-05-23 from https://api.ai-analytics.org/grant/nih/9965760. Licensed CC0.

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