# Structure-Function Investigation of Chemokine-GPCR Signaling in Tumor Progression and Metastasis

> **NIH NIH F30** · MEDICAL COLLEGE OF WISCONSIN · 2020 · $50,520

## Abstract

PROJECT SUMMARY
 Epithelial Ovarian Cancer (EOC) is the 5th leading cause of cancer death in women. EOC has a 90%
survival rate if detected early, but due to its non-specific symptoms, many cases go undetected until
metastases are already present. In its late metastatic stages, there are no effective treatments available for
EOC. Furthermore, EOC recurrence is common, and is frequently associated with loss of sensitivity to
available therapies. Thus, there is a dire need for novel EOC therapeutics, especially those that target
metastasis. One way that tumor cells can migrate to new sites is via chemokines. Chemokines are small
secreted proteins that direct the cell migration, or chemotaxis, in both disease and homeostatic processes.
Chemokines trigger cell migration by binding to their cognate cell-surface receptors, which are members of the
G-Protein Coupled Receptor superfamily. Binding of chemokines to their receptors triggers a signaling
cascade, culminating in cytoskeletal reorganization and chemotaxis to areas of high chemokine concentration.
Tumor cells can hijack this process by upregulating chemokine and chemokine receptor expression, allowing
tumor cells to migrate to distant sites along chemokine gradients. The chemokine receptor XCR1 has
increased expression in many cancers and has been associated with increased tumor cell proliferation and
migration. Silencing of XCR1 in murine models has been shown to significantly decrease metastasis of EOC.
Our lab recently performed in-depth characterization of XCL1, the chemokine ligand for XCR1, leading to the
identification of ligand residues that are critical for receptor binding and activation. This proposal aims to
advance this knowledge by elucidating important residues in XCR1, which is a more viable drug target than its
ligand, and to study the functional role of the XCL1-XCR1 axis in the metastasis of epithelial ovarian cancer.
 Specifically, the goal of this fellowship is use complementary biochemical and functional approaches to
test the hypothesis that specific intermolecular contacts at the XCL1-XCR1 interface are critical drivers of EOC
cell migration. The fellowship research will consist of two specific aims. Aim 1 will test the hypothesis that
certain residues in XCR1's orthosteric binding pocket are crucial for XCR1-XCL1 signaling. Aim 2 will test the
hypothesis that XCR1 is expressed by human EOC cell lines not previously probed for XCR1 expression, and
that variant XCL1 proteins will elicit unique chemotactic profiles in XCR1-positive human EOC cells including
those discovered in the first part of this aim. The research will take place in the Brian Volkman lab at the
Medical College of Wisconsin, a highly collaborative and stimulating environment that is well equipped with the
infrastructure and equipment to make this proposal a success. In all, understanding the fundamental structural
characteristics of chemokine ligand-receptor interactions will reveal mechanisms driving tum...

## Key facts

- **NIH application ID:** 9841725
- **Project number:** 5F30CA236182-02
- **Recipient organization:** MEDICAL COLLEGE OF WISCONSIN
- **Principal Investigator:** Acacia F Dishman
- **Activity code:** F30 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2020
- **Award amount:** $50,520
- **Award type:** 5
- **Project period:** 2019-01-01 → 2023-12-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/9841725

## Citation

> US National Institutes of Health, RePORTER application 9841725, Structure-Function Investigation of Chemokine-GPCR Signaling in Tumor Progression and Metastasis (5F30CA236182-02). Retrieved via AI Analytics 2026-05-22 from https://api.ai-analytics.org/grant/nih/9841725. Licensed CC0.

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