# Biased chemokine receptor signaling in cancer progression

> **NIH NIH R01** · MEDICAL COLLEGE OF WISCONSIN · 2020 · $390,452

## Abstract

Project Summary
Pancreatic cancer is a uniformly lethal form of cancer with patients rarely surviving two years after
diagnosis due to pronounced metastasis, immune suppression and evasion, desmoplasia, and
unchecked tumor proliferation that together confer therapeutic resistance. Cancer metastatic potential
is mediated by the G protein-coupled chemokine receptor CXCR4. The chemokine CXCL12 is the
cognate ligand for CXCR4 and is an immune mediator produced by both stromal cells in the tumor
microenvironment and normal cells at metastatic destinations. While a wealth of reports attribute
elevated CXCR4 expression with pro-tumorigenic effects in numerous cancers, the precise
mechanistic roles for CXCR4 and CXCL12 in non-metastatic pathways of pancreatic cancer
progression remain poorly understood. Our published and exciting preliminary data have revealed a
novel mechanism whereby CXCL12 can either promote or inhibit tumor progression and metastasis
based on its ability to activate CXCR4 as a monomer or dimer. In pursuit of determining the
mechanism behind CXCR4-mediated cancer progression, we have engineered a locked monomer
variant of CXCL12 that acts as a balanced agonist at CXCR4, activating the entirety of its G protein
and -arrestin signaling repertoire, as well as a locked dimer biased agonist variant which activates
only a subset. We hypothesize that biased signaling at CXCR4 prevents tumor migration and
progression while attracting cytotoxic T lymphocytes from the bone marrow and tumor periphery to
infiltrate the tumor and kill cancer cells. The overall goal of this proposal is to harness biased agonist
signaling as a multi-pronged anti-tumor approach to abrogate pancreatic cancer progression. Aim 1
will use genetically engineered mouse models of pancreatic cancer to analyze the in vivo influence of
biased agonist signaling in tumor progression. Aim 2 will use transgenic mouse models and cell
culture approaches to investigate the sparsely-studied effects of biased signaling on immune cell
trafficking, infiltration, and tumor cell killing in the tumor microenvironment. Aim 3 will delve into the
amino-acid level interactions between CXCL12 agonists with CXCR4 receptor to determine the
mechanisms responsible for anti-tumor ligand biased and tissue biased signaling. The overall impact
of the proposed work is that we will reveal a targetable structural and biochemical biased agonist
signaling mechanism that explains the pleiotropic effects of CXCL12 and CXCR4 in cancer.

## Key facts

- **NIH application ID:** 9837427
- **Project number:** 5R01CA226279-02
- **Recipient organization:** MEDICAL COLLEGE OF WISCONSIN
- **Principal Investigator:** Michael B Dwinell
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2020
- **Award amount:** $390,452
- **Award type:** 5
- **Project period:** 2019-01-01 → 2023-12-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/9837427

## Citation

> US National Institutes of Health, RePORTER application 9837427, Biased chemokine receptor signaling in cancer progression (5R01CA226279-02). Retrieved via AI Analytics 2026-05-23 from https://api.ai-analytics.org/grant/nih/9837427. Licensed CC0.

---

*[NIH grants dataset](/datasets/nih-grants) · CC0 1.0*