# CXCR3 in Pancreatic Cancer Progression and Metastasis

> **NIH NIH F30** · UNIVERSITY OF NEBRASKA MEDICAL CENTER · 2020 · $34,022

## Abstract

ABSTRACT
Pancreatic ductal adenocarcinoma (PDAC) is among the most lethal human malignancies accounting for over
47,000 cancer related deaths in the U.S. annually. Underlying the dismal prognosis of PDAC is the rapid
progression to locally advanced and metastatic disease. Ultimately, this rapid progression results in presentation
with late stage disease thereby limiting the number of patients eligible for curative resection, and predisposing
those patients eligible for resection to local and metastatic recurrence. Our cytokine screen in premalignant
lesion of aggressive (KPC) and indolent (KC) autochthonous PDAC mouse models identified two CXCR3 ligands
(PF4 and IP10) as being overexpressed only in the KPC model. Subsequent work identified that CXCR3A and
B (the high affinity receptors of IP10 and PF4 respectively) are aberrantly expressed in PDAC cells while IP10
is derived from pancreatic stellate cells (PSCs) and PF4 is derived from platelets and endothelium. in vitro
studies show that IP10/CXCR3 mediated signaling results in upregulation of EMT markers including MMPs in
PDAC cell line Capan 1 while PF4/CXCR3 signaling resulted in increased ability of Capan 1 cells to survive low
attachment conditions and adhere to endothelium. These results suggest that CXCR3 plays a role in the
dissemination of PDAC cells at multiple points in the metastatic process. In the presently proposed studies, I
will explore the significance and mechanism of CXCR3's contribution to PDAC invasion and metastasis using in
vitro and in vivo models to test the hypothesis that “microenvironment-derived PF4 and IP10 signaling mediated
by CXCR3 contributes to the invasion and intravascular phases of the PDAC metastatic process.” To test this
hypothesis, I have devised two independent specific aims. Aim 1, will delineate the mechanism by which PDAC
cells induce the expression of IP10 in cancer-associated (CA) PSCs and the modifications in CA-PSC biology
that are permissive of IP10 expression. Subsequently, I will explore the overall effects of IP10/CXCR3 signaling
on PDAC behavior as well as the mechanism through which IP10 elicits cellular effects in vitro and in vivo using
a qRT-PCR based screen coupled with biochemical validation of findings. Aim 2, focuses on the mechanism by
which PF4 affects the intravascular phase of hematogenous PDAC metastasis. Here in vitro work will expand
on preliminary data to elucidate signaling cascades activated by PF4/CXCR3 signaling in the context of platelet
degranulation and correlate activation of these pathways with outcomes of functional assays. Finally, the effects
of and mechanism(s) through which PF4 functions found in vitro will be tested in vivo using a tail vein injection
model of PDAC metastasis combined with genetic inhibition of CXCR3B and total CXCR3 expression.
Importantly, specific efforts will be made in each aim to distinguish the relative contributions of CXCR3A and B
isoforms to the phenomena in question thereby providin...

## Key facts

- **NIH application ID:** 9884540
- **Project number:** 5F30CA225117-03
- **Recipient organization:** UNIVERSITY OF NEBRASKA MEDICAL CENTER
- **Principal Investigator:** Andrew C Cannon
- **Activity code:** F30 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2020
- **Award amount:** $34,022
- **Award type:** 5
- **Project period:** 2018-03-01 → 2021-02-28

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/9884540

## Citation

> US National Institutes of Health, RePORTER application 9884540, CXCR3 in Pancreatic Cancer Progression and Metastasis (5F30CA225117-03). Retrieved via AI Analytics 2026-05-25 from https://api.ai-analytics.org/grant/nih/9884540. Licensed CC0.

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