# Dysregulation of Liver Macrophages in Pancreatic Cancer

> **NIH NIH F30** · UNIVERSITY OF PENNSYLVANIA · 2021 · $51,036

## Abstract

PROJECT SUMMARY
Pancreatic ductal adenocarcinoma (PDAC) is the third-leading cause of cancer-related deaths in the United
States. Metastasis is the major cause of mortality for patients with PDAC and the liver is the most common site
of metastatic disease. Thus, there is a clear unmet need for therapies that disrupt the metastatic process. During
cancer development, soluble factors precondition the liver for metastasis. In this process, the liver becomes a
“pro-metastatic niche” that supports the seeding of disseminated tumor cells and their subsequent outgrowth in
the liver. Macrophages are a prominent component of this niche, yet their role in regulating metastasis to the
liver remains poorly understood. Preliminary data suggest that liver macrophages restrict tumor cell seeding in
the liver, while published data shows that liver macrophages can promote tumor outgrowth after seeding has
already occurred. Given knowledge that macrophage biology is finetuned by signals received from their
surrounding environment, these data suggest that macrophages in the liver can be “educated” to possess either
anti- or pro-tumor properties. Within the liver in the absence of a niche, Kupffer cells (KCs) are the dominant
resident macrophage population. In contrast, bone marrow-derived macrophages (BMDMs) are recruited to the
liver in the setting of inflammation and accumulate in the liver during the formation of a pro-metastatic niche. It
is currently unknown how each macrophage subset uniquely contributes to the metastatic process. The central
hypothesis of this proposal is that KCs have an inherent anti-metastatic capacity that is defined by a balance
of stimulatory and inhibitory signals; however, during cancer development, this biology is undermined
by an influx of BMDMs into the liver that promote metastatic seeding and outgrowth. To test this
hypothesis, this proposal will incorporate strategies to selectively deplete KCs and BMDMs to study their distinct
roles in regulating cancer metastasis to the liver using mouse models of PDAC. Aim one will address the role of
liver macrophage subsets in regulating the metastatic process in the liver in the presence and absence of the
pro-metastatic niche. Aim two will assess the impact of stimulatory and inhibitory signals on the capacity of liver
macrophages to intervene on the metastatic cascade. Studies in this proposal will improve our understanding of
pathways regulating metastasis and may identify novel therapeutic strategies for the treatment of PDAC. This
project will be sponsored by an experienced investigator with skills in immunology and cancer biology as well as
a demonstrated commitment to mentorship and will occur at one of the foremost institutions for cancer
immunology. This project encompasses a graduate training plan which, in addition to training in scientific
research, includes didactics in the fields of immunology and cancer biology, training in scientific communication
and mentoring, and clinic...

## Key facts

- **NIH application ID:** 10141581
- **Project number:** 1F30CA257287-01
- **Recipient organization:** UNIVERSITY OF PENNSYLVANIA
- **Principal Investigator:** Stacy Katherine Thomas
- **Activity code:** F30 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2021
- **Award amount:** $51,036
- **Award type:** 1
- **Project period:** 2021-02-01 → 2024-01-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10141581

## Citation

> US National Institutes of Health, RePORTER application 10141581, Dysregulation of Liver Macrophages in Pancreatic Cancer (1F30CA257287-01). Retrieved via AI Analytics 2026-05-24 from https://api.ai-analytics.org/grant/nih/10141581. Licensed CC0.

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