# The Impact of Macrophage Origin on the Pathogenesis and Treatment Resistance of Pancreatic Cancer

> **NIH NIH R01** · WASHINGTON UNIVERSITY · 2021 · $354,375

## Abstract

PROJECT SUMMARY
 The prognosis for pancreatic cancer (PC) patients is poor. Data from several groups has shown that
significant infiltration of PC by macrophages decreases the efficacy of chemo-, radiation- and immunotherapy
in an animal models and correlates with poor clinical outcomes in patients. The classical assumption has been
that these tumor-associated macrophages are derived from circulating monocytes. Recent changes in the field
of developmental biology suggest this assumption is not entirely correct and offer a radically new view of
macrophage origins in many tissues. It is apparent that tissue-resident macrophages can also arise from
embryonic precursors that seed tissues in pre- or perinatal periods. In our recently published study we
established a key role for embryonically-derived macrophages (eMACs) in PC progression. We demonstrated
that: 1) eMACs expand exponentially during PC progression by in situ proliferation, 2) eMACs are more potent
drivers of PC progression than their monocyte-derived counterparts, and 3) eMACs have a distinct tissue
remodeling phenotype that significantly enhances PDAC fibrosis in vivo. Thus, a further study of the
interactions between various origin-based subsets of macrophages in PC may lead to an understanding of the
recalcitrant nature of the disease. Our overall hypothesis is that epigenetically poised, embryonically
derived pancreas-resident macrophages are critical regulators of pancreatic fibrosis and early disease
progression in PC. To test this hypothesis we will:
Aim 1. Determine the mechanisms by which eMACs drive fibrosis and early PDAC pathogenesis.
Aim 2. Determine the origin-specific epigenetic drivers of eMAC pro-fibrotic and pro-tumor activity.
Aim 3. Determine the impact of eMACs on therapeutic responsiveness.
Impact: Our classical assumption was that all TAMs are derived from monocytes, however this may not be
true. The fact that embryonic- and/or tissue resident-derived TAMs might impact PDAC progression and
response to therapy has significant implications for both basic science and clinical care.

## Key facts

- **NIH application ID:** 10145596
- **Project number:** 5R01CA177670-08
- **Recipient organization:** WASHINGTON UNIVERSITY
- **Principal Investigator:** David G DeNardo
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2021
- **Award amount:** $354,375
- **Award type:** 5
- **Project period:** 2014-04-01 → 2024-04-30

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10145596

## Citation

> US National Institutes of Health, RePORTER application 10145596, The Impact of Macrophage Origin on the Pathogenesis and Treatment Resistance of Pancreatic Cancer (5R01CA177670-08). Retrieved via AI Analytics 2026-05-22 from https://api.ai-analytics.org/grant/nih/10145596. Licensed CC0.

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