# Mediators of Pancreatic Cancer-Associated Cachexia

> **NIH NIH R21** · OHIO STATE UNIVERSITY · 2022 · $174,219

## Abstract

Project Summary
Cachexia associated with pancreatic ductal adenocarcinoma (PDAC) is correlated with shorter survival, reduced
efficacy of chemotherapy and surgery, and a reduction in quality of life. PDAC is the third leading cause of
cancer-related death in the US with a 5-year survival rate <10%. Cachexia is a common complication of PDAC
with 60-80% of patients exhibiting symptoms at the time of cancer diagnosis. Targeting cachexia is needed to
increase survival of PDAC patients. Tumor-derived pro-inflammatory cytokines can alter available metabolites
such as iron and free fatty acids in multiple cancer types to drive tumor progression. We have shown that the
pro-inflammatory cytokine lipocalin-2 (LCN2), an iron and fatty acid binding molecule, is overexpressed in PDAC
and involved in signaling within the tumor microenvironment. Moreover, in a cancer-associated cardiomyopathy
model, LCN2 interacts with iron-binding molecules, resulting in decreased free iron causing metabolic stress and
cachexia. In the adipose tissue, LCN2 interacts with fatty acids to mediate changes in metabolism and
thermogenesis. The mechanisms that drive cachexia in PDAC remain poorly understood, and no targeted
therapies are available to control cachexia or its detrimental effects. Therefore, our long-term goals are to identify
how PDAC contributes to the progression of cachexia by promoting changes in the adipose and skeletal muscle
tissue metabolism and regeneration. We intend to leverage our findings to identify therapeutic targets that could
mitigate cachexia symptoms and improve long-term survival in PDAC patients. We hypothesize that PDAC
contributes to cachexia by secreting factors that: 1) alter iron and fatty acid levels to promote adipose and skeletal
muscle tissue atrophy, and 2) alter skeletal muscle satellite cell differentiation, preventing muscle regeneration.
To test our hypotheses we propose the following aims: 1) Determine changes in iron and fatty acid content that
contribute to cachexia. We hypothesize that elevated LCN2 decreases free iron and alters free fatty acid content
increasing metabolic stress in adipose and skeletal muscle tissue. Plasma, adipose, and skeletal muscle tissue
from PDAC patients will be assessed for LCN2 expression, iron availability, and fatty acid content and correlated
with clinical indicators of cachexia. Then, using genetically engineered mouse models (GEMMs) of PDAC (-/+
Lcn2), we will determine whether LCN2’s binding of fatty acids and iron drive adipose and skeletal muscle tissue
wasting by assessing metabolism, oxidative stress, and autophagy. 2): Determine whether PDAC-secreted
cytokines contribute to cachexia by altering differentiation of satellite cells. We hypothesize that increased
expression of PDAC-secreted LCN2 promotes the dysregulation of satellite cells differentiation in the skeletal
muscle by overstimulating the NF-KB/Pax7 signaling pathway. We will use satellite cells isolated from patients
(+/- PDAC) an...

## Key facts

- **NIH application ID:** 10312143
- **Project number:** 5R21CA256409-02
- **Recipient organization:** OHIO STATE UNIVERSITY
- **Principal Investigator:** Zobeida Cruz-Monserrate
- **Activity code:** R21 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2022
- **Award amount:** $174,219
- **Award type:** 5
- **Project period:** 2020-12-04 → 2023-11-30

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10312143

## Citation

> US National Institutes of Health, RePORTER application 10312143, Mediators of Pancreatic Cancer-Associated Cachexia (5R21CA256409-02). Retrieved via AI Analytics 2026-05-23 from https://api.ai-analytics.org/grant/nih/10312143. Licensed CC0.

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