# Matricellular proteins of the CNN family as regulators of tumor-induced cachexia

> **NIH NIH R01** · UNIVERSITY OF FLORIDA · 2023 · $393,162

## Abstract

Summary/Abstract
Cancer-associated cachexia is a multifactorial syndrome characterized by the involuntary loss of body and
skeletal muscle mass (with or without fat loss) that reduces tolerance to cancer treatments, increases
complications following surgery and is strongly predictive of reduced survival. However, there are currently no
effective therapies to preserve, or reverse the loss of, muscle mass in cancer patients, highlighting a major gap
in treatment. Unpublished work from our lab implicates a key role for Cellular Communication Network Factor 2
(CCN2), also known as connective tissue growth factor (CTGF), in mediating cachexia induced by pancreatic
ductal adenocarcinoma (PDAC), a cancer type with high prevalence of cachexia. CTGF is a hypoxia-inducible
matricellular protein produced by pancreatic cancer cells and PDAC tumors which functions locally to induce
stromal remodeling, tumor growth and metastasis. In a mouse models of PDAC, we found that Ctgf and Hif1a
are upregulated in tumors at time points corresponding to cachexia initiation and progression, suggesting CTGF
production by hypoxic PDAC tumors could also be involved in cachexia. In preliminary studies we found that
genetic or pharmacological targeting of CTGF inhibited cachexia and blocked host- and tumor cell-secretion of
key circulating mediators of cachexia, despite controlling for CTGF-dependent effects on tumor growth, leading
us to hypothesize that CTGF promotes PDAC cachexia, at least in part, through promoting cytokine-dependent
signaling in peripheral tissues, which will be investigated in Aim 1. In addition to CTGF production within PDAC
tumors, CTGF is also upregulated in skeletal muscles of cachectic patients and mice with PDAC. We therefore
hypothesize that local production of CTGF within muscle tissue may also play a direct role in muscle wasting in
response to PDAC, which was supported through targeting of Ctgf-shRNA to muscle tissue using AAV. Through
single nucleus RNAseq we further identified Ctgf to be upregulated in both respiratory and peripheral skeletal
muscles of PDAC mice in a cell type-specific manner, with Ctgf commonly upregulated within a subpopulation
of mature skeletal muscle nuclei that show increased expression of atrophy-related genes. Using both in vitro
and in vivo models, Aim 2 will thus further investigate the cell-autonomous role of Ctgf in mediating skeletal
muscle wasting and dysfunction in response to PDAC, and the mechanisms involved. We anticipate that our
findings will elucidate key tissue-specific mechanisms of muscle wasting and weakness associated with cancer,
with high translational potential.

## Key facts

- **NIH application ID:** 10586444
- **Project number:** 1R01CA270025-01A1
- **Recipient organization:** UNIVERSITY OF FLORIDA
- **Principal Investigator:** Sarah M Judge
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2023
- **Award amount:** $393,162
- **Award type:** 1
- **Project period:** 2023-09-07 → 2028-08-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10586444

## Citation

> US National Institutes of Health, RePORTER application 10586444, Matricellular proteins of the CNN family as regulators of tumor-induced cachexia (1R01CA270025-01A1). Retrieved via AI Analytics 2026-05-24 from https://api.ai-analytics.org/grant/nih/10586444. Licensed CC0.

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