# NF-kB Regulation of the Muscle Microenvironment in Cancer Cachexia

> **NIH NIH R01** · MEDICAL UNIVERSITY OF SOUTH CAROLINA · 2022 · $478,114

## Abstract

ABSTRACT
Cachexia is a debilitating syndrome that results in severe, involuntary weight loss due to the depletion of
skeletal muscle mass. This syndrome occurs in a majority of cancers and contributes to approximately a third
of all cancer deaths. Currently, no effective therapy exists to combat this malignant disorder. For pancreatic
cancer the potential benefit for effective cachexia therapies may be even greater than for other cachexia
associated malignancies, since 90% of these patients lose on average 14% of their pre-illness weight, and
cachexia dramatically limits their ability to tolerate surgery, chemo- or radiotherapy. New therapies will likely
evolve from an enhanced understanding of the mechanisms leading to muscle wasting. Our recent efforts have
focused on events that occur outside the myofiber in the muscle microenvironment. We showed that circulating
tumor factors induce skeletal muscle damage leading to the activation of NF-kB in muscle progenitor cells that
associated with an engaged regeneration program. However, regeneration is inhibited leading to muscle
atrophy. We now find that NF-kB activation in muscle stem cells also promotes a local muscle inflammation,
characterized by the production of cytokines and chemokines. These signals promote the recruitment of
macrophages expressing M1 inflammatory and M2 anti-inflammatory makers. The goal of this application is to
test the hypothesis that NF-kB in muscle progenitor cells regulates this local inflammatory environment that
contributes to muscle atrophy. Towards this goal we seek to perform the following two specific aims: 1)
Determine how NF-kB regulates local muscle inflammation in cancer cachexia; and 2) Elucidate the phenotype
and relevance of macrophages in cancer-induced muscle wasting. Achieving this goal will not only provide
insight into the mechanisms and therapeutic targets of muscle wasting in cancer, but will also broaden an area
of cachexia research that is currently underexplored.

## Key facts

- **NIH application ID:** 10359196
- **Project number:** 5R01AR072714-03
- **Recipient organization:** MEDICAL UNIVERSITY OF SOUTH CAROLINA
- **Principal Investigator:** Denis C Guttridge
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2022
- **Award amount:** $478,114
- **Award type:** 5
- **Project period:** 2020-02-26 → 2024-12-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10359196

## Citation

> US National Institutes of Health, RePORTER application 10359196, NF-kB Regulation of the Muscle Microenvironment in Cancer Cachexia (5R01AR072714-03). Retrieved via AI Analytics 2026-05-22 from https://api.ai-analytics.org/grant/nih/10359196. Licensed CC0.

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