# Project 1 – IL-6/STAT3/NF-kB in Adipose-Muscle Crosstalk in the Pancreatic Cancer Macroenvironment

> **NIH NIH P01** · MEDICAL UNIVERSITY OF SOUTH CAROLINA · 2024 · $412,656

## Abstract

PROJECT SUMMARY: PROJECT 1
Cancer cachexia, or progressive weight loss featuring immunodysmetabolism, causes ~1/3 of cancer deaths.
Loss of muscle mass reduces performance status, predisposes to illness, and increases treatment toxicity while
reducing efficacy. Not merely a feature of end-stage cancer, cachexia is a disease with specific, targetable
mechanisms. Pre-clinical studies prove that targeting those mechanisms can preserve muscle and lengthen
survival, with or without chemotherapy. Cachexia is especially devastating in pancreatic ductal adenocarcinoma
(PDAC), afflicting 85% of PDAC patients, most of whom present with weight loss. There is no effective treatment
for PDAC and 5-year survival is ~9%. Thus, until PDAC can be cured early in its course, we must manage
cachexia, because preserving muscle mass and function will promote response to cancer treatment, improve
quality of life, and increase survival. Overall, our Program team hypothesizes that PDAC tumor progression
and cachexia is highly orchestrated by an IL-6/IL6R/STAT3/NF-B signaling axis. Project 2 will test NF-B
in muscle inflammation and tumor progression, and Project 3 will study IL-6/STAT3/NF-B in tumor-stroma-
immune interactions and the macroenvironment. Project 1 of this Program focuses on the crosstalk between
adipose and skeletal muscle induced by PDAC tumors, and how IL6R, STAT3, and NF-B combine to produce
fat and muscle loss in the PDAC macroenvironment. Abundant data demonstrate that weight loss in PDAC is
primarily fat loss in PDAC. Moreover, we showed that fat loss is as predictive of mortality in PDAC as muscle
loss, regardless of response to therapy, suggesting a central role for adipose wasting in cachexia. Now we
demonstrate that tumor-induced, muscle-derived soluble IL6R appears to induce IL-6 mediated adipocyte
lipolysis, products of which feed forward to induce myosteatosis, lipotoxicity, dysmetabolism, weakness and
atrophy through a novel PKC-θ to PDK4 axis. Thus, we hypothesize that PDAC induces a feed-forward loop
among tumor, fat, and muscle whereby tumor-induced IL-6 and other signals activate adipose STAT3 and
lipolysis, products of which are taken up by muscle leading to myosteatosis, PKC-θ activation and subsequent
myofiber STAT3, NF-B and PDK4 activation, which promote dysmetabolism, local inflammation and production
of soluble IL6R to feed-forward activate adipose wasting. Blocking this cycle will preserve adipose and muscle
wasting in PDAC. Using genetic mouse models, human specimens, advanced single cell resolution sequencing
as well as correlative cachexia studies in a clinical trial, we will test our hypothesis in these specific aims:
AIM 1. Interrogate the mechanisms of adipose-to-muscle crosstalk in the macroenvironment of PDAC
cachexia.
AIM 2. Interrogate mechanisms of muscle-to-adipose crosstalk in the macroenvironment of PDAC
cachexia.
AIM 3. Interrogate manifestations and mechanisms of the IL-6/IL6R/STAT3/NF-B pathway in patients
 ...

## Key facts

- **NIH application ID:** 10898563
- **Project number:** 5P01CA236778-04
- **Recipient organization:** MEDICAL UNIVERSITY OF SOUTH CAROLINA
- **Principal Investigator:** Teresa A Zimmers
- **Activity code:** P01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2024
- **Award amount:** $412,656
- **Award type:** 5
- **Project period:** 2021-07-01 → 2026-06-30

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10898563

## Citation

> US National Institutes of Health, RePORTER application 10898563, Project 1 – IL-6/STAT3/NF-kB in Adipose-Muscle Crosstalk in the Pancreatic Cancer Macroenvironment (5P01CA236778-04). Retrieved via AI Analytics 2026-05-23 from https://api.ai-analytics.org/grant/nih/10898563. Licensed CC0.

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