# Fiber-type vulnerability and proteostasis reprogramming in skeletal muscle during pancreatic cancer cachexia

## TL;DR

This study explores how pancreatic cancer causes skeletal muscle loss and identifies new molecular pathways that could be targeted for treatment.

## Contribution

The study reveals novel molecular mechanisms and intercellular signaling networks involved in muscle wasting during pancreatic cancer cachexia.

## Key findings

- Tumor growth alters genes related to proteolysis, mitochondrial biogenesis, and angiogenesis in skeletal muscle.
- mTORC1 signaling activity protects against muscle loss in tumor-bearing mice.
- New intercellular signaling networks were identified in the skeletal muscle microenvironment during cachexia.

## Abstract

Cachexia is a debilitating syndrome characterized by progressive skeletal muscle wasting, commonly affecting patients with cancer, particularly those with pancreatic cancer. Despite its clinical significance, the molecular mechanisms underlying cancer cachexia remain poorly understood. In this study, we utilized single-nucleus RNA-seq (snRNA-seq) and bulk RNA-seq, complemented by biochemical and histological analyses, to investigate molecular alterations in the skeletal muscle of the KPC mouse model of pancreatic cancer cachexia. Our findings demonstrated that KPC tumor growth induced myofiber-specific changes in the expression of genes involved in proteolytic pathways, mitochondrial biogenesis, and angiogenesis. Notably, tumor progression enhanced the activity of specific transcription factors that regulate the mTORC1 signaling pathway, along with genes involved in translational initiation and ribosome biogenesis. Skeletal muscle–specific, inducible inhibition of mTORC1 activity further exacerbated muscle loss in tumor-bearing mice, highlighting its protective role in maintaining muscle mass. Additionally, we uncovered new intercellular signaling networks within the skeletal muscle microenvironment during pancreatic cancer–induced cachexia. Our study reveals previously unrecognized molecular mechanisms that regulate skeletal muscle homeostasis, and it identifies potential therapeutic targets for the treatment of pancreatic cancer–associated cachexia.

This study identified previously unrecognized molecular mechanisms and intercellular communications that drive skeletal muscle wasting during pancreatic cancer-associated cachexia.