# Human neuromuscular organoids mimic cancer-induced muscle cachexia

## TL;DR

Researchers created human neuromuscular organoids that mimic cancer-induced muscle wasting, offering a new tool to study and develop treatments for this condition.

## Contribution

The study introduces a novel 3D in vitro model using human-induced pluripotent stem cells to replicate cancer cachexia features.

## Key findings

- NMOs exhibit muscle mass loss and impaired contraction when exposed to cachexia-inducing factors.
- Cachectic NMOs show mitochondrial dysfunction and metabolic shifts similar to human cancer cachexia.
- The model supports future therapeutic screening and patient-specific studies of muscle wasting.

## Abstract

Cancer cachexia, a devastating metabolic wasting syndrome affecting up to 80% of solid cancer patients, remains incurable despite advances in tumor biology understanding. This study introduces neuromuscular organoids (NMOs) derived from human-induced pluripotent stem cells (hiPSCs) as a platform to investigate cancer-driven muscle cachexia. We found that NMOs respond well to atrophic stimuli and replicate the key features of cancer cachexia when treated with conditioned media derived from cachexia-inducing cancer cells. Specifically, cachectic NMOs showed muscle mass loss, impairment of muscle contraction, alteration of intracellular calcium homeostasis, appearance of mitochondrial dysfunction with a metabolic shift, and enhancement of autophagy. Based on these results, we propose NMOs derived from hiPSCs as an in vitro tool for investigating human muscle cachexia, with potential future avenues of patient-specific modeling and therapeutic screening.

•⁠hiPSC-derived NMOs mature and respond to genetically induced muscle atrophy•⁠NMOs mimic cachectic muscle morphology and function under pro-cachectic factors•⁠Cachectic NMOs show cancer cachexia metabolic, mitochondrial, and molecular features•⁠NMOs offer a platform to study mechanisms and test potential cachexia therapies

⁠hiPSC-derived NMOs mature and respond to genetically induced muscle atrophy

⁠NMOs mimic cachectic muscle morphology and function under pro-cachectic factors

⁠Cachectic NMOs show cancer cachexia metabolic, mitochondrial, and molecular features

⁠NMOs offer a platform to study mechanisms and test potential cachexia therapies

The study of mechanisms behind cancer-induced muscle cachexia is a significant challenge. Currently available in vivo and in vitro models are limited and do not allow the study of cachexia in a context that is relevant to patients. We therefore sought to develop a multicellular, three-dimensional (3D) in vitro model derived from human cells that recapitulates the phenotypes observed in a cachectic muscle, including impairment of muscle contraction and cellular and molecular alterations.

Chiolerio et al. introduce neuromuscular organoids derived from human-induced pluripotent stem cells as an innovative in vitro platform to model cancer-induced muscle wasting. The organoids recapitulate key features of muscle cachexia, providing a multicellular, physiologically relevant human model to investigate underlying mechanisms and develop potential therapeutics.