PXD036752-2

PXD036752 is an original dataset announced via ProteomeXchange.

Title	Integrative study of mitochondrial dysfunction in skeletal muscle during pancreatic cancer cachexia
Description	Background. Pancreatic Ductal AdenoCarcinoma (PDAC), the most frequent pancreatic cancer, is a deadly cancer since often diagnosed late and resistant to current therapies. A high proportion of PDAC patients are affected by cachexia induced by the tumor. This cachexia, characterized by loss of muscle mass and strength, contributes to patient frailty and poor therapeutic response. We showed that mitochondrial metabolism is reprogrammed in PDAC tumor cell and constitutes a vulnerability, opening novel therapeutic avenues. The objective of the present work was to investigate the molecular mechanisms underlying mitochondrial remodeling in PDAC cachectic skeletal muscle. Methods. Our study focused on the gastrocnemius muscle of genetically-engineered mice developing spontaneously a PDAC associated with cachexia (KIC GEMM). We compared KIC mice developing a pancreatic tumor in 9-10 weeks to control littermates. We did an integrative study combining in vivo functional analyses by non-invasive Magnetic Resonance, and ex-vivo histology, Seahorse, RNA-sequencing, and proteomic mass spectrometry and western blotting analyses. Results. The cachectic KIC PDAC mice show a severe sarcopenia with loss of muscle mass and strength associated with a diminution in muscle fiber’s size and induction of protein degradation processes. Mitochondria in PDAC atrophic muscles show decreased respiratory capacities and structural alterations (“hyperfused” mitochondria), associated with deregulation of oxidative phosphorylation and mitochondrial dynamics pathways at the molecular level. Increased expression of multiple reactive oxygen species (ROS) defense genes suggests oxidative stress prone to affect mitochondrial macromolecules and homeostasis. Interestingly, multiple genes and proteins involved in DNA metabolism pathways, such as DNA damage, degradation of DNA, nucleotide synthesis, and folate pathway were found altered in sarcopenic mitochondria. While the number of mitochondria was not changed, the mitochondrial mass was decreased by a factor of 2 and the mitochondrial DNA by a factor of 3, suggesting a defect in mitochondrial genome homeostasis. Conclusions. We unveiled that mitochondrial alterations in skeletal muscle play a central role in PDAC-induced cachexia. Muscle atrophy is associated with strong mitochondrial metabolic defects that are not limited to carbohydrates and protein, but concern also lipids, ROS and nucleic acids. Our data provide a frame to guide towards the most relevant molecular markers that would be affected at the start of tumor development and could be targets in the clinic to limit PDAC-induced cachexia at early stages of the pathology.
HostingRepository	PRIDE
AnnounceDate	2024-10-22
AnnouncementXML	Submission_2024-10-22_06:35:33.216.xml
DigitalObjectIdentifier
ReviewLevel	Peer-reviewed dataset
DatasetOrigin	Original dataset
RepositorySupport	Unsupported dataset by repository
PrimarySubmitter	AUDEBERT Stephane
SpeciesList	scientific name: Mus musculus (Mouse); NCBI TaxID: 10090;
ModificationList	monohydroxylated residue; iodoacetamide derivatized residue
Instrument	Orbitrap Fusion Lumos

Revision	Datetime	Status	ChangeLog Entry
0	2022-09-14 14:35:06	ID requested
1	2024-04-09 05:48:59	announced
⏵ 2	2024-10-22 06:35:33	announced	2024-10-22: Updated project metadata.

10.7554/ELIFE.93312.1;

submitter keyword: gastrocnemius muscle, energetic metabolism, Mouse, cachexia, mitochondria, muscle wasting,LC-MSMS, pancreatic cancer

CARRIER Alice
contact affiliation	Centre de Recherche en Cancérologie de Marseille (CRCM) Inserm U1068 - CNRS UMR7258 - Institut Paoli-Calmettes - Aix-Marseille Université Campus de Luminy, Case 915, 163 Avenue de Luminy 13288 Marseille Cedex 9 - FRANCE
contact email	Alice.carrier@inserm.fr
lab head
AUDEBERT Stephane
contact affiliation	Marseille Proteomic, Centre de Recherche en Cancérologie de Marseille, Inserm UMR1068, CNRS UMR7258, Aix Marseille Université U105, Institut Paoli Calmettes, 27 Boulevard Leï Roure CS30059 13273 Marseille Cedex 09 France
contact email	stephane.audebert@inserm.fr
dataset submitter

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PRIDE project URI

• PRIDE
  1. PXD036752
     1. Label: PRIDE project
     2. Name: Integrative study of mitochondrial dysfunction in skeletal muscle during pancreatic cancer cachexia