PXD014753

PXD014753 is an original dataset announced via ProteomeXchange.

Title	Fascin Controls Metastatic Colonization and Mitochondrial Oxidative Phosphorylation by Remodeling Mitochondrial Actin Filaments/The mitochondrial deoxyguanosine kinase is required for the self-renewal of cancer stem-like cell in lung adenocarcinoma
Description	Project 1: The deregulation of the actin cytoskeleton has been extensively studied in metastatic dissemination. However, the post-dissemination role of the actin cytoskeleton dysregulation is poorly understood. Here we report that fascin, an actin-bundling protein, promotes lung cancer metastatic colonization by augmenting metabolic stress resistance and mitochondrial OXPHOS. Fascin is directly recruited to mitochondria under metabolic stress to stabilize mitochondrial actin filaments (mtF-actin). Using unbiased metabolomics and proteomics approaches, we discovered that fascin-mediated mtF-actin remodeling promotes mitochondrial OXPHOS by increasing the biogenesis of respiratory Complex I. Mechanistically, fascin and mtF-actin controls the homeostasis of mtDNA to promote mitochondrial OXPHOS. The disruption of mtFactin abrogates fascin-mediated lung cancer metastasis. Conversely, restoration of mitochondrial respiration using yeast NDI1 in fascin depleted cancer cells is able to rescue lung metastasis. Our findings indicate that the dysregulated actin cytoskeleton in metastatic lung cancer could be targeted to rewire mitochondrial metabolism and to prevent metastatic recurrence. Project 2: There is a pool of mitochondrial dNTP in the cell maintained by the mitochondrial deoxynucleoside salvage pathway and dedicated for the mtDNA homeostasis in slow-cycling and post-mitotic cells. The role of the mitochondrial deoxynucleoside salvage pathway in tumor initiation and progression is poorly understood. Here, we investigated the role of the mitochondrial deoxyguanosine kinase (DGUOK), a rate-limiting enzyme in the mitochondrial deoxynucleoside salvage pathway, in the self-renewal of lung adenocarcinoma cancer stem-like cells (CSC). Our data support that DGUOK overexpression strongly correlates with cancer progression and patient survival. The depletion of DGUOK robustly inhibited lung adenocarcinoma tumor growth, metastasis and CSC self-renewal. Mechanistically, DGUOK is required for the biogenesis of respiratory Complex I and mitochondrial OXPHOS, which in turn regulates CSC self-renewal through AMPK-YAP1 signaling. The restoration of mitochondrial OXPHOS in DGUOK depleted lung cancer cells using NDI1, a single subunit yeast NADH : ubiquinone oxidoreductase, was able to rescue AMPK-YAP1 signaling and CSC stemness. Genetic targeting of DGUOK using doxycycline-inducible CRISPR/Cas9 was able to markedly induce tumor regression. Our findings reveal a novel role for mitochondrial dNTP metabolism in lung cancer tumor growth and progression, and implicate that the mitochondrial deoxynucleotide salvage pathway could be potentially targeted to prevent CSC-mediated therapy resistance and metastatic recurrence.
HostingRepository	PRIDE
AnnounceDate	2019-09-12
AnnouncementXML	Submission_2019-09-12_00:40:56.xml
DigitalObjectIdentifier	https://dx.doi.org/10.6019/PXD014753
ReviewLevel	Peer-reviewed dataset
DatasetOrigin	Original dataset
RepositorySupport	Supported dataset by repository
PrimarySubmitter	John Koomen
SpeciesList	scientific name: Homo sapiens (Human); NCBI TaxID: 9606;
ModificationList	TMT6plex; Oxidation; Carbamidomethyl
Instrument	Q Exactive

Revision	Datetime	Status	ChangeLog Entry
0	2019-07-25 02:56:27	ID requested
⏵ 1	2019-09-12 00:48:12	announced

Dataset with its publication pending

submitter keyword: Fascin, Deoxyguanosine Kinase, Lung Cancer, Metastasis, Mitochondria, Actin Cytoskeleton, Stem-Like Cells

Shengyu Yang, PhD
contact affiliation	Department of Cellular & Molecular Physiology Milton S. Hershey Medical Center Penn State College of Medicine Hershey, PA, USA
contact email	syang2@hmc.psu.edu
lab head
John Koomen
contact affiliation	Moffitt Cancer Center
contact email	john.koomen@moffitt.org
dataset submitter

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PRIDE project URI

• PRIDE
  1. PXD014753
     1. Label: PRIDE project
     2. Name: Fascin Controls Metastatic Colonization and Mitochondrial Oxidative Phosphorylation by Remodeling Mitochondrial Actin Filaments/The mitochondrial deoxyguanosine kinase is required for the self-renewal of cancer stem-like cell in lung adenocarcinoma