Autophagy gene haploinsufficiency drives chromosome instability, increases migration, and promotes early ovarian tumors

Autor: Chandni Patel, Dwayne G. Stupack, Katherine K. Ortell, David D. Schlaepfer, Christian M. Jones, Isabelle Tancioni, Ralph Tanios, Olivier Harismendy, Jaidev Bapat, Mina Haghighiabyaneh, Albert R. La Spada, Maria Ramos-Zapatero, John W. DeStefano, Joe R. Delaney, Joshua Axelrod
Přispěvatelé: Kwiatkowski, David J
Jazyk: angličtina
Rok vydání: 2020
Předmět:
Cancer Research
endocrine system diseases
Epidemiology
Carcinogenesis
Gene Identification and Analysis
Genetic Networks
Haploinsufficiency
Tumor initiation
QH426-470
medicine.disease_cause
Suppressor Genes
Mice
0302 clinical medicine
Cell Movement
Chromosome instability
Medicine and Health Sciences
2.1 Biological and endogenous factors
Aetiology
Genetics (clinical)
Cancer
Ovarian Neoplasms
0303 health sciences
Mammalian Genomics
Tumor
Cell Death
Chromosome Biology
Cancer Risk Factors
Animal Models
Genomics
BECN1
Ovarian Cancer
3. Good health
Chromosome 17 (human)
Oncology
Experimental Organism Systems
Cell Processes
Metabolome
Female
Beclin-1
Microtubule-Associated Proteins
MAP1LC3B
Network Analysis
Research Article
Computer and Information Sciences
Chromosome Structure and Function
Autophagic Cell Death
Tumor Suppressor Genes
Genetic Causes of Cancer
Mouse Models
Biology
Research and Analysis Methods
Chromosomes
Cell Line
03 medical and health sciences
Model Organisms
Rare Diseases
Gene Types
Cell Line
Tumor
Chromosomal Instability
Breast Cancer
medicine
Genetics
Animals
Molecular Biology
Ecology
Evolution
Behavior and Systematics
030304 developmental biology
Human Genome
Biology and Life Sciences
Cancers and Neoplasms
Cell Biology
medicine.disease
Animal Genomics
Medical Risk Factors
Animal Studies
Cancer research
Ovarian cancer
Gynecological Tumors
030217 neurology & neurosurgery
Developmental Biology
Zdroj: PLoS Genetics, Vol 16, Iss 1, p e1008558 (2020)
PLoS genetics, vol 16, iss 1
PLoS Genetics
ISSN: 1553-7404
1553-7390
Popis: Autophagy, particularly with BECN1, has paradoxically been highlighted as tumor promoting in Ras-driven cancers, but potentially tumor suppressing in breast and ovarian cancers. However, studying the specific role of BECN1 at the genetic level is complicated due to its genomic proximity to BRCA1 on both human (chromosome 17) and murine (chromosome 11) genomes. In human breast and ovarian cancers, the monoallelic deletion of these genes is often co-occurring. To investigate the potential tumor suppressor roles of two of the most commonly deleted autophagy genes in ovarian cancer, BECN1 and MAP1LC3B were knocked-down in atypical (BECN1+/+ and MAP1LC3B+/+) ovarian cancer cells. Ultra-performance liquid chromatography mass-spectrometry metabolomics revealed reduced levels of acetyl-CoA which corresponded with elevated levels of glycerophospholipids and sphingolipids. Migration rates of ovarian cancer cells were increased upon autophagy gene knockdown. Genomic instability was increased, resulting in copy-number alteration patterns which mimicked high grade serous ovarian cancer. We further investigated the causal role of Becn1 haploinsufficiency for oncogenesis in a MISIIR SV40 large T antigen driven spontaneous ovarian cancer mouse model. Tumors were evident earlier among the Becn1+/- mice, and this correlated with an increase in copy-number alterations per chromosome in the Becn1+/- tumors. The results support monoallelic loss of BECN1 as permissive for tumor initiation and potentiating for genomic instability in ovarian cancer.
Author summary Life requires an excellent trash and recycling system. One system mammalian cells rely upon is called autophagy. Autophagy clears cells of larger forms of debris and is critical for normal cell function. We previously found that ovarian cancer cells are unable to execute normal cellular recycling during periods of stress, due to losses in core autophagy genes. Since autophagy has previously been implicated as a cancer cell survival factor, we directly investigated the impact of autophagy gene loss in ovarian cancer models. We discovered a reduction in autophagy proteins disabled normal genome quality control during cell division, leading to genomic instability. We document here for the first time whether reducing an autophagy gene in mice influences ovarian tumor formation. We found earlier ovarian tumors in autophagy deficient mice compared with control mice. We conclude that serous ovarian carcinomas, which rank among the most genetically altered cancers, gain their hallmark genomic instability in part by losing autophagy genes.
Databáze: OpenAIRE
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