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

Joe R Delaney,Mina Haghighiabyaneh,Christian M Jones,Ralph Tanios,Chandni B Patel,John W Destefano,Joshua Axelrod,Jaidev Bapat,Albert R La Spada,Maria Ramos-Zapatero,Katherine K Ortell,Isabelle Tancioni,Olivier Harismendy,Dwayne G Stupack,David D Schlaepfer,David J Kwiatkowski

doi:10.1371/journal.pgen.1008558

Joe R Delaney, Mina Haghighiabyaneh + Show 14 more

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https://doi.org/10.1371/journal.pgen.1008558

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Abstract

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.

Highlights

IntroductionThe canonical cellular task of autophagy is to recycle damaged proteins, organelles, and fatty acids [1]
The role of autophagy in cancer remains enigmatic
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

Summary

Introduction

The canonical cellular task of autophagy is to recycle damaged proteins, organelles, and fatty acids [1]. Autophagy is partially redundant and complementary to other cellular homeostasis pathways, such as the endoplasmic reticulum stress response and the ubiquitin-proteasome system. The role of autophagy as a tumor promoting cellular pathway is evident in Ras- or Raf-driven tumors. Complete deletion of Atg, an essential autophagy gene, dramatically slows tumor growth in these mouse models [3, 4]. This is in part due to depleted pools of glutamine and glutamate preventing nucleotide synthesis [5]. BECN1, known as beclin 1 [9], has been highlighted for its tumor suppressor roles ever since two independent labs generated heterozygous wholebody knockout mouse models; each study observed earlier cancer formation in Becn1+/- mice compared to Becn1+/+ mice [10, 11]

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