Related Experiment Video

Updated: Sep 20, 2025

Assessing Autophagic Flux by Measuring LC3, p62, and LAMP1 Co-localization Using Multispectral Imaging Flow Cytometry
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Assessing Autophagic Flux by Measuring LC3, p62, and LAMP1 Co-localization Using Multispectral Imaging Flow Cytometry

Published on: July 21, 2017

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Robustness of the Autophagy Pathway to Somatic Copy Number Losses

Pierfrancesco Polo1, Niklas Gremke1,2, Thorsten Stiewe1,3,4

  • 1Institute of Molecular Oncology, Philipps-University, 35043 Marburg, Germany.

Cells
|June 10, 2022
PubMed

Insights

Cancer cells with defects in autophagy genes (ATGs) may be vulnerable to metabolic drugs. However, even with copy number losses, the autophagy pathway remains robust, limiting therapeutic potential.

Area of Science:

  • Cellular Biology
  • Cancer Metabolism
  • Molecular Oncology

Background:

  • Autophagy is a cellular process that replenishes metabolites during energy stress, potentially sensitizing cancer cells to metabolic drugs.
  • Defects in autophagy could indicate a metabolically vulnerable cancer state, creating a therapeutic window.
  • While mutations in autophagy genes (ATGs) are rare, copy number losses frequently affect ATGs in various cancers.

Purpose of the Study:

  • To investigate the impact of autophagy gene copy number loss on cancer cell sensitivity to drugs targeting aerobic glycolysis.
  • To determine if reduced ATG copy numbers create a metabolic vulnerability in non-small cell lung cancer cells.

Main Methods:

  • Utilized CRISPR/Cas9 technology to delete varying numbers of copies of key autophagy genes (MAP1LC3B/ATG8F, BECN1/ATG6, ATG10) in non-small cell lung cancer cells.
  • Assessed the sensitivity of modified cancer cells to compounds targeting aerobic glycolysis.
  • Analyzed protein levels and p62 accumulation in cancer patients with ATG copy number loss to evaluate autophagic flux.

Main Results:

  • Complete knockout of a single ATG gene blocked autophagy and induced significant metabolic vulnerability.
  • Combinations of different nonhomozygous ATG deletions did not result in a similar blockade or vulnerability.
  • In cancer patients, ATG copy number loss had a blunted effect at the protein level, with no significant p62 accumulation indicating reduced autophagic flux.

Conclusions:

  • The autophagy pathway exhibits remarkable robustness and resilience, even when key autophagy genes experience copy number loss.
  • Concomitant copy number losses of multiple autophagy genes do not necessarily lead to a functionally impaired autophagy pathway or increased metabolic vulnerability in cancer.
  • The resilience of autophagy suggests that targeting this pathway through copy number alterations alone may not be a universally effective anticancer strategy.
Keywords:
aerobic glycolysisautophagycancer metabolismcopy number losshaploinsufficiencymetabolic cancer therapysomatic copy number alterations (SCNAs)

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