Publikationsserver
Exploiting metabolic vulnerabilities caused by autophagy defects for cancer therapy
Autophagy is a catabolic process that recycles non-essential cellular components, making metabolites newly available for the cell and helping it to cope with starvation and other cellular stress conditions. For years autophagy has been drawing increasing interest because of the role it plays in norm...
Gespeichert in:
| 1. Verfasser: | |
|---|---|
| Beteiligte: | |
| Format: | Dissertation |
| Sprache: | Englisch |
| Veröffentlicht: |
Philipps-Universität Marburg
2023
|
| Schlagworte: | |
| Online Zugang: | PDF-Volltext |
| Tags: |
Tag hinzufügen
Keine Tags, Fügen Sie den ersten Tag hinzu!
|
| Zusammenfassung: | Autophagy is a catabolic process that recycles non-essential cellular components, making metabolites newly available for the cell and helping it to cope with starvation and other cellular stress conditions. For years autophagy has been drawing increasing interest because of the role it plays in normal cellular physiology and pathologies, including cancer. Indeed, during cancer progression tumor cells go through a series of changes that alter their metabolism and dramatically increase their need for nutrients. This kind of metabolic reprogramming makes them strongly dependent on the autophagy pathway to survive nutrient shortages or exposure to drugs that target cellular metabolism. Therefore, it would be an advantage to identify novel vulnerabilities created by autophagy deficiency in cancer and exploit such defects for metabolic drug therapy, opening an effective and selective therapeutic window.
In this study, we analyzed two types of defects in the autophagic pathway and tested whether and how they would impact the cell's ability to withstand treatment with metabolic drugs such as dichloroacetate and 2-deoxy-D-glucose. First, we studied a model of chemoresistance in which mTOR upregulation drives cancer resistance against the chemotherapeutic cisplatin, but at the same time suppresses autophagy and makes cells sensitive to metabolic inhibitors causing severe energetic stress. Second, we studied the effects of somatic copy number alterations on the autophagic pathway. Autophagy-related genes (ATGs) are rarely affected by point mutations in cancer. However, they are often affected by somatic copy number losses. It has been hypothesized that the accumulation of multiple non-homozygous ATG deletions would reduce the autophagic flux and cause a metabolic vulnerability, but formal proof was still missing. We used CRISPR-Cas9 to induce deletions of key ATGs and established cell lines carrying multiple non-homozygous ATG deletions. While complete knockout of one single ATG gene heavily sensitized cells to metabolic drugs, cells with accumulation of non-homozygous deletions of multiple ATGs remained mostly unaffected, demonstrating the resilience of the autophagy pathway against this type of alteration. |
|---|---|
| DOI: | 10.17192/z2023.0446 |