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Transdifferentiation mediated tumor suppression by the endoplasmic reticulum stress sensor IRE-1 in C. elegans
Mor Levi-Ferber1, Hai Gian1, Reut Dudkevich1
1The Mina and Everard Goodman Faculty of Life Sciences, Bar-Ilan University, Ramat-Gan, Israel.
Abstract:
Deciphering effective ways to suppress tumor progression and to overcome acquired apoptosis resistance of tumor cells are major challenges in the tumor therapy field. We propose a new concept by which tumor progression can be suppressed by manipulating tumor cell identity. In this study, we examined the effect of ER stress on apoptosis resistant tumorous cells in a Caenorhabditis elegans germline tumor model. We discovered that ER stress suppressed the progression of the lethal germline tumor by activating the ER stress sensor IRE-1. This suppression was associated with the induction of germ cell transdifferentiation into ectopic somatic cells. Strikingly, transdifferentiation of the tumorous germ cells restored their ability to execute apoptosis and enabled their subsequent removal from the gonad. Our results indicate that tumor cell transdifferentiation has the potential to combat cancer and overcome the escape of tumor cells from the cell death machinery.
Insights
Tumor progression can be halted by altering tumor cell identity. Endoplasmic reticulum (ER) stress induces germ cell transdifferentiation, restoring apoptosis and enabling tumor cell removal in a C. elegans model.
Area of Science:
- Oncology
- Developmental Biology
- Cell Biology
Background:
- Tumor progression and apoptosis resistance are significant challenges in cancer therapy.
- Manipulating tumor cell identity offers a novel therapeutic strategy.
- Understanding the role of endoplasmic reticulum (ER) stress in cancer is crucial.
Purpose of the Study:
- To investigate the effect of ER stress on apoptosis-resistant tumor cells.
- To explore the potential of manipulating tumor cell identity to suppress tumor progression.
- To examine the role of the ER stress sensor IRE-1 in tumor suppression.
Main Methods:
- Utilized a Caenorhabditis elegans (C. elegans) germline tumor model.
- Induced and monitored Endoplasmic Reticulum (ER) stress.
- Analyzed germ cell transdifferentiation into ectopic somatic cells.
- Assessed the restoration of apoptosis and subsequent cell removal.
Main Results:
- ER stress effectively suppressed lethal germline tumor progression.
- Activation of the ER stress sensor IRE-1 was critical for tumor suppression.
- Tumorous germ cells underwent transdifferentiation into ectopic somatic cells.
- Transdifferentiation restored apoptosis in tumor cells, leading to their removal.
Conclusions:
- Tumor cell transdifferentiation is a viable strategy to combat cancer.
- This approach can overcome tumor cell resistance to apoptosis.
- Targeting ER stress pathways may offer new avenues for cancer therapy.
