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Updated: Apr 8, 2026
A Mouse Model of Incompletely Resected Soft Tissue Sarcoma for Testing Neoadjuvant Therapies
Published on: July 28, 2020
Signaling through alternative Integrated Stress Response pathways compensates for GCN2 loss in a mouse model of soft
Stacey L Lehman1, Sandra Ryeom2, Constantinos Koumenis1
1Deparment of Radiation Oncology, Perelman School of Medicine at the University of Pennsylvania, Philadelphia, PA, USA 19104.
Abstract:
The tumor microenvironment is characterized by deficiencies in oxygen and nutrients, such as glucose and amino acids. Activation of the GCN2 arm of the Integrated Stress Response (ISR) in response to amino acid deprivation is one mechanism by which tumor cells cope with nutrient stress. GCN2 phosphorylates the alpha subunit of the eukaryotic translation initiation factor eIF2, leading to global downregulation of translation to conserve amino acids and initiation of a transcriptional program through ATF4 to promote recovery from nutrient deprivation. Loss of GCN2 results in decreased tumor cell survival in vitro under amino acid deprivation and attenuated tumor growth in xenograft tumor models. However, it is not known what effects GCN2 loss has on the growth of autochthonous tumors that arise in their native microenvironment. Here, we demonstrate in a genetically engineered mouse model of soft tissue sarcoma that loss of GCN2 has no effect on tumor growth or animal survival. The sarcomas displayed compensatory activation of PERK or phospho-eIF2α independent upregulation of ATF4 in order to maintain ISR signaling, indicating that this pathway is critical for tumorigenesis. These results have important implications for the development and testing of small molecule inhibitors of ISR kinases as cancer therapeutics.
Insights
Loss of GCN2 kinase does not impede soft tissue sarcoma growth in mice. Tumor cells compensate by activating other pathways, suggesting the Integrated Stress Response is critical for cancer development.
Area of Science:
- Oncology
- Molecular Biology
- Cancer Research
Background:
- Tumor microenvironments often lack oxygen and nutrients, stressing cancer cells.
- The Integrated Stress Response (ISR), particularly the GCN2 pathway, helps tumor cells survive nutrient deprivation.
- GCN2 activation leads to reduced translation and activates ATF4 for recovery.
Purpose of the Study:
- To investigate the role of GCN2 in autochthonous tumor growth within the native microenvironment.
- To determine if GCN2 loss affects soft tissue sarcoma progression in a genetically engineered mouse model.
Main Methods:
- Utilized a genetically engineered mouse model of soft tissue sarcoma.
- Assessed tumor growth and animal survival in the absence of GCN2.
- Analyzed compensatory ISR signaling pathways, including PERK and ATF4 activation.
Main Results:
- Loss of GCN2 did not significantly impact soft tissue sarcoma growth or animal survival.
- Sarcomas exhibited compensatory activation of PERK or ATF4, independent of phospho-eIF2α.
- This compensatory signaling maintained ISR pathway activity critical for tumorigenesis.
Conclusions:
- GCN2 is not essential for the growth of autochthonous soft tissue sarcomas.
- Tumor cells can bypass GCN2 dependency through alternative ISR signaling pathways.
- Targeting ISR kinases requires careful consideration of compensatory mechanisms for effective cancer therapy.
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