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Updated: Jul 17, 2026
Simultaneous Imaging and Flow-Cytometry-based Detection of Multiple Fluorescent Senescence Markers in Therapy-Induced Senescent Cancer Cells
Published on: July 12, 2022
Oncogene inactivation-induced senescence facilitates tumor relapse
Philipp Schmitt1,2,3, Katrin Hönig1, Maria Teresa Norcia1,4,5,6
1Max-Delbrück Center for Molecular Medicine in the Helmholtz Association, Berlin, Germany.
Abstract:
Oncogene-directed therapies can induce profound tumor regression in oncogene-addicted cancers, but their long-term benefit is often limited by resistance and relapse. Here we show that oncogene inactivation rapidly induces senescence and a pro-inflammatory senescence-associated secretory phenotype (SASP). In vivo, oncogene inactivation-induced senescence (OIIS) predisposes tumors to relapse, accompanied by polyploidy, chromosomal instability, acquisition of alternative oncogenic pathways including mouse double minute 2 homolog (Mdm2) upregulation, and tumor microenvironmental remodeling toward neovascularization and immunosuppression. Spectral flow cytometry reveals a shift from an immune-activated to an immunosuppressive milieu during relapse. OIIS features are also observed in human BRAFV600E melanoma cells treated with vemurafenib, supporting clinical relevance. Together, our findings establish OIIS as a double-edged process: it initially restrains tumor growth but simultaneously creates conditions that favor recurrence. By defining the genetic, metabolic and microenvironmental hallmarks of OIIS, our study highlights adaptations to oncogene deprivation that limit the durability of targeted therapies.
Insights
Targeted cancer therapies can cause relapse by inducing oncogene inactivation-induced senescence (OIIS). This process initially halts tumor growth but creates conditions for recurrence, limiting treatment durability.
Area of Science:
- Oncology
- Cancer Biology
- Molecular Therapy
Background:
- Targeted therapies offer profound tumor regression in oncogene-addicted cancers.
- Long-term efficacy is frequently compromised by acquired resistance and tumor relapse.
Purpose of the Study:
- To investigate the consequences of oncogene inactivation beyond initial tumor regression.
- To define the mechanisms underlying relapse following oncogene-directed therapy.
Main Methods:
- Induction of oncogene inactivation in preclinical cancer models.
- Analysis of cellular senescence and senescence-associated secretory phenotype (SASP).
- In vivo tumor growth, relapse dynamics, and tumor microenvironment characterization using spectral flow cytometry.
Main Results:
- Oncogene inactivation rapidly triggers senescence and a pro-inflammatory SASP.
- Relapse is associated with polyploidy, chromosomal instability, Mdm2 upregulation, and neovascularization.
- Tumor microenvironment shifts towards immunosuppression during relapse.
- OIIS features are observed in human BRAFV600E melanoma treated with vemurafenib.
Conclusions:
- Oncogene inactivation-induced senescence (OIIS) is a critical factor in tumor relapse.
- OIIS creates a pro-tumorigenic microenvironment that favors recurrence.
- Understanding OIIS hallmarks is crucial for developing strategies to improve the durability of targeted cancer therapies.
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