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Updated: May 8, 2025
Combining 3D Magnetic Force Actuator and Multi-Functional Fluorescence Imaging to Study Nucleus Mechanobiology
Published on: July 5, 2022
A multiparametric screen uncovers FDA-approved small molecules that potentiate the nuclear mechano-dysfunctions in
Maria Rosaria Cera1, Giulia Bastianello1,2, Divya Purushothaman1,3
1IFOM ETS, The AIRC Institute of Molecular Oncology, Milan, Italy.
Abstract:
Targeting nuclear mechanics is emerging as a promising therapeutic strategy for sensitizing cancer cells to immunotherapy. Inhibition of the mechano-sensory kinase ATR leads to mechanical vulnerability of cancer cells, causing nuclear envelope softness and collapse and activation of the cGAS-STING-mediated innate immune response. Finding novel compounds that interfere with the non-canonical role of ATR in controlling nuclear mechanics presents an intriguing therapeutic opportunity. We carried out a multiparametric high-content screen to identify small molecules that affect nuclear envelope shape and to uncover novel players that could either ameliorate or further compromise the nuclear mechanical abnormalities of ATR-defective cells. The screen was performed in HeLa cells genetically depleted for ATR. Candidate hits were also tested in combination with the chemical inhibition of ATR by AZD6738, and their efficacy was further validated in the triple-negative breast cancer cell lines BT549 and HCC1937. We show that those compounds enhancing the abnormal nuclear shape of ATR-defective cells also synergize with AZD6738 to boost the expression of interferon-stimulated genes, highlighting the power of multiparametric screens to identify novel combined therapeutic interventions targeting nuclear mechanics for cancer immunotherapy.
Insights
Targeting nuclear mechanics enhances cancer immunotherapy. Inhibiting the ATR kinase softens cancer cells, activating immune responses. Novel compounds amplifying this effect synergize with ATR inhibitors to boost anti-cancer immunity.
Area of Science:
- Cellular mechanics
- Cancer immunotherapy
- Innate immune response
Background:
- Targeting nuclear mechanics is a novel strategy to sensitize cancer cells to immunotherapy.
- The mechano-sensory kinase ATR plays a role in cancer cell mechanics and innate immune response activation via the cGAS-STING pathway.
- Understanding ATR's non-canonical functions in nuclear mechanics is crucial for developing new cancer therapies.
Purpose of the Study:
- To identify small molecules that modulate nuclear envelope shape and mechanics in ATR-defective cancer cells.
- To discover novel therapeutic interventions that enhance the anti-cancer effects of ATR inhibition.
- To explore combination therapies targeting nuclear mechanics for improved cancer immunotherapy.
Main Methods:
- Conducted a multiparametric high-content screen in ATR-depleted HeLa cells to identify compounds affecting nuclear shape.
- Tested candidate compounds in combination with the ATR inhibitor AZD6738.
- Validated efficacy in triple-negative breast cancer cell lines (BT549 and HCC1937).
Main Results:
- Identified small molecules that exacerbate the abnormal nuclear shape in ATR-defective cells.
- Compounds enhancing abnormal nuclear shape synergized with AZD6738 to increase interferon-stimulated gene expression.
- Demonstrated the potential of multiparametric screens for discovering combination therapies.
Conclusions:
- Novel compounds targeting nuclear mechanics can enhance cancer cell sensitization to immunotherapy.
- Combined targeting of ATR and nuclear mechanics shows promise for boosting innate immune responses against cancer.
- Multiparametric screening is an effective approach for identifying synergistic therapeutic strategies in cancer treatment.
