An Embryonic Diapause-like Adaptation with Suppressed Myc Activity Enables Tumor Treatment Persistence
Eugen Dhimolea1, Ricardo de Matos Simoes1, Dhvanir Kansara2
1Department of Medical Oncology, Dana-Farber Cancer Institute Boston, MA, USA; Harvard Medical School, Boston, MA, USA; Broad Institute of MIT and Harvard, Cambridge, MA, USA; Ludwig Center at Harvard, Boston, MA, USA.
Cancer Cell
|January 8, 2021
Summary
Cancer cells develop a dormant, embryonic diapause-like state to survive chemotherapy. Suppressing Myc or targeting specific pathways may offer new therapeutic strategies against persistent tumors.
Area of Science:
- Oncology
- Developmental Biology
- Molecular Biology
Background:
- Treatment-persistent residual tumors are a major obstacle to curative cancer therapy.
- Understanding the cellular mechanisms driving treatment persistence is crucial for developing effective strategies.
Purpose of the Study:
- To investigate the transcriptional state of treatment-persistent cancer cells.
- To identify potential therapeutic targets for eliminating residual tumors.
Main Methods:
- Generation of models simulating treatment-persistent residual tumors (organoids, xenografts, patient samples).
- Analysis of transcriptional programs and key molecular players (Myc, Brd4, cyclin-dependent kinase 9).
- Assessment of drug cytotoxicity and apoptotic priming in response to molecular manipulations.
Main Results:
- Treatment-persistent tumor cells exhibit a transcriptional program similar to embryonic diapause, characterized by suppressed Myc activity and reduced biosynthesis.
- Depleting Myc or inhibiting Brd4 leads to a diapause-like adaptation, reducing sensitivity to chemotherapy.
- Upregulating Myc enhances acute chemotherapeutic activity.
Conclusions:
- Cancer cells co-opt a diapause-like mechanism, involving adaptive Myc inactivation, to survive chemotherapy.
- Inhibiting Myc activity or cyclin-dependent kinase 9 could be therapeutic strategies to eliminate chemotherapy-persistent residual cells.
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