Summary
Cancer cells constantly change their cellular identity during tumor progression and upon therapy exposure. To maintain their cellular identity, cells have to transmit this information during cell division. However, the exact mechanisms how cells achieve that is not yet understood. During mitosis, most of the transcription factors (TFs) are evicted from chromatin, histone post-translational modifications (PTMs) are reduced, gene expression is reduced to a basal level and long-range chromatin interactions are lost. Of note, some TFs and co-factors remain associated with mitotic chromatin and bookmark these regions for rapid reactivation. After completion of mitosis, the daughter cells reactivate the initial transcriptional program to maintain cellular identity. Functional dissection of these bookmarking mechanisms upon therapy and tumor progression might allow exploiting these mechanisms to avoid therapy resistance development and alter tumor cell identity.
Major Research Goals
- Decipher therapy-induced alterations of mitotic bookmarking patterns in breast cancer
- Exploit bookmarking factors as potential therapeutical targets
- Overcome therapy resistance development by interference with memory mechanisms
Figure 1. Therapy induced alterations of bookmarking patterns.
Upon cancer therapy, different mitotic bookmarking factors, such as TFs, co-factors and histone PTMs, can be altered and thereby affect cell identity propagation and adaptation to therapy.
Highlights
- Oncogenic enhancers establish transcriptional memory to evade immune invasion in triple-negative breast cancer
- Interference with TF function prior to mitosis alters the post-mitotic phenotype by increasing NK cell-mediated killing
Outlook
Understand how TF dosage and combinations alter therapy efficiency
Identify common bookmarking mechanisms in different cancer types and treatment combinations