2025-07-24 ノースウェスタン大学
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<関連情報>
- https://news.northwestern.edu/stories/2025/07/new-strategy-doubles-chemo-effectiveness-in-treatment-resistant-cancer/
- https://www.pnas.org/doi/10.1073/pnas.2425319122
クロマチン包装領域を活用して、生体内の化学療法回避を標的とする Leveraging chromatin packing domains to target chemoevasion in vivo
Jane Frederick, Ranya K. A. Virk, I Chae Ye, +22 , and Vadim Backman
Proceedings of the National Academy of Sciences July 22, 2025
DOI:https://doi.org/10.1073/pnas.2425319122
Significance
Gaining insight into cancer cell adaptability is critical for optimizing therapeutic strategies. This study introduces a biophysical framework that links chromatin structure to therapy resistance, addressing a critical gap in our understanding of cancer cell behavior. By integrating live-cell chromatin imaging with physics-based modeling, we reveal how chromatin organization influences cell-fate decisions through its effects on transcriptional responsiveness. Our approach, grounded in the first principles of physics, accurately predicts cell survival under cytotoxic stress across diverse cancer types. Importantly, we demonstrate that coadministering chemotherapy with agents that target chromatin packing domains significantly enhances efficacy in vitro and in vivo. This new strategy offers a promising approach to combat treatment resistance, potentially transforming outcomes for cancer patients.
Abstract
Cancer cells exhibit a remarkable resilience to cytotoxic stress, often adapting through transcriptional changes linked to alterations in chromatin structure. In several types of cancer, these adaptations involve epigenetic modifications and restructuring of topologically associating domains. However, the underlying principles by which chromatin architecture facilitates such adaptability across different cancers remain poorly understood. To investigate the role of chromatin in this process, we developed a physics-based model that connects chromatin organization to cell fate decisions, such as survival following chemotherapy. Our model builds on the observation that chromatin forms packing domains, which influence transcriptional activity through macromolecular crowding. The model accurately predicts chemoevasion in vitro, suggesting that changes in packing domains affect the likelihood of survival. Consistent results across diverse cancer types indicate that the model captures fundamental principles of chromatin-mediated adaptation, independent of the specific cancer or chemotherapy mechanisms involved. Based on these insights, we hypothesized that compounds capable of modulating packing domains, termed Transcriptional Plasticity Regulators (TPRs), could prevent cellular adaptation to chemotherapy. We conducted a proof-of-concept compound screen using live-cell chromatin imaging to identify several TPRs that synergistically enhanced chemotherapy-induced cell death. The most effective TPR significantly improved therapeutic outcomes in a patient-derived xenograft model of ovarian cancer. These findings underscore the central role of chromatin in cellular adaptation to cytotoxic stress and present a framework for enhancing cancer therapies, with broad potential across multiple cancer types.
