bims-ectoca Biomed News
on Epigenetic control of tolerance in cancer
Issue of 2024–10–20
four papers selected by
Ankita Daiya, OneCell Diagnostics Inc.



  1. Mol Oncol. 2024 Oct 18.
      The ability of cancer cells to change and adapt poses a critical challenge to identifying curative solutions. Tumor evolution has been extensively studied from a genetic perspective, to guide clinicians in selecting the most appropriate therapeutic option based on a patient's mutational profile. However, several studies reported that tumors can evolve toward more aggressive stages or become resistant to therapies without changing their genetic makeup. Indeed, several cell-intrinsic and cell-extrinsic mechanisms contribute to tumor evolution. In this viewpoint, I focus on how chromatin, epigenetic, and transcriptional changes contribute to tumor evolution, allowing cancer cells to transition to different cell states and bypass response to therapies. Although tumor nongenetic evolution is harder to trace and predict, understanding its principles might open new therapeutic opportunities.
    Keywords:  chromatin; epigenetics; evolution; heterogeneity; transcription
    DOI:  https://doi.org/10.1002/1878-0261.13753
  2. bioRxiv. 2024 Oct 13. pii: 2024.10.11.617876. [Epub ahead of print]
      Torsional stress in chromatin plays a fundamental role in cellular functions, influencing key processes such as transcription, replication, and chromatin organization. Transcription and other processes may generate and be regulated by torsional stress. In the genome, the interplay of these processes creates complicated patterns of both positive (+) and negative (-) torsion. However, a challenge in generating an accurate torsion map is determining the zero-torsion baseline signal, which is conflated with chromatin accessibility. Here, we introduce a high-resolution method based on the intercalator trimethylpsoralen (TMP) to address this challenge. We describe a method to establish the zero-torsion baseline while preserving the chromatin state of the genome. This approach enables both high-resolution mapping of accessibility and torsional stress in chromatin in the cell. Our analysis reveals transcription-generated torsional domains consistent with the twin-supercoiled-domain model of transcription and suggests a role for torsional stress in recruiting topoisomerases and in regulating 3D genome architecture via cohesin. This new method provides a potential path forward for using TMP to measure torsional stress in the genome without the confounding contribution of accessibility in chromatin.
    DOI:  https://doi.org/10.1101/2024.10.11.617876
  3. bioRxiv. 2024 Oct 13. pii: 2024.10.11.617852. [Epub ahead of print]
      Hippo-YAP signaling orchestrates epithelial tissue repair and is therefore an attractive target in regenerative medicine. Yet it is unresolved how YAP controls the underlying transient proliferative response. Here we show that YAP-TEAD activation increases the nuclear cyclin D1/p27 protein ratio in G1 phase, towards a threshold level that dictates whether individual cells enter or exit the cell cycle. YAP increases this ratio indirectly, by increasing EGFR and other receptor activities that signal primarily through ERK. Conversely, contact inhibition suppresses YAP activity which gradually downregulates mitogen signaling and the cyclin D1/p27 ratio. Increasing YAP activity by ablating the suppressor Merlin/NF2 reveals a robust balancing mechanism in which YAP can still be inhibited after cell division further increases local cell density. Thus, critical for tissue repair, the proliferation response is intrinsically transient since the YAP-induced and mitogen-mediated increase in the cyclin D1/p27 ratio is reliably reversed through delayed contact inhibition of YAP.
    HIGHLIGHTS: YAP signaling controls cell cycle entry and exit by up- and down-regulating the cyclin D1/p27 ratio above and below a conserved thresholdYAP-induced proliferation is intrinsically transient since contact inhibition of YAP suppresses EGFR signaling after a delay to reduce this cyclin D1/p27 ratioYAP can still be robustly inhibited after Merlin/NF2 ablation but only at higher local cell densityThe YAP-regulated cyclin D1/p27 ratio is primarily controlled by MEK-ERK rather than mTOR activity.
    DOI:  https://doi.org/10.1101/2024.10.11.617852
  4. Pharmacol Rev. 2024 Oct 15. pii: PHARMREV-AR-2023-001049. [Epub ahead of print]
      Precision cancer medicine is widely established, and numerous molecularly targeted drugs for various tumor entities are approved or in development. Personalized pharmacotherapy in oncology has so far been based primarily on tumor characteristics, e.g., somatic mutations. However, the response to drug treatment also depends on pharmacological processes summarized under the term ADME (absorption, distribution, metabolism, and excretion). Variations in ADME genes have been the subject of intensive research for more than five decades, considering individual patients' genetic makeup, referred to as pharmacogenomics (PGx). The combined impact of a patient's tumor and germline genome is only partially understood and often not adequately considered in cancer therapy. This may be attributed, in part, to the lack of methods for combined analysis of both data layers. Optimized personalized cancer therapies should, therefore, aim to integrate molecular information about the tumor and the germline, taking into account existing PGx guidelines for drug therapy. Moreover, such strategies should provide the opportunity to consider genetic variants of previously unknown functional significance. Bioinformatic analysis methods and corresponding algorithms for data interpretation need to be developed to consider PGx data in interdisciplinary molecular tumor boards, where cancer patients are discussed to provide evidence-based recommendations for clinical management based on individual tumor profiles. Significance Statement The era of personalized oncology has seen the emergence of drugs tailored to genetic variants associated with cancer biology. However, full potential of targeted therapy remains untapped due to the predominant focus on acquired tumor-specific alterations. Optimized cancer care must integrate tumor and patient genomes, guided by pharmacogenomic principles. An essential prerequisite for realizing truly personalized drug treatment of cancer patients is the development of bioinformatic tools for comprehensive analysis of all data layers generated in modern precision oncology programs.
    Keywords:  Cytochrome P450 (CYP); Transporter-mediated drug/metabolite disposition; cancer; clinical pharmacology; cytochrome P450 function; drug; drug efficacy; pharmacogenetics/pharmacogenomics
    DOI:  https://doi.org/10.1124/pharmrev.124.001049