bims-ectoca Biomed News
on Epigenetic control of tolerance in cancer
Issue of 2024‒03‒10
seven papers selected by
Ankita Daiya, BITS Pilani
  1. Joint analysis of mutational and transcriptional landscapes in human cancer reveals key perturbations during cancer evolution.
  2. MYC activity at enhancers drives prognostic transcriptional programs through an epigenetic switch.
  3. Inheritance of epigenetic transcriptional memory.
  4. On epigenetic stochasticity, entropy and cancer risk.
  5. Discovery of non-genomic drivers of YAP signaling modulating the cell plasticity in CRC tumor lines.
  6. Changes in chromatin accessibility and transcriptional landscape induced by HDAC inhibitors in TP53 mutated patient-derived colon cancer organoids.
  7. Social influence and external feedback control in humans.
  1. Genome Biol. 2024 Mar 08. 25(1): 65
    Joint analysis of mutational and transcriptional landscapes in human cancer reveals key perturbations during cancer evolution.
    Jae-Won Cho, Jingyi Cao, Martin Hemberg.
      BACKGROUND: Tumors are able to acquire new capabilities, including traits such as drug resistance and metastasis that are associated with unfavorable clinical outcomes. Single-cell technologies have made it possible to study both mutational and transcriptomic profiles, but as most studies have been conducted on model systems, little is known about cancer evolution in human patients. Hence, a better understanding of cancer evolution could have important implications for treatment strategies.RESULTS: Here, we analyze cancer evolution and clonal selection by jointly considering mutational and transcriptomic profiles of single cells acquired from tumor biopsies from 49 lung cancer samples and 51 samples with chronic myeloid leukemia. Comparing the two profiles, we find that each clone is associated with a preferred transcriptional state. For metastasis and drug resistance, we find that the number of mutations affecting related genes increases as the clone evolves, while changes in gene expression profiles are limited. Surprisingly, we find that mutations affecting ligand-receptor interactions with the tumor microenvironment frequently emerge as clones acquire drug resistance.
    CONCLUSIONS: Our results show that lung cancer and chronic myeloid leukemia maintain a high clonal and transcriptional diversity, and we find little evidence in favor of clonal sweeps. This suggests that for these cancers selection based solely on growth rate is unlikely to be the dominating driving force during cancer evolution.
    Keywords:  Cancer evolution; Clonal selection; Drug resistance; Genetic-transcription perturbation; Metabolism; Metastasis; Tumor microenvironment
    DOI:  https://doi.org/10.1186/s13059-024-03201-1
  2. Nat Genet. 2024 Mar 07.
    MYC activity at enhancers drives prognostic transcriptional programs through an epigenetic switch.
    Simon T Jakobsen, Rikke A M Jensen, Maria S Madsen, Tina Ravnsborg, Christian S Vaagenso, Majken S Siersbæk, Hjorleifur Einarsson, Robin Andersson, Ole N Jensen, Rasmus Siersbæk.
      The transcription factor MYC is overexpressed in most cancers, where it drives multiple hallmarks of cancer progression. MYC is known to promote oncogenic transcription by binding to active promoters. In addition, MYC has also been shown to invade distal enhancers when expressed at oncogenic levels, but this enhancer binding has been proposed to have low gene-regulatory potential. Here, we demonstrate that MYC directly regulates enhancer activity to promote cancer type-specific gene programs predictive of poor patient prognosis. MYC induces transcription of enhancer RNA through recruitment of RNA polymerase II (RNAPII), rather than regulating RNAPII pause-release, as is the case at promoters. This process is mediated by MYC-induced H3K9 demethylation and acetylation by GCN5, leading to enhancer-specific BRD4 recruitment through its bromodomains, which facilitates RNAPII recruitment. We propose that MYC drives prognostic cancer type-specific gene programs through induction of an enhancer-specific epigenetic switch, which can be targeted by BET and GCN5 inhibitors.
    DOI:  https://doi.org/10.1038/s41588-024-01676-z
  3. Curr Opin Genet Dev. 2024 Feb 29. pii: S0959-437X(24)00023-6. [Epub ahead of print]85 102174
    Inheritance of epigenetic transcriptional memory.
    Tiffany Ge, Jason H Brickner.
      Epigenetic memory allows organisms to stably alter their transcriptional program in response to developmental or environmental stimuli. Such transcriptional programs are mediated by heritable regulation of the function of enhancers and promoters. Memory involves read-write systems that enable self-propagation and mitotic inheritance of cis-acting epigenetic marks to induce stable changes in transcription. Also, in response to environmental cues, cells can induce epigenetic transcriptional memory to poise inducible genes for faster induction in the future. Here, we discuss modes of epigenetic inheritance and the molecular basis of epigenetic transcriptional memory.
    DOI:  https://doi.org/10.1016/j.gde.2024.102174
  4. Philos Trans R Soc Lond B Biol Sci. 2024 Apr 22. 379(1900): 20230054
    On epigenetic stochasticity, entropy and cancer risk.
    Andrew E Teschendorff.
      Epigenetic changes are known to accrue in normal cells as a result of ageing and cumulative exposure to cancer risk factors. Increasing evidence points towards age-related epigenetic changes being acquired in a quasi-stochastic manner, and that they may play a causal role in cancer development. Here, I describe the quasi-stochastic nature of DNA methylation (DNAm) changes in ageing cells as well as in normal cells at risk of neoplastic transformation, discussing the implications of this stochasticity for developing cancer risk prediction strategies, and in particular, how it may require a conceptual paradigm shift in how we select cancer risk markers. I also describe the mounting evidence that a significant proportion of DNAm changes in ageing and cancer development are related to cell proliferation, reflecting tissue-turnover and the opportunity this offers for predicting cancer risk via the development of epigenetic mitotic-like clocks. Finally, I describe how age-associated DNAm changes may be causally implicated in cancer development via an irreversible suppression of tissue-specific transcription factors that increases epigenetic and transcriptomic entropy, promoting a more plastic yet aberrant cancer stem-cell state. This article is part of a discussion meeting issue 'Causes and consequences of stochastic processes in development and disease'.
    Keywords:  DNA methylation; ageing; cancer risk; epigenetic clock; stochasticity
    DOI:  https://doi.org/10.1098/rstb.2023.0054
  5. iScience. 2024 Mar 15. 27(3): 109247
    Discovery of non-genomic drivers of YAP signaling modulating the cell plasticity in CRC tumor lines.
    Nobuhiko Ogasawara, Yoshihito Kano, Yosuke Yoneyama, Sakurako Kobayashi, Satoshi Watanabe, Sakura Kirino, Fausto D Velez-Bravo, Yourae Hong, Aleksandra Ostapiuk, Pavlo Lutsik, Iichiroh Onishi, Shinichi Yamauchi, Yui Hiraguri, Go Ito, Yusuke Kinugasa, Kenichi Ohashi, Mamoru Watanabe, Ryuichi Okamoto, Sabine Tejpar, Shiro Yui.
      In normal intestines, a fetal/regenerative/revival cell state can be induced upon inflammation. This plasticity in cell fate is also one of the current topics in human colorectal cancer (CRC). To dissect the underlying mechanisms, we generated human CRC organoids with naturally selected genetic mutation profiles and exposed them to two different conditions by modulating the extracellular matrix (ECM). Among tested mutation profiles, a fetal/regenerative/revival state was induced following YAP activation via a collagen type I-enriched microenvironment. Mechanistically, YAP transcription was promoted by activating AP-1 and TEAD-dependent transcription and suppressing intestinal lineage-determining transcription via mechanotransduction. The phenotypic conversion was also involved in chemoresistance, which could be potentially resolved by targeting the underlying YAP regulatory elements, a potential target of CRC treatment.
    Keywords:  Cancer; Classification Description; Stem cell plasticity; Transcriptomics
    DOI:  https://doi.org/10.1016/j.isci.2024.109247
  6. Biomed Pharmacother. 2024 Mar 04. pii: S0753-3322(24)00258-0. [Epub ahead of print]173 116374
    Changes in chromatin accessibility and transcriptional landscape induced by HDAC inhibitors in TP53 mutated patient-derived colon cancer organoids.
    Teresa Gagliano, Emanuela Kerschbamer, Umberto Baccarani, Martina Minisini, Eros Di Giorgio, Emiliano Dalla, Christian X Weichenberger, Vittorio Cherichi, Giovanni Terrosu, Claudio Brancolini.
      Here we present the generation and characterization of patient-derived organoids (PDOs) from colorectal cancer patients. PDOs derived from two patients with TP53 mutations were tested with two different HDAC inhibitors (SAHA and NKL54). Cell death induction, transcriptome, and chromatin accessibility changes were analyzed. HDACIs promote the upregulation of low expressed genes and the downregulation of highly expressed genes. A similar differential effect is observed at the level of chromatin accessibility. Only SAHA is a potent inducer of cell death, which is characterized by the upregulation of BH3-only genes BIK and BMF. Up-regulation of BIK is associated with increased accessibility in an intronic region that has enhancer properties. SAHA, but not NKL54, also causes downregulation of BCL2L1 and decreases chromatin accessibility in three distinct regions of the BCL2L1 locus. Both inhibitors upregulate the expression of innate immunity genes and members of the MHC family. In summary, our exploratory study indicates a mechanism of action for SAHA and demonstrate the low efficacy of NKL54 as a single agent for apoptosis induction, using two PDOs. These observations need to be validated in a larger cohort of PDOs.
    Keywords:  Apoptosis; BCL2; HDAC; MHC; TP53
    DOI:  https://doi.org/10.1016/j.biopha.2024.116374
  7. F1000Res. 2023 ;12 438
    Social influence and external feedback control in humans.
    Martin Weiß, Mario Gollwitzer, Johannes Hewig.
      This article aims to unravel the dynamics of social influence by examining the processes that occur when one person is the target of another's influence. We hypothesized that these processes are part of a feedback loop system in an individual. This loop involves the situation (input), a goal state (reference), a comparator, a selection mechanism, a feedback predictor, and an action (output). Each element can become the target of social influence, and different types of social influence can be classified and explained by how these elements are targeted. For instance, attempting to persuade another person with strong arguments targets the goal state of the affected individual, while obedience targets the selection mechanism, and violence targets the action. In summary, this article aims to categorize, order, and explain phenomena in social influence research using a feedback loop framework focusing on the influenced individual.
    Keywords:  feedback control; social influence; social interaction
    DOI:  https://doi.org/10.12688/f1000research.133295.3
This page is being maintained by Thomas Krichel. It was last updated on 2024‒03‒18 at 7:52.