bims-ectoca 2024-10-13 papers

Issue of 2024–10–13
four papers selected by
Ankita Daiya, OneCell Diagnostics Inc.

Mol Oncol. 2024 Oct 06.

Combined blockade of GPX4 and activated EGFR/HER3 bypass pathways inhibits the development of ALK-inhibitor-induced tolerant persister cells in ALK-fusion-positive lung cancer.

Koh Furugaki, Takaaki Fujimura, Narumi Sakaguchi, Yasutaka Watanabe, Ken Uchibori, Eisaku Miyauchi, Hidetoshi Hayashi, Ryohei Katayama, Shigeki Yoshiura.

Cancers can develop resistance to treatment with ALK tyrosine kinase inhibitors (ALK-TKIs) via emergence of a subpopulation of drug-tolerant persister (DTP) cells that can survive initial drug treatment long enough to acquire genetic aberrations. DTP cells are thus a potential therapeutic target. We generated alectinib-induced DTP cells from a patient-derived ALK+ non-small-cell lung cancer (NSCLC) cell line and screened 3114 agents in the anticancer compounds library (TargetMol). We identified phospholipid hydroperoxide glutathione peroxidase GPX4 as being involved in promoting the survival of DTP cells. GPX4 was found to be upregulated in DTP cells and to promote cell survival by suppressing reactive oxygen species (ROS) accumulation; GPX4 inhibitors blocked this upregulation and facilitated ROS-mediated cell death. Activated bypass signals involving epidermal growth factor receptor (EGFR)/receptor tyrosine-protein kinase erbB-3 (HER3) were also identified in DTP cells, and co-treatment with EGFR-TKI plus ALK-TKI enhanced ROS levels. Triple combination with an ALK-TKI plus a bypass pathway inhibitor plus a GPX4 inhibitor suppressed cell growth and induced intracellular ROS accumulation more greatly than did treatment with each agent alone. The combined inhibition of ALK plus inhibition of activated bypass signals plus inhibition of GPX4 may be a potent therapeutic strategy for patients with ALK+ NSCLC to prevent the development of resistance to ALK-TKIs and lead to tumor eradication.

Keywords: ALK; EGFR; FGFR; GPX4; drug‐tolerant persister

DOI: https://doi.org/10.1002/1878-0261.13746

Mol Cells. 2024 Oct 07. pii: S1016-8478(24)00146-8. [Epub ahead of print] 100121

Practical approaches for visualization of endogenous enhancer-promoter interactions in a single nucleus through chromatin labeling.

Gunhee Park, Won-Ki Cho.

Recent studies highlight the critical role of nuclear genome organization in regulating gene expression. Dynamic changes in the hierarchical structure of chromatin modulate transcription by influencing the recruitment of transcription factors and altering the epigenetic landscape. Among these regulatory mechanisms, enhancer-promoter (E-P) interactions are of particular importance. Enhancers physically interact with the promoters of target genes, a process mediated by various co-activators, which facilitates the transfer of enhancer-bound transcription factors and ultimately leads to transcriptional bursting. While next-generation sequencing techniques have provided significant insights into the features of E-P interactions, the effects of cell-to-cell heterogeneity and the physical dynamics of these interactions remain poorly understood due to the lack of spatiotemporal information. In this article, we introduce a platform that enables imaging-based approaches to visualize E-P interactions at the single-cell level.

Keywords: CRISPR; Chromatin labeling; E-P interaction; MS2 tagging; TetO-TetR

DOI: https://doi.org/10.1016/j.mocell.2024.100121

Exp Mol Med. 2024 Oct 11.

Histone lysine methylation modifiers controlled by protein stability.

Sungryul Park, Jin Hwa Cho, Jeong-Hoon Kim, Jung-Ae Kim.

Histone lysine methylation is pivotal in shaping the epigenetic landscape and is linked to cell physiology. Coordination of the activities of multiple histone lysine methylation modifiers, namely, methyltransferases and demethylases, modulates chromatin structure and dynamically alters the epigenetic landscape, orchestrating almost all DNA-templated processes, such as transcription, DNA replication, and DNA repair. The stability of modifier proteins, which is regulated by protein degradation, is crucial for their activity. Here, we review the current knowledge of modifier-protein degradation via specific pathways and its subsequent impact on cell physiology through epigenetic changes. By summarizing the functional links between the aberrant stability of modifier proteins and human diseases and highlighting efforts to target protein stability for therapeutic purposes, we aim to promote interest in defining novel pathways that regulate the degradation of modifiers and ultimately increase the potential for the development of novel therapeutic strategies.

DOI: https://doi.org/10.1038/s12276-024-01329-5

Proc Natl Acad Sci U S A. 2024 Oct 15. 121(42): e2411672121

Nuclear compensatory evolution driven by mito-nuclear incompatibilities.

Debora Princepe, Marcus A M de Aguiar.

Mitochondrial function relies on the coordinated expression of mitochondrial and nuclear genes, exhibiting remarkable resilience despite high mitochondrial mutation rates. The nuclear compensation mechanism suggests deleterious mitochondrial alleles drive compensatory nuclear mutations to preserve mito-nuclear compatibility. However, prevalence and factors conditioning this phenomenon remain debated due to its conflicting evidence. Here, we investigate how mito-nuclear incompatibilities impact substitutions in a model for species radiation. Mating success depends on genetic compatibility (nuclear DNA) and spatial proximity. Populations evolve from partially compatible mito-nuclear states, simulating mitochondrial DNA (mtDNA) introgression. Mutations do not confer advantages nor disadvantages, but individual fecundity declines with increasing incompatibilities, selecting for mito-nuclear coordination. We find that selection for mito-nuclear compatibility affects each genome differently based on their initial state. In compatible gene pairs, selection reduces substitutions in both genomes, while in incompatible nuclear genes, it consistently promotes compensation, facilitated by more mismatches. Interestingly, high mitochondrial mutation rates can reduce nuclear compensation by increasing mtDNA rectification, while substitutions in initially compatible nuclear gene are boosted. Finally, the presence of incompatibilities accelerates species radiation, but equilibrium richness is not directly correlated to substitution rates, revealing the complex dynamics triggered by mitochondrial introgression and mito-nuclear coevolution. Our study provides a perspective on nuclear compensation and the role of mito-nuclear incompatibilities in speciation by exploring extreme scenarios and identifying trends that empirical data alone cannot reveal. We emphasize the challenges in detecting these dynamics and propose analyzing specific genomic signatures could shed light on this evolutionary process.

Keywords: mito-nuclear coevolution; mitochondrial mutation rate; mtDNA introgression; nuclear compensation

DOI: https://doi.org/10.1073/pnas.2411672121