bims-ectoca 2025-01-05 papers

Issue of 2025–01–05
five papers selected by
Ankita Daiya, OneCell Diagnostics Inc.

Cancer Res. 2025 Jan 02. 85(1): 7-9

Persistence and/or Senescence: Not So Lasting at Last?

Therapy-exposed surviving cancer cells may have encountered profound epigenetic remodeling that renders these drug-tolerant persisters candidate drivers of particularly aggressive relapses. Typically presenting as slow-to-nongrowing cells, persisters are senescent or senescence-like cells. In this issue of Cancer Research, Ramponi and colleagues study mTOR/PI3K inhibitor-induced embryonic diapause-like arrest (DLA) as a model of persistence in lung cancer and melanoma cells and compare this persister condition with therapy-induced senescence in the same cells. The DLA phenotype recapitulated some but not all features attributed to senescent cells, lacking, for instance, an inflammatory secretome otherwise known as the senescence-associated secretory phenotype. A CRISPR dropout screen pointed to methyl group-providing one-carbon metabolism and further to H4K20me3-mediated repression of senescence-associated secretory phenotype-related IFN response genes selectively in DLA-like persister cells. Conversely, inhibition of H4K20-active KMT5B/C methyltransferases derepressed inflammatory programs and was toxic in DLA cells. These findings not only suggest exploitable vulnerabilities of DLA-like persister cells but also unveil general technical and conceptual challenges of cultured multipassage cell line-based persister studies. Collectively, the approach chosen and insights obtained will stimulate a productive scientific debate on senescence-like features and their reversibility across drug-tolerant persister cells. See related article by Ramponi et al., p. 32.

DOI: https://doi.org/10.1158/0008-5472.CAN-24-3744

Histochem Cell Biol. 2025 Jan 03. 163(1): 23

Differential cell architecture and microenvironmental responses of pretumoral and tumoral cellular models exposed to coverslip-induced hypoxia.

Magdalena Millán, Felipe Parietti, Florencia Lamela, María Cecilia De Rossi, Belén Benítez, Valeria Levi, Manoela Domingues, Ronell Bologna-Molina, Miguel Arocena, Jimena Hochmann.

The tumor microenvironment is an altered milieu that imposes multiple selective pressures leading to the survival and dissemination of aggressive and fit tumor cell subpopulations. How pre-tumoral and tumoral cells respond to changes in their microenvironment will determine the subsequent evolution of the tumor. In this study, we have subjected pre-tumoral and tumoral cells to coverslip-induced hypoxia, which recapitulates the intracellular hypoxia and extracellular acidification characteristic of the early tumor microenvironment, and we have used a combination of quantitative phase microscopy and epifluorescence to analyze diverse cellular responses to this altered environment. In normoxia, tumor cells showed differences in nuclear organization, as evidenced by decreased numbers of HP1 foci, and in hypoxia major changes in nuclear architecture were observed, with tumor cells significantly increasing the number of high dry mass density foci in the nucleus compared to pre-tumoral and non-tumoral cells. Conversely, compared to pre-tumoral and normal cells, mitochondrial ATP levels decayed markedly in tumor cells in hypoxia, whereas the activation of executioner caspases increased only in tumor cells in this condition. Therefore, in terms of cellular organization, metabolic changes and activation of cell death processes, tumor cells showed more dramatic responses to an altered microenvironment than their pre-tumoral and normal counterparts, responses which in turn could play fundamental roles in shaping future tumor development.

Keywords: Hypoxia; Nuclear architecture; Pre-tumoral cells; Tumor development

DOI: https://doi.org/10.1007/s00418-024-02350-5

Nucleic Acids Res. 2024 Dec 31. pii: gkae1251. [Epub ahead of print]

Hybrid exons evolved by coupling transcription initiation and splicing at the nucleotide level.

Steven T Mick, Christine L Carroll, Maritere Uriostegui-Arcos, Ana Fiszbein.

Exons within transcripts are traditionally classified as first, internal or last exons, each governed by different regulatory mechanisms. We recently described the widespread usage of 'hybrid' exons that serve as terminal or internal exons in different transcripts. Here, we employ an interpretable deep learning pipeline to dissect the sequence features governing the co-regulation of transcription initiation and splicing in hybrid exons. Using ENCODE data from human tissues, we identified 80 000 hybrid first-internal exons. These exons often possess a relaxed chromatin state, allowing transcription initiation within the gene body. Interestingly, transcription start sites of hybrid exons are typically centered at the 3' splice site, suggesting tight coupling between splicing and transcription initiation. We identified two subcategories of hybrid exons: the majority resemble internal exons, maintaining strong 3' splice sites, while a minority show enrichment in promoter elements, resembling first exons. Diving into the evolution of their sequences, we found that human hybrid exons with orthologous first exons in other species usually gained 3' splice sites or whole exons upstream, while those with orthologous internal exons often gained promoter elements. Overall, our findings unveil the intricate regulatory landscape of hybrid exons and reveal stronger connections between transcription initiation and RNA splicing than previously acknowledged.

DOI: https://doi.org/10.1093/nar/gkae1251

Cancer Med. 2025 Jan;14(1): e70542

Efficacy and Safety of Chemotherapy or EGFR-TKIs as First-Line Therapy in NSCLC Patients Harboring Non-Ex 20 Ins Uncommon EGFR Mutations: A Retrospective Study in China.

Chen Liao, Li Bai, Tingting He, Qingle Liang, Defeng Hu, Shipeng Lei, Yong He, Yubo Wang.

BACKGROUND: Uncommon EGFR mutations are a kind of heterogeneous group of mutations with various responses to EGFR-TKIs and are often excluded from most prospective clinical trials. In this real-world retrospective study, we retrospectively compared the efficacy and safety of chemotherapy or various generations of EGFR-TKIs as first-line therapy in NSCLC Chinese patients harboring non-ex 20 ins uncommon EGFR mutations.
METHODS: We enrolled 139 NSCLC patients with non-ex 20 ins uncommon EGFR mutations in this study retrospectively. Patients' clinical characteristics and the efficacy and safety of different first-line therapies were analyzed and compared.
RESULTS: Our data reviewed that for first-line therapy, NSCLC patients harboring non-ex 20 ins uncommon EGFR mutations benefited more from EGFR-TKIs compared with chemotherapy. Afatinib performed with great efficacy for the majority of non-ex 20 ins uncommon EGFR mutations (N = 43, ORR = 41.86%, mPFS = 13.5 months, mOS = 20.8 months), especially in L861Q mutation (mPFS = 18.4 months). Osimertinib also demonstrated efficacy in patients harboring non-ex 20 ins uncommon EGFR mutations (N = 36, ORR = 27.78%, mPFS = 10.0 months, mOS = 21.0 months), especially in those without L861Q and G719X mutations (mPFS = 12.1 months). When treated with afatinib, patients harboring non-ex 20 ins uncommon EGFR mutations should pay attention to the management of safety, especially for gastrointestinal-related AE and rash, while osimertinib was safer.
CONCLUSION: Taking into account both efficacy and safety, afatinib and osimertinib are better choices than chemotherapy and first-generation EGFR-TKIs for NSCLC patients with non-ex 20 ins uncommon EGFR mutations. L861Q showed a trend toward a better response to afatinib, while in those without L861Q and G719X mutations, osimertinib might be a better choice. Safety also should be a concern when choosing EGFR-TKI for treatment, patients should pay attention to the management of safety when using afatinib while osimertinib is safer.

Keywords: EGFR‐TKI; NSCLC; efficacy; safety; uncommon EGFR mutation

DOI: https://doi.org/10.1002/cam4.70542

Genome Biol. 2024 Dec 30. 25(1): 320

Chromatin-based memory as a self-stabilizing influence on cell identity.

Charles C Bell, Geoffrey J Faulkner, Omer Gilan.

Cell types are traditionally thought to be specified and stabilized by gene regulatory networks. Here, we explore how chromatin memory contributes to the specification and stabilization of cell states. Through pervasive, local, feedback loops, chromatin memory enables cell states that were initially unstable to become stable. Deeper appreciation of this self-stabilizing role for chromatin broadens our perspective of Waddington's epigenetic landscape from a static surface with islands of stability shaped by evolution, to a plasticine surface molded by experience. With implications for the evolution of cell types, stabilization of resistant states in cancer, and the widespread plasticity of complex life.

DOI: https://doi.org/10.1186/s13059-024-03461-x