bims-ectoca 2024-08-18 papers

Issue of 2024–08–18
five papers selected by
Ankita Daiya, OneCell Diagnostics Inc.

Signal Transduct Target Ther. 2024 Aug 14. 9(1): 209

Drug tolerant persister cell plasticity in cancer: A revolutionary strategy for more effective anticancer therapies.

Jun He, Zejing Qiu, Jingjing Fan, Xiaohong Xie, Qinsong Sheng, Xinbing Sui.

Non-genetic mechanisms have recently emerged as important drivers of anticancer drug resistance. Among these, the drug tolerant persister (DTP) cell phenotype is attracting more and more attention and giving a predominant non-genetic role in cancer therapy resistance. The DTP phenotype is characterized by a quiescent or slow-cell-cycle reversible state of the cancer cell subpopulation and inert specialization to stimuli, which tolerates anticancer drug exposure to some extent through the interaction of multiple underlying mechanisms and recovering growth and proliferation after drug withdrawal, ultimately leading to treatment resistance and cancer recurrence. Therefore, targeting DTP cells is anticipated to provide new treatment opportunities for cancer patients, although our current knowledge of these DTP cells in treatment resistance remains limited. In this review, we provide a comprehensive overview of the formation characteristics and underlying drug tolerant mechanisms of DTP cells, investigate the potential drugs for DTP (including preclinical drugs, novel use for old drugs, and natural products) based on different medicine models, and discuss the necessity and feasibility of anti-DTP therapy, related application forms, and future issues that will need to be addressed to advance this emerging field towards clinical applications. Nonetheless, understanding the novel functions of DTP cells may enable us to develop new more effective anticancer therapy and improve clinical outcomes for cancer patients.

DOI: https://doi.org/10.1038/s41392-024-01891-4

Transl Oncol. 2024 Aug 08. pii: S1936-5233(24)00196-7. [Epub ahead of print]49 102069

Drug tolerance and persistence in bacteria, fungi and cancer cells: Role of non-genetic heterogeneity.

Imane El Meouche, Paras Jain, Mohit Kumar Jolly, Jean-Pascal Capp.

A common feature of bacterial, fungal and cancer cell populations upon treatment is the presence of tolerant and persistent cells able to survive, and sometimes grow, even in the presence of usually inhibitory or lethal drug concentrations, driven by non-genetic differences among individual cells in a population. Here we review and compare data obtained on drug survival in bacteria, fungi and cancer cells to unravel common characteristics and cellular pathways, and to point their singularities. This comparative work also allows to cross-fertilize ideas across fields. We particularly focus on the role of gene expression variability in the emergence of cell-cell non-genetic heterogeneity because it represents a possible common basic molecular process at the origin of most persistence phenomena and could be monitored and tuned to help improve therapeutic interventions.

Keywords: Antibiotics; Antifungal; Chemotherapy; Drug persistence; Drug tolerance; Phenotypic heterogeneity; Stochastic gene expression; Targeted therapy

DOI: https://doi.org/10.1016/j.tranon.2024.102069

bioRxiv. 2024 Aug 10. pii: 2024.08.10.607443. [Epub ahead of print]

YAP charge patterning mediates signal integration through transcriptional co-condensates.

Kirstin Meyer, Klaus Yserentant, Rasmi Cheloor-Kovilakam, Kiersten M Ruff, Chan-I Chung, Xiaokun Shu, Bo Huang, Orion D Weiner.

Transcription factor dynamics are used to selectively engage gene regulatory programs. Biomolecular condensates have emerged as an attractive signaling substrate in this process, but the underlying mechanisms are not well-understood. Here, we probed the molecular basis of YAP signal integration through transcriptional condensates. Leveraging light-sheet single-molecule imaging and synthetic condensates, we demonstrate charge-mediated co-condensation of the transcriptional regulators YAP and Mediator into transcriptionally active condensates in stem cells. IDR sequence analysis and YAP protein engineering demonstrate that instead of the net charge, YAP signaling specificity is established through its negative charge patterning that interacts with Mediator's positive charge blocks. The mutual enhancement of YAP/Mediator co-condensation is counteracted by negative feedback from transcription, driving an adaptive transcriptional response that is well-suited for decoding dynamic inputs. Our work reveals a molecular framework for YAP condensate formation and sheds new light on the function of YAP condensates for emergent gene regulatory behavior.

DOI: https://doi.org/10.1101/2024.08.10.607443

Cell Death Discov. 2024 Aug 14. 10(1): 365

Regulation of Hippo/YAP axis in colon cancer progression by the deubiquitinase JOSD1.

Yanan Sun, Dongyi Liu, Xiaobo Zhang, Peng Su, Xin Li, Zhongbo Li, Yingwen Gai, Jingying Li, Zhiyong Yang, Yinlu Ding, Jian Zhu, Xiaodong Tan.

Colon cancer is a prevalent malignancy, while recent studies revealed the dys-regulation of Hippo signaling as the important driver for colon cancer progression. Several studies have indicated that post-translational modifications on YAP play crucial roles in both Hippo signaling activity and cancer progression. This raises a puzzling question about why YAP/TAZ, an auto-inhibitory pathway, is frequently over-activated in colon cancer, despite the suppressive cascade of Hippo signaling remaining operational. The protein stability of YAP is subject to a tiny balance between ubiquitination and deubiquitination processes. Through correlation analysis of DUBs (deubiquitinases) expression and Hippo target gene signature in colon cancer samples, we found JOSD1 as a critical deubiquitinase for Hippo signaling and colon cancer progression. JOSD1 could facilitate colon cancer progression and in colon cancer, inhibition of JOSD1 via shRNA has been demonstrated to impede tumorigenesis. Furthermore, molecular mechanism studies have elucidated that JOSD1 enhances the formation of the Hippo/YAP transcriptome by impeding K48-linked polyubiquitination on YAP. ChIP assays have shown that YAP binds to JOSD1's promoter region, promoting its gene transcription. These results suggest that JOSD1 is involved in both activating and being targeted by the Hippo signaling pathway in colon cancer. Consequently, a positive regulatory loop between JOSD1 and Hippo signaling has been identified, underscoring their interdependence during colon cancer progression. Thus, targeting JOSD1 may represent a promising therapeutic approach for managing colon cancer.

DOI: https://doi.org/10.1038/s41420-024-02136-7

Transl Cancer Res. 2024 Jul 31. 13(7): 3556-3574

Stratifying osteosarcoma patients using an epigenetic modification-related prognostic signature: implications for immunotherapy and chemotherapy selection.

Zhichao Li, Yong Xue, Xianxing Huang, Gang Xiao.

Background: Osteosarcoma (OS) poses significant challenges in treatment and lacks reliable prognostic markers. Epigenetic alterations play a crucial role in disease progression. This study aimed to develop an accurate prognostic signature for OS using epigenetic modification genes (EMGs).
Methods: The Therapeutically Applicable Research to Generate Effective Treatments (TARGET)-OS cohort was analyzed. Univariate Cox analysis identified survival-associated EMGs. Based on least absolute shrinkage and selection operator (LASSO) regression and multivariate analysis, a 6-gene prognostic signature termed the epigenetic modification-related prognostic signature (EMRPS) was derived in the testing cohort. Kaplan-Meier and receiver operating characteristic (ROC) curve analysis confirmed predictive accuracy through internal and external validation (GEO accession GSE21257). A prognostic nomogram incorporating EMRPS and clinical features was constructed. Transcriptomic analysis including differential gene expression, Gene Ontology (GO), gene set enrichment analysis (GSEA), and immune infiltration analysis was conducted to explore mechanisms linking EMRPS to OS prognosis. Additionally, EMRPS impact on drug sensitivity was predicted.
Results: A 6-gene EMRPS comprising DDX24, DNAJC1, HDAC4, SIRT7, SP140 and UHRF2 was successfully developed. The high-risk group showed significantly shorter survival, consistently observed in both internal and external validation. EMRPS demonstrated high predictive efficacy for 1-, 3-, and 5-year overall survival, with area under curve (AUC) >0.85 in training and ~0.7 in testing. The nomogram integrating age, gender, metastasis status, and EMRPS exhibited high predictive performance based on concordance index analysis. Mechanistic analysis indicated the low-risk group had increased immune infiltration and activity with higher immune checkpoint expression, reflecting an immune-activated tumor microenvironment (TME) suitable for immunotherapy. Drug sensitivity analysis revealed the low-risk group had increased sensitivity to cisplatin, a first-line OS chemotherapy.
Conclusions: Our study successfully established an efficient EMRPS and nomogram, highlighting their potential as novel prognostic markers and indicators for selecting appropriate immunotherapy and chemotherapy candidates in OS treatment.

Keywords: Osteosarcoma (OS); epigenetic modification; immunotherapy; nomogram; prognostic signature

DOI: https://doi.org/10.21037/tcr-23-2300