bims-ectoca 2024-09-08 papers

Issue of 2024–09–08
seven papers selected by
Ankita Daiya, OneCell Diagnostics Inc.

PLoS One. 2024 ;19(9): e0304939

Mitochondrial DNA is a sensitive surrogate and oxidative stress target in oral cancer cells.

Cellular oxidative stress mediated by intrinsic and/or extrinsic reactive oxygen species (ROS) is associated with disease pathogenesis. Oxidative DNA damage can naturally be substituted by mitochondrial DNA (mtDNA), leading to base lesion/strand break formation, copy number changes, and mutations. In this study, we devised a single test for the sensitive quantification of acute mtDNA damage, repair, and copy number changes using supercoiling-sensitive quantitative PCR (ss-qPCR) and examined how oxidative stress-related mtDNA damage responses occur in oral cancer cells. We observed that exogenous hydrogen peroxide (H2O2) induced dynamic mtDNA damage responses, as reflected by early structural DNA damage, followed by DNA repair if damage did not exceed a particular threshold. However, high oxidative stress levels induced persistent mtDNA damage and caused a 5-30-fold depletion in mtDNA copy numbers over late responses. This dramatic depletion was associated with significant growth arrest and apoptosis, suggesting persistent functional consequences. Moreover, oral cancer cells responded differentially to oxidative injury when compared with normal cells, and different ROS species triggered different biological consequences under stress conditions. In conclusion, we developed a new method for the sensitive detection of mtDNA damage and copy number changes, with exogenous H2O2 inducing dynamic mtDNA damage responses associated with functional changes in stressed cancer cells. Finally, our method can help characterize oxidative DNA damage in cancer and other human diseases.

DOI: https://doi.org/10.1371/journal.pone.0304939

Nat Rev Cancer. 2024 Sep 02.

Cancer drug-tolerant persister cells: from biological questions to clinical opportunities.

The emergence of drug resistance is the most substantial challenge to the effectiveness of anticancer therapies. Orthogonal approaches have revealed that a subset of cells, known as drug-tolerant 'persister' (DTP) cells, have a prominent role in drug resistance. Although long recognized in bacterial populations which have acquired resistance to antibiotics, the presence of DTPs in various cancer types has come to light only in the past two decades, yet several aspects of their biology remain enigmatic. Here, we delve into the biological characteristics of DTPs and explore potential strategies for tracking and targeting them. Recent findings suggest that DTPs exhibit remarkable plasticity, being capable of transitioning between different cellular states, resulting in distinct DTP phenotypes within a single tumour. However, defining the biological features of DTPs has been challenging, partly due to the complex interplay between clonal dynamics and tissue-specific factors influencing their phenotype. Moreover, the interactions between DTPs and the tumour microenvironment, including their potential to evade immune surveillance, remain to be discovered. Finally, the mechanisms underlying DTP-derived drug resistance and their correlation with clinical outcomes remain poorly understood. This Roadmap aims to provide a comprehensive overview of the field of DTPs, encompassing past achievements and current endeavours in elucidating their biology. We also discuss the prospect of future advancements in technologies in helping to unveil the features of DTPs and propose novel therapeutic strategies that could lead to their eradication.

DOI: https://doi.org/10.1038/s41568-024-00737-z

Int J Cancer. 2024 Sep 06.

14-3-3σ restricts YY1 to the cytoplasm, promoting therapy resistance, and tumor progression in colorectal cancer.

Amol Lonare, Kumarkrishna Raychaudhuri, Sanket Shah, Gifty Madhu, Anoushka Sachdeva, Sneha Basu, Rahul Thorat, Sanjay Gupta, Sorab N Dalal.

14-3-3σ functions as an oncogene in colorectal cancer and is associated with therapy resistance. However, the mechanisms underlying these observations are not clear. The results in this report demonstrate that loss of 14-3-3σ in colorectal cancer cells leads to a decrease in tumor formation and increased sensitivity to chemotherapy. The increased sensitivity to chemotherapy is due to a decrease in the expression of UPR pathway genes in the absence of 14-3-3σ. 14-3-3σ promotes expression of the UPR pathway genes by binding to the transcription factor YY1 and preventing the nuclear localization of YY1. YY1, in the absence of 14-3-3σ, shows increased nuclear localization and binds to the promoter of the UPR pathway genes, resulting in decreased gene expression. Similarly, a YY1 mutant that cannot bind to 14-3-3σ also shows increased nuclear localization and is enriched on the promoter of the UPR pathway genes. Finally, inhibition of the UPR pathway with genetic or pharmacological approaches sensitizes colon cancer cells to chemotherapy. Our results identify a novel mechanism by which 14-3-3σ promotes tumor progression and therapy resistance in colorectal cancer by maintaining UPR gene expression.

Keywords: 14‐3‐3σ; 5‐fluorouracil; colorectal cancer; unfolded protein response

DOI: https://doi.org/10.1002/ijc.35176

Epigenomics. 2024 Sep 04. 1-5

Breaking the epigenetic code with MARCS: the Modification Atlas of Regulation by Chromatin States.

Andrey Tvardovskiy, Saulius Lukauskas, Till Bartke.

Keywords: Epigenetics; MARCS; chromatin modifications; histone code; online resource

DOI: https://doi.org/10.1080/17501911.2024.2387527

bioRxiv. 2024 Aug 23. pii: 2024.08.21.609031. [Epub ahead of print]

Tracking clonal evolution of drug resistance in ovarian cancer patients by exploiting structural variants in cfDNA.

Drug resistance is the major cause of therapeutic failure in high-grade serous ovarian cancer (HGSOC). Yet, the mechanisms by which tumors evolve to drug resistant states remains largely unknown. To address this, we aimed to exploit clone-specific genomic structural variations by combining scaled single-cell whole genome sequencing with longitudinally collected cell-free DNA (cfDNA), enabling clonal tracking before, during and after treatment. We developed a cfDNA hybrid capture, deep sequencing approach based on leveraging clone-specific structural variants as endogenous barcodes, with orders of magnitude lower error rates than single nucleotide variants in ctDNA (circulating tumor DNA) detection, demonstrated on 19 patients at baseline. We then applied this to monitor and model clonal evolution over several years in ten HGSOC patients treated with systemic therapy from diagnosis through recurrence. We found drug resistance to be polyclonal in most cases, but frequently dominated by a single high-fitness and expanding clone, reducing clonal diversity in the relapsed disease state in most patients. Drug-resistant clones frequently displayed notable genomic features, including high-level amplifications of oncogenes such as CCNE1 , RAB25 , NOTCH3 , and ERBB2 . Using a population genetics Wright-Fisher model, we found evolutionary trajectories of these features were consistent with drug-induced positive selection. In select cases, these alterations impacted selection of secondary lines of therapy with positive patient outcomes. For cases with matched single-cell RNA sequencing data, pre-existing and genomically encoded phenotypic states such as upregulation of EMT and VEGF were linked to drug resistance. Together, our findings indicate that drug resistant states in HGSOC pre-exist at diagnosis and lead to dramatic clonal expansions that alter clonal composition at the time of relapse. We suggest that combining tumor single cell sequencing with cfDNA enables clonal tracking in patients and harbors potential for evolution-informed adaptive treatment decisions.

DOI: https://doi.org/10.1101/2024.08.21.609031

Genes (Basel). 2024 Jul 26. pii: 988. [Epub ahead of print]15(8):

Dynamic Changes in Histone Modifications Are Associated with Differential Chromatin Interactions.

Yumin Nie, Mengjie Wang.

Eukaryotic genomes are organized into chromatin domains through long-range chromatin interactions which are mediated by the binding of architectural proteins, such as CTCF and cohesin, and histone modifications. Based on the published Hi-C and ChIP-seq datasets in human monocyte-derived macrophages, we identified 206 and 127 differential chromatin interactions (DCIs) that were not located within transcription readthrough regions in influenza A virus- and interferon β-treated cells, respectively, and found that the binding positions of CTCF and RAD21 within more than half of the DCI sites did not change. However, five histone modifications, H3K4me3, H3K27ac, H3K36me3, H3K9me3, and H3K27me3, showed significantly more dramatic changes than CTCF and RAD21 within the DCI sites. For H3K4me3, H3K27ac, H3K36me3, and H3K27me3, significantly more dramatic changes were observed outside than within the DCI sites. We further applied a motif scanning approach to discover proteins that might correlate with changes in histone modifications and chromatin interactions and found that PRDM9, ZNF384, and STAT2 frequently bound to DNA sequences corresponding to 1 kb genomic intervals with gains or losses of a histone modification within the DCI sites. This study explores the dynamic regulation of chromatin interactions and extends the current knowledge of the relationship between histone modifications and chromatin interactions.

Keywords: CTCF; differential chromatin interaction; histone modification

DOI: https://doi.org/10.3390/genes15080988

Cytoskeleton (Hoboken). 2024 Sep 06.

Characterization of open chromatin sensitive to actin polymerization and identification of core-binding factor subunit beta as mechanosensitive nucleocytoplasmic shuttling protein.

Yaxin Li, Kangjing Li, Fumihiko Nakamura.

Mechanotransduction leads to a variety of biological responses including gene expression, changes in cell shape, migration, tissue development, and immune responses. Dysregulation of mechanotransduction is implicated in the progression of various diseases such as cardiovascular diseases and cancer. The actin cytoskeleton plays a crucial role in transmitting mechanical stimuli. Actin filaments, essential for cell motility and shape changes, respond to mechanical cues by remodeling, influencing gene expression via the linker of nucleoskeleton and cytoskeleton complex and mechanosensitive transcription factors. This study employs the dithiobis(succinimidyl propionate) (DSP)-micrococcal nuclease (MNase) proteogenomics method to explore the relationship between cellular mechanosensing, chromatin architecture, and the identification of proteins involved in mechanosensitive nucleocytoplasmic shuttling, revealing how actin polymerization affects chromatin and gene expression. We found that depolymerization of actin filaments by latrunculin B (Lat B) for 30 min is sufficient to alter open chromatin and identified core-binding factor subunit beta as mechanosensitive nucleocytoplasmic shuttling protein.

Keywords: CBFB; actin; chromatin; cytoskeleton; mechanotransduction

DOI: https://doi.org/10.1002/cm.21925