bims-ectoca 2024-10-06 papers

Issue of 2024‒10‒06
six papers selected by
Ankita Daiya, OneCell Diagnostics Inc.

Anticancer Res. 2024 Oct;44(10): 4213-4218

Loss of Malignancy of Super-Methotrexate-resistant Osteosarcoma Cells Is Associated With an Increase of Methylated Histone Marks H3K9me3 and H3K27me3.

Yusuke Aoki, Yutaro Kubota, Noriyuki Masaki, Koya Obara, Yasunori Tome, Michael Bouvet, Kotaro Nishida, Robert M Hoffman.

BACKGROUND/AIM: Methotrexate (MTX) resistance in osteosarcoma results in a very poor patient prognosis. We previously reported that super MTX-resistant osteosarcoma (143B-MTXSR) cells, selected from parental 143B osteosarcoma (143B-P) cells by culturing them with increasing concentrations of MTX, exhibited reduced malignancy, despite the over-expression of oncogenes. The present study explored the mechanism of reduced malignancy in the super MTX-resistant osteosarcoma cells.MATERIALS AND METHODS: Previously selected 143B-MTXSR cells which are 5,500 times more MTX resistant than parental cells, were used for this study. The status of methylated histone H3K9me3 and H3K27me3 marks was examined with western immunoblotting and compared between 143B-MTXSR and parental 143B-P cells.
RESULTS: Histone H3K9me3 and H3K27me3 marks were over-expressed in 143B-MTXSR compared to 143B-P (p<0.05, p<0.01, respectively).
CONCLUSION: Over-expression of histone H3K9me3 and H3K27me3 marks may be related to super-MTX resistance and to the loss of malignancy of super MTX-resistant osteosarcoma cells due to the fundamental relationship of methylation and cancer.

Keywords: H3K27me3; H3K9me3; Osteosarcoma; histone; malignancy; methotrexate; methylation; resistance

DOI: https://doi.org/10.21873/anticanres.17251

Exp Mol Med. 2024 Oct 01.

YAP promotes global mRNA translation to fuel oncogenic growth despite starvation.

Daehee Hwang, Seonguk Baek, Jeeyoon Chang, Taejun Seol, Bomin Ku, Hongseok Ha, Hyeonji Lee, Suhyeon Cho, Tae-Young Roh, Yoon Ki Kim, Dae-Sik Lim.

Yes-associated protein (YAP) and transcriptional co-activator with PDZ-binding motif (TAZ) play fundamental roles in stem/progenitor cell expansion during homeostasis, and their dysregulation often leads to tissue overgrowth. Here, we show that YAP activation is sufficient to overcome the restriction of global protein synthesis induced by serum starvation, enabling cells to sustain proliferation and survival despite an unfavorable environment. Mechanistically, YAP/TAZ selectively promoted the mTORC1-dependent translation of mRNAs containing 5' terminal oligopyrimidine (5'TOP) motifs, ultimately increasing the cellular polysome content. Interestingly, DNA damage-inducible transcript 4 (DDIT4), a negative regulator of mTORC1, was upregulated by serum starvation but repressed by YAP/TAZ. DDIT4 was sufficient to suppress the translation and transformative potential of uveal melanoma cells, which are often serum unresponsive due to G protein mutations. Our findings reveal a vital role for protein synthesis as a key modality of YAP/TAZ-induced oncogenic transformation and indicate the potential for targeting mTORC1 or translation to treat YAP/TAZ-driven malignancies.

DOI: https://doi.org/10.1038/s12276-024-01316-w

bioRxiv. 2024 Sep 20. pii: 2024.09.17.613488. [Epub ahead of print]

Extrachromosomal DNA Associates with Nuclear Condensates and Reorganizes Chromatin Structures to Enhance Oncogenic Transcription.

Aziz Taghbalout, Chia-Hao Tung, Patricia A Clow, Ping Wang, Harianto Tjong, Chee Hong Wong, Diane D Mao, Rahul Maurya, Meng-Fan Huang, Chew Yee Ngan, Albert H Kim, Chia-Lin Wei.

Extrachromosomal, circular DNA (ecDNA) is a prevalent oncogenic alteration in cancer genomes, often associated with aggressive tumor behavior and poor patient outcome. While previous studies proposed a chromatin-based mobile enhancer model for ecDNA-driven oncogenesis, its precise mechanism and impact remains unclear across diverse cancer types. Our study, utilizing advanced multi-omics profiling, epigenetic editing, and imaging approaches in three cancer models, reveals that ecDNA hubs are an integrated part of nuclear condensates and exhibit cancer-type specific chromatin connectivity. Epigenetic silencing of the ecDNA-specific regulatory modules or chemically disrupting liquid-liquid phase separation breaks down ecDNA hubs, displaces MED1 co-activator binding, inhibits oncogenic transcription, and promotes cell death. These findings substantiate the trans -activator function of ecDNA and underscore a structural mechanism driving oncogenesis. This refined understanding expands our views of oncogene regulation and opens potential avenues for novel therapeutic strategies in cancer treatment.

DOI: https://doi.org/10.1101/2024.09.17.613488

PLoS Comput Biol. 2024 Oct 02. 20(10): e1012449

Quantitative evaluation of DNA damage repair dynamics to elucidate predictors of autism vs. cancer in individuals with germline PTEN variants.

Ruipeng Wei, Masahiro Hitomi, Tammy Sadler, Lamis Yehia, Daniela Calvetti, Jacob Scott, Charis Eng.

Persons with germline variants in the tumor suppressor gene phosphatase and tensin homolog, PTEN, are molecularly diagnosed with PTEN hamartoma tumor syndrome (PHTS). PHTS confers high risks of specific malignancies, and up to 23% of the patients are diagnosed with autism spectrum disorder (ASD) and/or developmental delay (DD). The accurate prediction of these two seemingly disparate phenotypes (cancer vs. ASD/DD) for PHTS at the individual level remains elusive despite the available statistical prevalence of specific phenotypes of the syndrome at the population level. The pleiotropy of the syndrome may, in part, be due to the alterations of the key multi-functions of PTEN. Maintenance of genome integrity is one of the key biological functions of PTEN, but no integrative studies have been conducted to quantify the DNA damage response (DDR) in individuals with PHTS and to relate to phenotypes and genotypes. In this study, we used 43 PHTS patient-derived lymphoblastoid cell lines (LCLs) to investigate the associations between DDR and PTEN genotypes and/or clinical phenotypes ASD/DD vs. cancer. The dynamics of DDR of γ-irradiated LCLs were analyzed using the exponential decay mathematical model to fit temporal changes in γH2AX levels which report the degree of DNA damage. We found that PTEN nonsense variants are associated with less efficient DNA damage repair ability resulting in higher DNA damage levels at 24 hours after irradiation compared to PTEN missense variants. Regarding PHTS phenotypes, LCLs from PHTS individuals with ASD/DD showed faster DNA damage repairing rate than those from patients without ASD/DD or cancer. We also applied the reaction-diffusion partial differential equation (PDE) mathematical model, a tumor cell growth model with a DNA damage term, to accurately describe the DDR process in the LCLs. For each LCL, we can derive parameters of the PDE. Then we averaged the numerical results by PHTS phenotypes. By performing simple subtraction of two subgroup average results, we found that PHTS-ASD/DD is associated with higher live cell density at lower DNA damage level but lower cell density level at higher DNA damage level compared to LCLs from individuals with PHTS-cancer and PHTS-neither.

DOI: https://doi.org/10.1371/journal.pcbi.1012449

Pharmacol Ther. 2024 Sep 28. pii: S0163-7258(24)00146-3. [Epub ahead of print]263 108726

Microtubule dynamics in cancer metastasis: Harnessing the underappreciated potential for therapeutic interventions.

Snehal Mangaonkar, Sangeeta Nath, Biswa Prasun Chatterji.

Microtubules, dynamic cytoskeletal structures crucial for cellular processes, have surfaced as promising targets for cancer therapy owing to their pivotal role in cancer progression and metastasis. This review comprehensively explores the multifaceted landscape of microtubule-targeting drugs and their potential to inihibit cancer metastasis. Although the role of Actin cytoskeleton is well known in controlling metastasis, only recently Microtubules are emerging as a potential controller of metastasis. We delve into the processes at the core of antimetastatic impacts of microtubule-targeting agents, both through direct modulation of microtubules and via alternative pathways. Drawing from in vitro and in vivo studies, we analyze the cytotoxic and antimetastatic doses of various compounds, shedding light on their therapeutic potential. Furthermore, we discuss the emerging class of microtubule targeting drugs, and their role in metastasis inhibition, such as microtubules acetylation inhibitory drugs, particularly histone deacetylase inihibitors and antibody-drug conjugates. Histone deacetylase (HDAC) strengthens the microtubule cytoskeleton through acetylation. Recently, HDAC inhibitors have been discovered to have antimetastatic properties. Here, the role of HDAC inhibitors in stopping metastasis is discussed with respect to microtubule cytoskeleton. Surprisingly, novel antibody conjugates of microtubule-targeting agents, which are in clinical trials, were found to be antimetastatic. This review discusses these antibody conjugates in detail. Additionally, we elucidate the intricate crosstalk between microtubules and other cytoskeletal proteins, unveiling novel therapeutic strategies for metastasis suppression. By providing a wide-ranging overview of the complex interplay between microtubules and cancer metastasis, this review contributes to the comprehension of cancer's biological mechanisms and the development of innovative therapeutic interventions to mitigate metastatic progression.

Keywords: Antibody-drug conjugates; HDAC6 inhibitors; Metastasis inhibition; Microtubule acetyaltion inhibitors; Microtubule targeting agents; Microtubule-actin crosstalk

DOI: https://doi.org/10.1016/j.pharmthera.2024.108726

bioRxiv. 2024 Sep 22. pii: 2024.09.18.613544. [Epub ahead of print]

Development and extensive sequencing of a broadly-consented Genome in a Bottle matched tumor-normal pair for somatic benchmarks.

Genome in a Bottle Consortium

The Genome in a Bottle Consortium (GIAB), hosted by the National Institute of Standards and Technology (NIST), is developing new matched tumor-normal samples, the first to be explicitly consented for public dissemination of genomic data and cell lines. Here, we describe a comprehensive genomic dataset from the first individual, HG008, including DNA from an adherent, epithelial-like pancreatic ductal adenocarcinoma (PDAC) tumor cell line (HG008-T) and matched normal cells from duodenal tissue (HG008-N-D) and pancreatic tissue (HG008-N-P). The data come from thirteen whole genome measurement technologies: Illumina paired-end, Element standard and long insert, Ultima UG100, PacBio (HiFi and Onso), Oxford Nanopore (standard and ultra-long), Bionano Optical Mapping, Arima and Phase Genomics Hi-C, G-banded karyotyping, directional genomic hybridization, and BioSkryb Genomics single-cell ResolveDNA. Most tumor data is from a large homogenous batch of non-viable cells after 23 passages of the primary tumor cells, along with some data from different passages to enable an initial understanding of genomic instability. These data will be used by the GIAB Consortium to develop matched tumor-normal benchmarks for somatic variant detection. In addition, extensive data from two different normal tissues from the same individual can enable understanding of mosaicism. Long reads also contain methylation tags for epigenetic analyses. We expect these data to facilitate innovation for whole genome measurement technologies, de novo assembly of tumor and normal genomes, and bioinformatic tools to identify small and structural somatic mutations. This first-of-its-kind broadly consented open-access resource will facilitate further understanding of sequencing methods used for cancer biology.

DOI: https://doi.org/10.1101/2024.09.18.613544