bims-ectoca 2024-12-01 papers

bims-ectoca

Biomed News

on Epigenetic control of tolerance in cancer

Issue of 2024–12–01
thirteen papers selected by
Ankita Daiya, OneCell Diagnostics Inc.

The Hippo Signaling Pathway, Reactive Oxygen Species Production, and Oxidative Stress: A Two-Way Traffic Regulation.
The Hippo pathway as an antitumor target: time to focus on.
Altered Mechanobiology of PDAC Cells with Acquired Chemoresistance to Gemcitabine and Paclitaxel.
Cancers adapt to their mutational load by buffering protein misfolding stress.
EZH2 directly methylates PARP1 and regulates its activity in cancer.
Tumor Site-Specific In Vivo Theranostics Enabled by Microenvironment-Dependent Chemical Transformation and Self-Amplifying Effect.
In silico screening of phytochemicals against chromatin modifier, SETD7 for remodeling of the immunosuppressive tumor microenvironment in renal cancer.
Empowering Precision Oncology: Advancing Cancer Research by Augmenting Single-cell RNA and Bulk RNA Sequencing for Confronting the Heterogeneity in Ovarian Cancer.
Interplay between epigenetics, senescence and cellular redox metabolism in cancer and its therapeutic implications.
Next-generation combination approaches for immune checkpoint therapy.
Association of epigenetic landscapes with heterogeneity and plasticity in pancreatic cancer.
Collateral lethality: A unique type of synthetic lethality in cancers.
Ancestral differences in anti-cancer treatment efficacy and their underlying genomic and molecular alterations.

Cells. 2024 Nov 11. pii: 1868. [Epub ahead of print]13(22):

The Hippo Signaling Pathway, Reactive Oxygen Species Production, and Oxidative Stress: A Two-Way Traffic Regulation.

Bella Amanda, Rangga Pragasta, Haris Cakrasana, Arifa Mustika, Zakiyatul Faizah, Delvac Oceandy.

  The Hippo signaling pathway is recognized for its significant role in cell differentiation, proliferation, survival, and tissue regeneration. Recently, the Hippo signaling pathway was also found to be associated with oxidative stress and reactive oxygen species (ROS) regulation, which are important in the regulation of cell survival. Studies indicate a correlation between components of the Hippo signaling pathway, including MST1, YAP, and TAZ, and the generation of ROS. On the other hand, ROS and oxidative stress can activate key components of the Hippo signaling pathway. For example, ROS production activates MST1, which subsequently phosphorylates FOXO3, leading to apoptotic cell death. ROS was also found to regulate YAP, in addition to MST1/2. Oxidative stress and ROS formation can impair lipids, proteins, and DNA, leading to many disorders, including aging, neurodegeneration, atherosclerosis, and diabetes. Consequently, understanding the interplay between the Hippo signaling pathway, ROS, and oxidative stress is crucial for developing future disease management strategies. This paper aimed to review the association between the Hippo signaling pathway, regulation of ROS production, and oxidative stress to provide beneficial information in understanding cell function and pathological processes.

Keywords:  Hippo pathway; good health and well-being; oxidative stress; reactive oxygen species; the mammalian Ste20-like kinases; yes-associated protein

DOI:  https://doi.org/10.3390/cells13221868
Expert Opin Investig Drugs. 2024 Nov 26. 1-9

The Hippo pathway as an antitumor target: time to focus on.

Olga A Koroleva, Alexander V Kurkin, Alexander A Shtil.

   INTRODUCTION: The Hippo signaling governs the expression of genes critically important for cell proliferation and survival. The components of this pathway are considered antitumor drug targets. However, the design of Hippo inhibitors is a challenge given the complexity of the network and redundancy of its elements.
AREAS COVERED: We review the current state-of-the-art in the structure of the Hippo pathway, the microenvironment-induced extracellular cues, the strategies to design pharmacological instruments for inactivation of the Hippo signaling using small molecular weight modulators, as well as the results of initial clinical trials.
EXPERT OPINION: One special characteristic of the Hippo signaling is the adverse role of phosphorylation: opposite to classical kinase cascades that activate the transcription factors, the Hippo kinases retain their partners in a transcriptionally inactive state. Therefore, approaches for pharmacological or genetic inhibition of Hippo protein kinases are counterproductive. The developing alternatives such as disruption of protein-protein interactions or PROTAC techniques are straightforward for preventing the Hippo signaling in cancer therapy.

Keywords:  Hippo pathway; TEAD protein; YAP/TAZ proteins; antitumor treatment; low molecular weight inhibitors; transcription

DOI:  https://doi.org/10.1080/13543784.2024.2432395
Cancers (Basel). 2024 Nov 18. pii: 3863. [Epub ahead of print]16(22):

Altered Mechanobiology of PDAC Cells with Acquired Chemoresistance to Gemcitabine and Paclitaxel.

Alessandro Gregori, Cecilia Bergonzini, Mjriam Capula, Rick Rodrigues de Mercado, Erik H J Danen, Elisa Giovannetti, Thomas Schmidt.

  Background: Pancreatic ductal adenocarcinoma acquired resistance to chemotherapy poses a major limitation to patient survival. Despite understanding some biological mechanisms of chemoresistance, much about those mechanisms remains to be uncovered. Mechanobiology, which studies the physical properties of cells, holds promise as a potential target for addressing the challenges of chemoresistance in PDAC. Therefore, we, here in an initial step, assessed the altered mechanobiology of PDAC cells with acquired chemoresistance to gemcitabine and paclitaxel. Methods: Five PDAC cell lines and six stably resistant subclones were assessed for force generation on elastic micropillar arrays. Those measurements of mechanical phenotype were complemented by single-cell motility and invasion in 3D collagen-based matrix assays. Further, the nuclear translocation of Yes-associated protein (YAP), as a measure of active mechanical status, was compared, and biomarkers of the epithelial-to-mesenchymal transition (EMT) were evaluated using RT-qPCR. Results: The PDAC cells with acquired chemoresistance exert higher traction forces than their parental/wild-type (WT) cells. In 2D, single-cell motility was altered for all the chemoresistant cells, with a cell-type specific pattern. In 3D, the spheroids of the chemoresistant PDAC cells were able to invade the matrix and remodel collagen more than their WT clones. However, YAP nuclear translocation and EMT were not significantly altered in relation to changes in other physical parameters. Conclusions: This is the first study to investigate and report on the altered mechanobiological features of PDAC cells that have acquired chemoresistance. A better understanding of mechanical features could help in identifying future targets to overcome chemoresistance in PDAC.

Keywords:  PDAC; chemoresistance; mechanobiology

DOI:  https://doi.org/10.3390/cancers16223863
Elife. 2024 Nov 25. pii: RP87301. [Epub ahead of print]12

Cancers adapt to their mutational load by buffering protein misfolding stress.

Susanne Tilk, Judith Frydman, Christina Curtis, Dmitri A Petrov.

  In asexual populations that don't undergo recombination, such as cancer, deleterious mutations are expected to accrue readily due to genome-wide linkage between mutations. Despite this mutational load of often thousands of deleterious mutations, many tumors thrive. How tumors survive the damaging consequences of this mutational load is not well understood. Here, we investigate the functional consequences of mutational load in 10,295 human tumors by quantifying their phenotypic response through changes in gene expression. Using a generalized linear mixed model (GLMM), we find that high mutational load tumors up-regulate proteostasis machinery related to the mitigation and prevention of protein misfolding. We replicate these expression responses in cancer cell lines and show that the viability in high mutational load cancer cells is strongly dependent on complexes that degrade and refold proteins. This indicates that the upregulation of proteostasis machinery is causally important for high mutational burden tumors and uncovers new therapeutic vulnerabilities.

Keywords:  cancer; cancer biology; evolutionary biology; human; mutational load; proteostasis; somatic evolution

DOI:  https://doi.org/10.7554/eLife.87301
Sci Adv. 2024 Nov 29. 10(48): eadl2804

EZH2 directly methylates PARP1 and regulates its activity in cancer.

Qingshu Meng, Jiangchuan Shen, Yanan Ren, Qi Liu, Rui Wang, Qiaqia Li, Weihua Jiang, Quan Wang, Yixiang Zhang, Jonathan C Trinidad, Xiaotong Lu, Tingyou Wang, Yanqiang Li, Chaehyun Yum, Yang Yi, Yongyong Yang, Dongyu Zhao, Clair Harris, Sundeep Kalantry, Kaifu Chen, Rendong Yang, Hengyao Niu, Qi Cao.

DNA repair dysregulation is a key driver of cancer development. Understanding the molecular mechanisms underlying DNA repair dysregulation in cancer cells is crucial for cancer development and therapies. Here, we report that enhancer of zeste homolog 2 (EZH2) directly methylates poly(adenosine diphosphate-ribose) polymerase-1 (PARP-1), an essential enzyme involved in DNA repair, and regulates its activity. Functionally, EZH2-catalyzed methylation represses PARP1 catalytic activity, down-regulates the recruitment of x-ray repair cross-complementing group-1 to DNA lesions and its associated DNA damage repair; on the other hand, it protects the cells from nicotinamide adenine dinucleotide overconsumption upon DNA damage formation. Meanwhile, EZH2-mediated methylation regulates PARP1 transcriptional and oncogenic activity, at least in part, through impairing PARP1-E2F1 interaction and E2F1 transcription factor activity. EZH2 and PARP1 inhibitors synergistically suppress prostate cancer growth. Collectively, our findings uncover an insight of EZH2 functions in fine-tuning PARP1 activity during DNA damage repair and cancer progression, which provides a rationale for combinational targeting EZH2 and PARP1 in cancer.

DOI: https://doi.org/10.1126/sciadv.adl2804
Adv Sci (Weinh). 2024 Nov 29. e2409506

Tumor Site-Specific In Vivo Theranostics Enabled by Microenvironment-Dependent Chemical Transformation and Self-Amplifying Effect.

Yunfei Zuo, Pei Li, Wen-Jin Wang, Changhuo Xu, Shuting Xu, Herman H Y Sung, Jianwei Sun, Guorui Jin, Weiping Wang, Ryan T K Kwok, Jacky W Y Lam, Ben Zhong Tang.

  Precise tumor diagnosis and treatment remain complex challenges. While numerous fluorescent probes have been developed for tumor-specific imaging and therapy, few exhibit effective function in vivo. Herein, a probe called TQ-H2 is designed that can realize robust theranostic effects both in vitro and in vivo. In vitro, TQ-H2 specifically targets the lysosome and reacts with hydroxyl radical (·OH) to generate TQ-HA, which lights up the cells. TQ-HA generates reactive oxygen species (ROS) under light irradiation, enabling the simultaneous induction and monitoring of apoptosis and ferroptosis in tumor cells. Remarkably, TQ-HA also acts as a self-amplifier, autocatalytically activating TQ-H2 by generating ·OH under light exposure. This self-amplification aligns with the tumor microenvironment, where TQ-H2 undergoes chemical transformation, distinguishing tumors from healthy tissue via near-infrared (NIR) fluorescence imaging. Furthermore, ROS generated by TQ-HA effectively kills tumor cells and inhibits tumor growth without harming normal cells. This study offers a promising strategy for targeted tumor theranostics using self-amplifying microenvironment-responsive fluorescent probes.

Keywords:  aggregation‐induced emission; autocatalytic reaction; cancer theranostics; hydroxyl radical probes; specific targeting

DOI:  https://doi.org/10.1002/advs.202409506
Mol Divers. 2024 Nov 27.

In silico screening of phytochemicals against chromatin modifier, SETD7 for remodeling of the immunosuppressive tumor microenvironment in renal cancer.

Nikhil Gadewal, Diya Patidar, Abhiram Natu, Sanjay Gupta, Virupaksha Bastikar.

  The tumor microenvironment and immune evasion function in a complex cellular network profoundly challenge the clinical outcome of promising therapies. Our recently published study reported that the subset of genes upregulated in ccRCC due to H3K4me1 and DNA demethylation potentially leads to an immunosuppressive environment. Thus, modulating H3K4me1 chromatin modifier SETD7 with a natural inhibitor in combination with immunotherapy might improve the immune landscape for a better therapeutic outcome. The present study was conducted via virtual screening and MD simulation using compounds from the literature, IMPPAT, and SuperNatural database. The phytochemical IMPHY002979 showed better binding affinity and lower energy than the reported R-PFI-2 and cyproheptadine inhibitors. The phytochemicals interact with the SET domain through H-bonding, as confirmed by MD simulation and molecular interaction analysis. Further, the compound was assessed using ADME parameters and free energy estimation, showing better pharmacokinetic properties. Therefore, the non-accessibility of the histone methyltransferase activity domain of SET7 with IMPHY002979 can downregulate H3K4me1 and, thereby, the expression of genes potentially responsible for immunosuppressive TME. Thus, patient stratification based on molecular markers for immunotherapy and combining epigenetic modulators with therapeutic drugs will improve the efficacy of immunotherapy in ccRCC.

Keywords:  Epigenetic; Natural inhibitor; Phytochemical; SETD7

DOI:  https://doi.org/10.1007/s11030-024-11038-w
J Midlife Health. 2024 Jul-Sep;15(3):15(3): 194-196

Empowering Precision Oncology: Advancing Cancer Research by Augmenting Single-cell RNA and Bulk RNA Sequencing for Confronting the Heterogeneity in Ovarian Cancer.

Muhammed Ali Siham, A Ashwin Prabahar.

  Ovarian cancer presents significant challenges in clinical oncology due to its high prevalence, heterogeneity, and late-stage diagnosis. Our study explores the application of single-cell RNA sequencing (scRNA-Seq) and bulk RNA sequencing to enhance our understanding of ovarian cancer at the molecular level. We highlight the diagnostic strategies and emphasize the critical role of scRNA-Seq in unraveling the intricate cellular composition and phenotypic plasticity within ovarian tumors. We also discuss the identification of rare cell subtypes, characterization of distinct cell types, and elucidation of molecular features, signaling pathways, and dysregulated networks using scRNA-Seq. Furthermore, our study showcases how scRNA-Seq aids in the discovery of novel biomarkers for diagnosis, prognosis, and treatment response prediction, as well as identifying therapeutic targets and pathways associated with drug resistance.

Keywords:  Bulk RNA sequencing; cellular composition; ovarian cancer; single-cell RNA sequencing; tumors

DOI:  https://doi.org/10.4103/jmh.jmh_93_23
Redox Biol. 2024 Nov 23. pii: S2213-2317(24)00419-1. [Epub ahead of print]78 103441

Interplay between epigenetics, senescence and cellular redox metabolism in cancer and its therapeutic implications.

Geoffrey Balamurli, Angeline Qiu Xia Liew, Wee Wei Tee, Shazib Pervaiz.

  There is accumulating evidence indicating a close crosstalk between key molecular events regulating cell growth and proliferation, which could profoundly impact carcinogenesis and its progression. Here we focus on reviewing observations highlighting the interplay between epigenetic modifications, irreversible cell cycle arrest or senescence, and cellular redox metabolism. Epigenetic alterations, such as DNA methylation and histone modifications, dynamically influence tumour transcriptome, thereby impacting tumour phenotype, survival, growth and spread. Interestingly, the acquisition of senescent phenotype can be triggered by epigenetic changes, acting as a double-edged sword via its ability to suppress tumorigenesis or by facilitating an inflammatory milieu conducive for cancer progression. Concurrently, an aberrant redox metabolism, which is a function of the balance between reactive oxygen species (ROS) generation and intracellular anti-oxidant defences, influences signalling cascades and genomic stability in cancer cells by serving as a critical link between epigenetics and senescence. Recognizing this intricate interconnection offers a nuanced perspective for therapeutic intervention by simultaneously targeting specific epigenetic modifications, modulating senescence dynamics, and restoring redox homeostasis.

Keywords:  Cancer; Epigenetic modifications; Redox status; SASP; Senescence

DOI:  https://doi.org/10.1016/j.redox.2024.103441
Nat Immunol. 2024 Dec;25(12): 2186-2199

Next-generation combination approaches for immune checkpoint therapy.

Sangeeta Goswami, Kristen E Pauken, Linghua Wang, Padmanee Sharma.

Immune checkpoint therapy has revolutionized cancer treatment, leading to dramatic clinical outcomes for a subset of patients. However, many patients do not experience durable responses following immune checkpoint therapy owing to multiple resistance mechanisms, highlighting the need for effective combination strategies that target these resistance pathways and improve clinical responses. The development of combination strategies based on an understanding of the complex biology that regulates human antitumor immune responses has been a major challenge. In this Review, we describe the current landscape of combination therapies. We also discuss how the development of effective combination strategies will require the integration of small, tissue-rich clinical trials, to determine how therapy-driven perturbation of the human immune system affects downstream biological responses and eventual clinical outcomes, reverse translation of clinical observations to immunocompetent preclinical models, to interrogate specific biological pathways and their impact on antitumor immune responses, and novel computational methods and machine learning, to integrate multiple datasets across clinical and preclinical studies for the identification of the most relevant pathways that need to be targeted for successful combination strategies.

DOI: https://doi.org/10.1038/s41590-024-02015-4
Crit Rev Oncol Hematol. 2024 Nov 22. pii: S1040-8428(24)00316-0. [Epub ahead of print]206 104573

Association of epigenetic landscapes with heterogeneity and plasticity in pancreatic cancer.

Paul Manoukian, Leo C Kuhnen, Hanneke W M van Laarhoven, Maarten F Bijlsma.

  Pancreatic ductal adenocarcinoma (PDAC) has a poor prognosis. Due to a lack of clear symptoms, patients often present with advanced disease, with limited clinical intervention options. The high mortality rate of PDAC is, however, also a result of several other factors that include a high degree of heterogeneity and treatment resistant cellular phenotypes. Molecular subtypes of PDAC have been identified that are thought to represent cellular phenotypes at the tissue level. The epigenetic landscape is an important factor that dictates these subtypes. Permissive epigenetic landscapes serve as drivers of molecular heterogeneity and cellular plasticity in developing crypts as well as metaplastic lesions. Drawing parallels with other cancers, we hypothesize that epigenetic permissiveness is a potential driver of cellular plasticity in PDAC. In this review will explore the epigenetic alterations that underlie PDAC cell states and relate them to cellular plasticity from other contexts. In doing so, we aim to highlight epigenomic drivers of PDAC heterogeneity and plasticity and, with that, offer some insight to guide pre-clinical research.

Keywords:  Cell state; Epigenetics; Heterogeneity; Hybrid chromatin states; Pancreatic ductal adenocarcinoma; Plasticity

DOI:  https://doi.org/10.1016/j.critrevonc.2024.104573
Pharmacol Ther. 2024 Nov 23. pii: S0163-7258(24)00175-X. [Epub ahead of print]265 108755

Collateral lethality: A unique type of synthetic lethality in cancers.

Zichen Zhao, Lingling Zhu, Yu Luo, Heng Xu, Yan Zhang.

  Genetic interactions play crucial roles in cell-essential functions. Intrinsic genetic defects in tumors typically involve gain-of- and loss-of-function mutations in tumor suppressor genes (TSGs) and oncogenes, respectively, providing potential antitumor vulnerabilities. Moreover, tumor cells with TSG deficiencies exhibit heightened sensitivity to the inhibition of compensatory pathways. Synthetic and collateral lethality are two strategies used for exploiting novel drug targets in multiple types of cancer. Collateral lethality is a unique type of synthetic lethality that occurs when passenger genes are co-deleted in neighboring TSGs. Although synthetic lethality has already been successfully demonstrated in clinical practice, antitumor therapeutics based on collateral lethality are predominantly still in the preclinical phase. Therefore, screening for potential genetic interactions within the cancer genome has emerged as a promising approach for drug development. Here, the two conceptual therapeutic strategies that involve the deletion or inactivation of cancer-specific TSGs are discussed. Moreover, existing approaches for screening and identifying potential gene partners are also discussed. Particularly, this review highlights the current advances of "collateral lethality" in the preclinical phase and addresses the challenges involved in translating them into therapeutic applications. This review provides insights into these strategies as new opportunities for the development of personalized antitumor therapies.

Keywords:  Collateral lethality; Genomic vulnerabilities; Passenger deletions; Synthetic lethality; Tumor suppressor gene

DOI:  https://doi.org/10.1016/j.pharmthera.2024.108755
Cancer Discov. 2024 Nov 27.

Ancestral differences in anti-cancer treatment efficacy and their underlying genomic and molecular alterations.

Mei Luo, Jingwen Yang, Alejandro A Schaffer, Chengxuan Chen, Yuan Liu, Yamei Chen, Chunru Lin, Lixia Diao, Yong Zang, Yanyan Lou, Huda Salman, Gordon B Mills, Eytan Ruppin, Leng Han.

Systematic multi-omics analysis revealed ancestry-dependent molecular alterations, but their impact on the efficacy of anti-cancer treatment is yet largely unknown. Here, we analyzed clinical trials from ClinicalTrials.gov and found that only 8,779/102,721 (8.5%) oncology clinical trials posted information on enrollment by race/ethnicity. The underrepresentation of non-White populations suggests that it remains challenging to determine differences in the efficacy of anti-tumor treatments among different racial groups. Through a comprehensive analysis of clinically actionable genes, imputed drug responses, and immune features, we identified potential differences in treatment response to targeted, chemo and immunotherapies between different ancestral populations. Further analysis of multiple independent cohorts confirmed some of our key findings. Such potential ancestral effects are also identified in response to emerging new treatments like CAR-T therapy and PROTACs. These findings are made publicly available in a comprehensive web portal, Ancestral Differences of Efficacy in Cancers (ADEC; https://hanlaboratory.com/ADEC), to facilitate their further investigation.

DOI: https://doi.org/10.1158/2159-8290.CD-24-0827