ABSTRACT Pancreatic ductal adenocarcinoma (PDAC) develops within a desmoplastic and stiffened microenvironment that critically shapes tumor progression and therapeutic resistance, yet these features are not reproduced by conventional rigid plastic culture systems. Here, we leverage a tuneable bioengineered platform that mimics stromal stiffening to investigate how mechanical cues regulate PDAC cell behaviour and to identify pharmacological strategies that counteract stiffness-driven malignancy. We show that increasing matrix stiffness promotes key hallmarks of PDAC aggressiveness, including enhanced cell spreading, focal adhesions maturation, and cytoskeletal tension. Notably, we identify the glucocorticoid budesonide as a selective suppressor of stiffness-induced malignant phenotypes. Transcriptomic profiling reveals that budesonide counteracts stiffness-associated gene programs, prominently affecting pathways governing cytoskeletal dynamics, nuclear envelope organization, and YAP nucleocytoplasmic transport. Consistently, budesonide reduced force transmission to the nucleus, restoring nuclear wrinkling and constraining nuclear size and shape. These effects are mediated through both glucocorticoid receptor-dependent and -independent mechanisms, revealing a previously unrecognized mode of action. Together, our findings establish mechanical context as a critical determinant of PDAC vulnerability and identify budesonide as a candidate for therapeutic repurposing to target stiffness–driven cancer progression.

BACKGROUND AND AIMS:Oncostatin M (OSM) has been shown to contribute to metabolic dysfunction-associated steatohepatitis (MASH) progression to hepatocellular carcinoma (HCC). Here, we investigated its role in shaping an immunosuppressive tumor microenvironment (TIME) in MASH-HCCs. APPROACH AND RESULTS:OSM role was investigated through combined analyses of MASLD/MASH patients with or without HCC, MASH-related HCCs originating in wild-type and hepatocyte-specific OSM receptor-β (hOSMRβ -/- ) deficient mice, and in vitro experiments performed on liver cancer and immune cell lines. Analysis of OSM-expressing HCC patients with mixed etiology (TCGA-database) revealed a positive correlation between OSM transcripts and those of several TIME markers. A similar pattern was also observed in murine MASH-HCC tumors. hOSMRβ -/- mice had significantly reduced tumor volume and weight without altering macrophage infiltration and OSM production. However, TIME markers transcripts were lower in HCCs from hOSMRβ -/- mice. These effects are associated with a lowering in tumor STAT3 phosphorylation and COX-2 activity. Single-cell RNA-seq analysis of human HCCs identified malignant hepatocytes as the source of CCL15, a cytokine associated with immunosuppression in HCCs. Circulating CCL15 was markedly elevated in both human and rodent MASH-HCCs and significantly reduced by hOSMRβ deletion. Blocking autocrine OSM signaling in HepG2 or Huh7 cells overexpressing OSM reduced STAT3 phosphorylation, CCL15 production, and prevented TIME markers expression by co-cultured macrophage-derived THP-1 cells. CONCLUSIONS:Our findings provide compelling evidence for an autocrine role of the OSM/OSMRβ axis in promoting CCL15 production by tumor cells, which, in turn, stimulates an immunosuppressive TIME in MASH-HCCs, suggesting OSM as a potential therapeutic target for HCC treatment.

Abstract Epigenetic regulation, particularly histone acetylation, plays a critical role in skeletal muscle differentiation by modulating gene expression programs without altering DNA sequence. Histone deacetylases (HDACs) tightly regulate myogenesis by controlling the timing of differentiation. Pharmacological inhibition of HDACs has shown context-dependent effects on muscle cells. We investigated the effects of 1 µM SAHA (suberoylanilide hydroxamic acid) on C2C12 and L6 myoblasts during differentiation using morphological, immunofluorescence, transcriptomic, and proteomic analyses. SAHA delayed early differentiation, reducing myotube formation with partial recovery at later stages. Transcriptomic analysis revealed time-dependent changes in pathways related to cytoskeleton, cell cycle, and chromatin regulation. Proteomics showed increased mitochondrial metabolism and reduced cytoskeletal components in C2C12 cells, while L6 cells displayed alterations in muscle structural and extracellular matrix proteins. SAHA induces stage- and model-dependent reprogramming of myogenesis, highlighting the importance of timing and cellular context in HDAC-targeted therapies.

Bisphenol A (BPA) belongs to the class of chemicals known as endocrine disruptors and has been also involved in the pathogenesis and progression of endocrine related cancer such as breast and prostate cancers. Here, we have investigated the effect of BPA in human prostate cancer LNCaP cells and in human non-transformed epithelial prostate EPN cells. Our data showed that BPA induces the down regulation of cyclin D1 expression and the upregulation of the cell cycle inhibitors p21 and p27, leading to cell cycle arrest. Interestingly, we found that the BPA anti-proliferative response depends on a strong and rapid activation of epidermal growth factor receptor (EGFR), which stimulates ERK-dependent pathway. This, in turn, induces expression of p53 and its phosphorylation on residue Ser15, which is responsible for cell cycle arrest. EGFR activation occurs upon a cross talk with androgen (AR) and estradiol receptor-β (ERβ) which are known to bind BPA. Altogether, these findings show a novel signaling pathway in which EGFR activation plays a key role on BPA-induced cell cycle inhibition through a pathway involving AR and ERβ/EGFR complexes, ERK and p53. Our results provide new insights for understanding the molecular mechanisms in human prostate cancer. On the other, they could allow the development of new compounds that may be used to overcome human prostate cancer resistance to endocrine therapy in promising target therapeutic approaches.

The glucocorticoid receptor (GR) has been implicated in tumor progression and therapy resistance, yet its role in ovarian cancer (OC) remains controversial. In particular, how GR integrates environmental cues to control OC plasticity and therapeutic responses is poorly understood. We investigated GR function in ovarian cancer (OC) cells by integrating genetic and pharmacological approaches. By using both OC cell lines and patient-derived cells, we performed a comprehensive set of phenotypic, molecular and functional assays alongside genome-wide transcriptomic analyses. We also extended these analyses to physiologically relevant 3D systems, including tumor spheroids and organotypic cultures, to better recapitulate the in vivo tumor microenvironment. We provided unprecedented evidence that GR modulates OC behavior in a context-dependent manner. Under 2D culture conditions, GR enhanced cellular heterogeneity, epithelial–mesenchymal transition and migration, thereby increasing cisplatin resistance. Conversely, in a 3D context, GR exerted a marked yet reversible antiproliferative effect, characterized by reduced protein synthesis and adaptative stress responses. Mechanistically, GR activity converged on inhibition of glycolysis and activation of gluconeogenesis. Indeed, pharmacological inhibition of glycolysis with 2-deoxyglucose phenocopied GR-induced mesenchymalization in 2D cultures and growth inhibition in 3D models. Moreover, inhibition of gluconeogenesis with metformin prevented the GR-dependent antiproliferative effect in 3D models. Consistently, the glucocorticoid budesonide further potentiates the anti-proliferative effects of GR in OC spheroids. Transcriptomic analyses revealed that GR regulates gene programs involved in extracellular matrix organization and cell adhesion, uncovering a previously unrecognized role for GR in tumor microenvironment remodeling. Our findings reveal distinct, context-dependent effect of GR in OC cells, whereby GR activation promotes chemoresistance and migratory behavior in 2D cultures, while inducing a reversible slow proliferative state under 3D conditions. These results underscore the importance of cellular context in interpreting GR activity and suggest that selective GR modulators, including budesonide, may offer new therapeutic avenues for treating advanced-stage OC.

Pancreatic ductal adenocarcinoma is traditionally characterized as a glycolytic tumor. However, the extent and clinical relevance of its metabolic heterogeneity remain poorly understood. In this study, we investigated whether glycolytic activity follows a consistent expression pattern across pancreatic ductal adenocarcinoma patients and explored how metabolic diversity influences therapeutic responses. Using spatial transcriptomics of ex vivo primary human pancreatic ductal adenocarcinoma specimens, along with single-cell and bulk RNA sequencing, we mapped glycolytic heterogeneity within the tumor microenvironment. Patient-derived cell models representing distinct glycolytic phenotypes were employed to assess metabolic profiles and responses to glycolytic pathway inhibition. A multiomics approach—including metabolomics, proteomics, and lipidomics—was integrated through a robust bioinformatics pipeline to identify pathway-specific variations. Our findings revealed pronounced glycolytic heterogeneity across pancreatic ductal adenocarcinoma tumors, with distinct transcriptional profiles that maintained cellular identity and spatial architecture. These glycolytic patterns are associated with clinical outcomes, suggesting their potential as prognostic indicators. Functional studies confirmed differential sensitivity to metabolic inhibitors in organoids and demonstrated their safety across models, supporting the therapeutic relevance of glycolytic stratification. Overall, this study reveals clinically significant metabolic heterogeneity in pancreatic ductal adenocarcinoma and proposes a glycolysis-based framework for patient stratification, which could guide personalized metabolic therapies and advance precision oncology in pancreatic cancer.

The incidence of metabolic dysfunction–associated steatohepatitis (MASH) – related hepatocellular carcinoma (HCC) is markedly increased in recent years, paralleling the global rise in obesity, type 2 diabetes, and metabolic syndrome. This form of HCC exhibits a distinct metabolic profile characterized by enhanced glycolysis and pentose phosphate pathway (PPP) activity. Glucose-6-phosphate dehydrogenase (G6PD), the rate-limiting enzyme of the PPP, plays a pivotal role in maintaining NADPH production, redox homeostasis, lipid metabolism, and tumour growth, thus emerging as a key determinant of metabolic adaptation and therapy resistance in MASH-related HCC. This study aims is to investigate the role of G6PD in metabolic reprogramming, immune modulation, and tumor progression in MASH-associated HCC, and to evaluate its potential as a therapeutic target.We analyzed liver specimens from MASH patients and MASH-associated HCC and integrated these data with public TCGA-LIHC datasets. In vitro studies were performed using Huh7 cells with G6PD overexpression. Experimental approaches included enzymatic activity and metabolic profiling, cell proliferation and spheroid formation assays, gene expression analysis of lipid metabolism pathways, oxidative stress and redox measurements, macrophage polarization assays, and pharmacological inhibition using G6PD-targeting compounds.Analysis of public datasets, including TCGA-LIHC, revealed that elevated G6PD expression is associated with advanced BCLC stage and poor prognosis. Further examination of paraffin-embedded liver specimens from MASH patients showed a progressive increase in G6PD levels across fibrosis stages (F0–F4), with highest expression in MASH-associated HCC versus both late-stage fibrosis (F3–F4) and HCC of viral or alcoholic aetiology.Overexpression of G6PD in Huh7 cells leads to increased enzymatic activity, resulting in altered cellular metabolism and the promotion of multiple pro-tumorigenic processes. These include (i) enhanced cell proliferation and spheroid growth, (ii) upregulation of lipid metabolism genes (FASN, PPARγ, CD36, and SREBP1c) with consequent increases in fatty acid synthesis and storage, (iii) reduced oxidative stress through NADPH production and Nrf2 activation, and (iv) polarization of macrophages toward an immunosuppressive M2-like phenotype (TGF-β, CD206, CCL22, IL-10), thereby fostering a permissive tumour microenvironment.Finally, AB109 and AB196 drugs, developed from the commercial G6PDi scaffold, produced more potent and selective inhibition of G6PD-overexpressing cells, resulting in dose-dependent anti-proliferative effect, further supporting G6PD as a promising therapeutic target.These findings outline G6PD as a pivotal regulator of metabolic reprogramming, immune evasion, and tumor progression in MASH-associated HCC, highlighting its dual potential as a prognostic biomarker and a strategic target for novel metabolism-focused therapeutic interventions.

In the original publication [...].

BACKGROUND AND OBJECTIVES:Fc gamma receptor 3A (FCGR3A) V158F polymorphism has been shown to modify the response to anti-CD20 therapy across several autoimmune diseases. Ocrelizumab (OCR), an anti-CD20 agent, suppresses inflammatory activity in multiple sclerosis (MS), yet whether FCGR3A V158F polymorphism affects its efficacy in MS remains unclear. Here, we tested whether this genetic variant influences B-cell repopulation and disease activity in MS participants treated with OCR and assessed genotype-dependent differences in OCR binding to FcγRIIIa-expressing natural killer (NK) cells. METHODS:In this observational cohort study, we enrolled people with MS treated with OCR consecutively between May 2022 and August 2025. FCGR3A V158F genotyping was performed by pyrosequencing. The primary outcome was preinfusion CD19+ B-cell repopulation, defined as CD19+ B cells ≥1%. Secondary outcomes included clinical and MRI inflammatory activity and composite disease activity/disability-worsening measures. In a parallel mechanistic ex vivo substudy, OCR or rituximab (RTX) binding to NK cells was evaluated in genotype-selected donors by flow cytometry. Cycle-based repeated measures were analyzed using mixed-effects logistic regression. RESULTS:In 101 participants, 500 interinfusion intervals were analyzed. The odds of B-cell repopulation decreased with higher cycle number (odds ratio [OR] per cycle 0.77; 95% CI 0.65-0.91; p = 0.002) and increased with longer infusion intervals (OR per +30 days, 2.02; 95% CI 1.27-3.21; p = 0.0029). FCGR3A F-carrier status significantly modified the effect of interval length (interaction OR, 2.47; 95% CI 1.04-5.89; p = 0.042). Specifically, the odds of B-cell repopulation increased with longer intervals in MS participants carrying the FCGR3A-F allele (OR, 3.67; 95% CI 1.84-7.34; p = 0.00023) but not in FCGR3A-VV individuals (OR, 1.49; 95% CI 0.87-2.54; p = 0.146). FCGR3A genotype was not associated with clinical or MRI activity outcomes. In ex vivo assays, NK cells from FCGR3A-FF donors exhibited significantly lower binding of OCR (p = 4.34 × 10-4) and RTX (p = 0.00172) as compared with VV donors. DISCUSSION:Longer OCR infusion intervals were associated with higher odds of B-cell repopulation. The FCGR3A V158F polymorphism modified this interval-dependent repopulation, possibly by affecting OCR binding to NK cells. Prospective studies are needed to determine whether FCGR3A V158F polymorphism and B-cell repletion kinetics can inform optimized interval-based OCR dosing in MS.

BACKGROUND:Chronic lymphocytic leukemia (CLL) can still be a therapeutic challenge; notwithstanding substantial progress in therapeutic approaches with small molecule inhibitors, the emergence of inhibitor resistance and suboptimal long-term outcomes highlight the persistent need for novel, more effective treatment strategies, especially targeting resistance. PATIENTS AND METHODS:Kinase activity screening was performed on UVI5008, followed by computational study. The findings were validated through a comprehensive set of in vitro and ex vivo assays, including enzymatic, cellular, transcriptional, genetic, epigenetic, and genomic assays, on primary CLL patient-derived peripheral blood mononuclear cells and cell lines, as well as through in vivo studies using genetically engineered mouse models. RESULTS:We identified a novel tyrosine kinase inhibitory activity of UVI5008, currently the only known epigenetic modulator (epi-inhibitor) that directly targets Bruton's tyrosine kinase (BTK), affecting both BTK expression and enzymatic function. Our comprehensive analysis, combining in silico, ex vivo, and in vivo approaches, revealed that UVI5008 effectively inhibits both wild-type BTK and the C481S mutated BTK isoform, commonly associated with BTK-inhibitor resistance in CLL. Treatment with UVI5008 in B-cell lymphoma and leukemia disorders led to a substantial increase in cellular apoptosis, accompanied by a notable reduction in phosphorylation and BTK protein levels, as well as attenuation of downstream signaling, thus demonstrating superior efficacy compared to ibrutinib. Ex vivo treatment of patient-derived CLL samples and in vivo murine models corroborated these results, further supporting the potential of UVI5008 as a promising therapeutic agent. CONCLUSION:UVI5008 represents a promising pharmacological alternative to current BTK inhibitors. As the first-in-class, non-covalent, reversible, BTK inhibitor and epi-inhibitor of expression. UV15008 demonstrates potent in vitro anti-tumor efficacy in relapsed/refractory CLL cells, including cases with the C481S BTK mutation and in in vivo animal studies.

Cellular plasticity refers to the ability of healthy cells to shift between phenotypic states and modify their characteristics to maintain tissue homeostasis and integrity. In the tumor context, cancer stem cells (CSCs) exploit this flexibility to withstand stress, facilitate tumor dissemination, and evade therapeutic interventions. Epigenetic regulation, particularly DNA methylation at CpG sites, is recognized as a well-known driver of tumor plasticity by repressing differentiation programs through modulation of chromatin accessibility. More recently, RNA modifications (epitranscriptomics) have emerged as crucial post-transcriptional regulators of gene expression that shape RNA fate and function. Among these, N6-methyladenosine (m6A), 5-methylcytosine (m5C), N1-methyladenosine (m1A), and N7-methylguanosine (m7G) contribute to the regulation of cell identity by modulating stemness-differentiation balance, stress adaptation, and epithelial-to-mesenchymal transition (EMT). Notably, dysregulation of both DNA and RNA methylation signatures is frequently observed in tumors, suggesting potential functional interactions between these regulatory layers. Emerging evidence indicates that DNA CpG methylation and RNA methylation pathways may cooperate to influence stemness, survival, and EMT-associated signaling, thereby supporting CSCs' plasticity. Although the molecular mechanisms underlying this crosstalk remain incompletely understood, accumulating studies suggest that DNA and RNA methylation could converge within interconnected regulatory networks that contribute to the control of cancer cell identity. A deeper understanding of these interactions may uncover novel vulnerabilities for targeting tumor plasticity. In this review, we summarize the current knowledge on the interplay between DNA and RNA methylation in regulating tumor plasticity, highlighting emerging mechanistic insights, functional interactions, and potential implications for future epigenetic and epitranscriptomic therapeutic strategies.

Pancreatic ductal adenocarcinoma (PDAC) is an aggressive malignancy characterized by a dense desmoplastic tumor microenvironment (TME) that limits drug penetration and promotes immune evasion. Effective treatment, therefore, requires simultaneous modulation of multiple signaling pathways. Here, we describe a directed polypharmacological strategy to identify dual modulators of c−MET and Smoothened (SMO), aiming to disrupt the protective stroma through SMO inhibition while directly suppressing tumor cell survival via c−MET targeting. An AI−guided virtual screening workflow combining the machine−learning platform PyRMD, trained on known c−MET and SMO ligands, with structure−based molecular docking was applied to a library of over 9 million compounds. This approach led to the identification of compound 21, an aminopyrimidine−benzamide−phenoxyquinoline derivative, as a dual c−MET/SMO inhibitor. Biochemical and cellular studies demonstrated that compound 21 selectively binds the SMO orthosteric site (pKi = 5.60), inhibits agonist−induced GLI (Glioma−associated oncogene) signaling (pIC50 = 5.50), and potently suppresses c−MET kinase activity (pIC50 = 6.94). Western blot analyses further revealed that compound 21 promotes ubiquitin−proteasome−mediated degradation of c−MET, eliminating receptor availability and limiting compensatory resistance signaling. In 3D heterotypic models comprising MIAPaCa2 pancreatic cancer cells and CAF154−hTERT fibroblasts, dual inhibition of SMO−mediated stromal support and c−MET−driven tumor progression resulted in greater cytotoxicity than the combination of the selective inhibitors Sonidegib and PHA−665752. Overall, compound 21 overcomes stromal−mediated resistance, enhances tumor cell death, and validates dual SMO/c−MET targeting as a promising single−agent therapeutic strategy for PDAC.

Dysregulation of alternative splicing is increasingly associated with cancer development and tumor progression. BCL2-associated transcription factor 1 (BCLAF1) is involved in a wide range of biological processes and it is continuously being investigated due to its intricate function in tumorigenesis and drug resistance. In acute myeloid leukemia (AML) cell lines, we identified two distinct, unbalanced isoforms of BCLAF1: the full-length isoform, which exhibits oncogenic properties, and the short-length isoform, which seems to act as a tumor suppressor. Treatment with specific epidrugs can re-establish the physiological balance of full- and short-length isoforms, restoring their correct equilibrium. Our results suggest the existence of a newly identified mechanism underlying the regulation of BCLAF1 splicing orchestrated, at least in part, by the interplay between HDAC1 and DNMT3A, and directly correlated with the healthy or cancerous state of hematopoietic cells. Our findings shed light on a novel regulatory axis in AML and highlight the potential of epidrugs to restore normal splicing patterns, paving the way for innovative therapies.

CBX7, a member of the Chromobox protein family and a core subunit of Polycomb Repressive Complex 1 (PRC1), has recently gained attention as an important regulator of chromatin organization and gene expression. In tumorigenesis, CBX7 can act as an oncogene or tumor suppressor highlighting a complex role to be investigated. In glioblastoma multiforme (GBM), CBX7 acts primarily as a tumor suppressor. Reduced CBX7 activity is related to poor patient survival by inducing glioblastoma cell hyperproliferation and invasiveness. Several molecular studies have highlighted the direct involvement of CBX7 in fundamental processes such as cell cycle regulation and the maintenance of stem-like characteristics. In GBM, epigenetic phenomena (such as hypermethylation of the CBX7 promoter region), regulation mediated by specific miRNAs, and protein-protein interactions are responsible for CBX7 downregulation. Restoring CBX7 expression in GBM reduced cell invasiveness and migration, highlighting its importance as a prognostic indicator and potential therapeutic target. Overall, current data support a model in which CBX7 operates as a crucial epigenetic regulator in glioblastoma, and its modulation may offer new opportunities for the development of targeted treatment strategies.

Although cancer treatment strategies have made considerable progress in recent decades, the challenge of selectively killing tumor cells while minimizing damage to healthy tissue remains. Radiotherapy (RT) continues to be crucial for tumor growth control when combined with surgery, chemotherapy, and immunotherapy. RT effectiveness depends on factors such as cancer type, tumor features, and the choice of external or internal treatment. Given its non-invasive nature and low systemic toxicity, RT is a suitable strategy for elderly patients. However, despite its efficacy, variations in cell sensitivity to radiation influence treatment outcomes, and normal cells surrounding the tumor can also be affected. Radiation-induced DNA damage can trigger cellular senescence, a permanent cell cycle arrest with a pro-inflammatory secretory phenotype, contributing to tissue damage in healthy cells and radio-resistance in tumor cells. RT causes not only DNA breakage but also epigenetic remodeling. Epigenetic pathways are involved in RT response, and the radiosensitivity of tumor cells can be modulated using epigenetic compounds. Emerging treatments based on more precise forms of RT, such as boron neutron capture therapy (BNCT), offer promising results by selectively targeting tumors while potentially preserving healthy tissues. BNCT has shown efficacy in glioblastoma, recurrent head and neck carcinoma, and melanoma. This review i) examines the mechanisms and challenges of conventional RT, focusing on aging and its role in treatment efficacy and tolerability, ii) describes the impact of senescence and epigenetic factors on resistance, iii) explores advances in BNCT, and iv) considers the potential of epigenetic drugs to optimize RT outcomes.

Differentially enriched hallmark gene sets after cytotoxic chemotherapy and targeted therapy of B1003b PDX tumor samples.

Aging is a key driver of cardiac dysfunction, promoting structural remodeling, metabolic alterations, and loss of cellular resilience. In aged hearts, extracellular matrix remodeling and collagen accumulation reduce ventricular compliance, impairing both diastolic function and stress adaptability. Cardiomyocytes exhibit diminished regenerative capacity and dysregulated stress responses, with mitochondrial dysfunction emerging as a central contributor to energy imbalance, oxidative stress, and fibrosis. Traditional single-omics approaches are insufficient to capture the complexity of these interconnected changes. To address this, we employed an integrative multi-omics strategy-combining spatial transcriptomics, proteomics, and metabo-lipidomics with electron microscopy-to investigate cardiac aging in mice at three life stages: adult (12 months), middle-aged (24 months), and elderly (30 months). Electron microscopy revealed enlarged, structurally compromised mitochondria. Spatial transcriptomics showed reduced expression of cardioprotective genes (MANF, CISH, and BNP) and increased expression of profibrotic markers like CTGF. Proteomics revealed widespread mitochondrial dysregulation and impaired ATP production. Metabolic and lipidomic profiling identified reduced antioxidant metabolites and accumulation of lipotoxic species, such as ceramides and diacylglycerols. This multiscale analysis highlights key molecular and metabolic alterations driving cardiac aging, identifying potential therapeutic targets to mitigate age-related functional decline. Overall, our findings highlight the value of integrated, system-level approaches for uncovering the complex mechanisms that drive organ aging. Although our study was conducted in mice, validation in human models will be crucial to establish the translational relevance of these results and to guide future research with potential impact across diverse biomedical fields.

Colorectal cancer (CRC) arises in the colorectal tissue driven by genetic disorder or the accumulation of somatic mutations, leading to abnormal epithelial cell growth. In this study, we employed single-nucleus multi-omics analysis, including single-nucleus RNA-seq and single-nucleus ATAC-seq, on over 100,000 high-quality nuclei to investigate the molecular landscape of both primary tissue and patient-derived organoids (PDOs). Our analysis showed that normal PDOs (N-PDOs) derived from tissue adjacent to tumors replicate the cellular composition and differentiation trajectory of colorectal crypts. In contrast, tumor PDOs (T-PDOs) showed patient-specific transcriptomic and epigenomic heterogeneity yet consistently maintained a stem cell-like state. T-PDOs retained the somatic mutation profile of the primary tumor while also exhibiting de novo mutations not detected in either the primary tumor or N-PDOs. Notably, inferred cell-cell interaction analysis highlighted the activin signaling pathway as a potential unique feature of fibroblast-epithelial interactions within the tumor microenvironment. This study provides a comprehensive view of the transition from normal to malignant colorectal epithelium and underscores the utility of PDOs as a faithful model for capturing both conserved and patient-specific features of colorectal cancer.

Cardiovascular disease (CVD) is the primary cause of mortality globally with a multifactorial etiology that involves epigenetics. Chromobox 3 (CBX3), the major isoform of heterochromatin protein 1, is involved in intricate epigenetic mechanisms affecting congestive heart failure. In patients with CVD affected by lung cancer risk, CBX3 exerts a sophisticated mechanism of action, suppressing the proliferation, migration, and formation of neointima in vascular smooth muscle cells (VSMCs) by affecting the Notch3 pathway, indicating a potential protective function against vascular remodeling and atherosclerosis. However, the broader im- pact of CBX3 on endothelial function, as well as its effects on monocyte/macro- phage and lymphocyte infiltration and function within the arterial wall, remain poorly understood. Since very little is known so far, more definite research would be needed to reveal the fine mechanisms of CBX3 action, along with its relationship in molecular processes and prospects as a biomarker. Specifically, CBX3 biological features could be examined to gain a greater insight into CVD risks. This review outlines the role of CBX3 in mechanisms associated with CVD and feasibility for optimizing pre-existing therapy and developing new therapeutic strategies based on personalized medicine.