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Jessica Okosun, Csaba Bödör and colleagues performed whole-genome or whole-exome sequencing on 10 follicular lymphoma and transformed follicular lymphoma pairs, followed by deep sequencing of 28 target genes in an additional 122 cases. They identify recurrent mutations in linker histone genes and genes involved in JAK-STAT signaling, NF-κB signaling and B cell development. Follicular lymphoma is an incurable malignancy 1 , with transformation to an aggressive subtype representing a critical event during disease progression. Here we performed whole-genome or whole-exome sequencing on 10 follicular lymphoma–transformed follicular lymphoma pairs followed by deep sequencing of 28 genes in an extension cohort, and we report the key events and evolutionary processes governing tumor initiation and transformation. Tumor evolution occurred through either a 'rich' or 'sparse' ancestral common progenitor clone (CPC). We identified recurrent mutations in linker histone, JAK-STAT signaling, NF-κB signaling and B cell developmental genes. Longitudinal analyses identified early driver mutations in chromatin regulator genes ( CREBBP , EZH2 and KMT2D (MLL2)), whereas mutations in EBF1 and regulators of NF-κB signaling ( MYD88 and TNFAIP3 ) were gained at transformation. Collectively, this study provides new insights into the genetic basis of follicular lymphoma and the clonal dynamics of transformation and suggests that personalizing therapies to target key genetic alterations in the CPC represents an attractive therapeutic strategy.

Epigenetic alteration has been proposed to give rise to numerous classic hallmarks of cancer. Impaired DNA methylation plays a central role in the onset and progression of several types of malignancies, and DNA methylation is mediated by DNA methyltransferases (DNMTs) consisting of DNMT1, DNMT3A, and DNMT3B. DNMTs are frequently implicated in the pathogenesis and aggressiveness of acute myeloid leukaemia (AML) patients. In this review, we describe and discuss the oncogenic roles of DNMT1, DNMT3A, and DNMT3B in AML. The clinical response predictive roles of DNMTs in clinical trials utilising hypomethylating agents (azacitidine and decitabine) in AML patients are presented. Novel hypomethylating agent (guadecitabine) and experimental DNMT inhibitors in AML are also discussed. In summary, hypermethylation of tumour suppressors mediated by DNMT1 or DNMT3B contributes to the progression and severity of AML (except MLL-AF9 and inv(16)(p13;q22) AML for DNMT3B), while mutation affecting DNMT3A represents an early genetic lesion in the pathogenesis of AML. In clinical trials of AML patients, expression of DNMTs is downregulated by hypomethylating agents while the clinical response predictive roles of DNMT biomarkers remain unresolved. Finally, nucleoside hypomethylating agents have continued to show enhanced responses in clinical trials of AML patients, and novel non-nucleoside DNMT inhibitors have demonstrated cytotoxicity against AML cells in pre-clinical settings.

Highlights This paper reviews the fundamentals and research progress of carbon-based multivariable chemical sensors, with a particular focus on the classification and identification of multiple analytes. Carbon-based multivariable chemical sensors consisting of carbon nanotubes/graphene as the sensing material and field effect transistors as the transducers are discussed in detail. A comprehensive analysis of multivariable sensing mechanisms is presented and design criteria for carbon-based multivariable sensors are summarized. Over recent decades, carbon-based chemical sensor technologies have advanced significantly. Nevertheless, significant opportunities persist for enhancing analyte recognition capabilities, particularly in complex environments. Conventional monovariable sensors exhibit inherent limitations, such as susceptibility to interference from coexisting analytes, which results in response overlap. Although sensor arrays, through modification of multiple sensing materials, offer a potential solution for analyte recognition, their practical applications are constrained by intricate material modification processes. In this context, multivariable chemical sensors have emerged as a promising alternative, enabling the generation of multiple outputs to construct a comprehensive sensing space for analyte recognition, while utilizing a single sensing material. Among various carbon-based materials, carbon nanotubes (CNTs) and graphene have emerged as ideal candidates for constructing high-performance chemical sensors, owing to their well-established batch fabrication processes, superior electrical properties, and outstanding sensing capabilities. This review examines the progress of carbon-based multivariable chemical sensors, focusing on CNTs/graphene as sensing materials and field-effect transistors as transducers for analyte recognition. The discussion encompasses fundamental aspects of these sensors, including sensing materials, sensor architectures, performance metrics, pattern recognition algorithms, and multivariable sensing mechanism. Furthermore, the review highlights innovative multivariable extraction schemes and their practical applications when integrated with advanced pattern recognition algorithms.

The tumor microenvironment (TME) is reprogrammed by cancer cells and participates in all stages of tumor progression. The contribution of stromal cells to the reprogramming of the TME is not well understood. Here, we provide evidence of the role of the cytokine oncostatin M (OSM) as central node for multicellular interactions between immune and nonimmune stromal cells and the epithelial cancer cell compartment. OSM receptor (OSMR) deletion in a multistage breast cancer model halted tumor progression. We ascribed causality to the stromal function of the OSM axis by demonstrating reduced tumor burden of syngeneic tumors implanted in mice lacking OSMR. Single-cell and bioinformatic analysis of murine and human breast tumors revealed that OSM expression was restricted to myeloid cells, whereas OSMR was detected predominantly in fibroblasts and, to a lower extent, cancer cells. Myeloid-derived OSM reprogrammed fibroblasts to a more contractile and tumorigenic phenotype and elicited the secretion of VEGF and proinflammatory chemokines CXCL1 and CXCL16, leading to increased myeloid cell recruitment. Collectively, our data support the notion that the stromal OSM/OSMR axis reprograms the immune and nonimmune microenvironment and plays a key role in breast cancer progression.

The discovery of the intrarenal renin-angiotensin system (iRAS), which regulates angiogenesis, cell differentiation and proliferation, has opened new perspectives in the knowledge of kidney carcinogenesis. In this study we analyzed the immunohistochemical expression and fluorimetric activity of four key peptidases of iRAS in tumor tissue (n = 144) and serum samples (n = 128) from patients with renal neoplasms. Neutral endopeptidase (NEP/CD10), Angiotensin-converting enzyme-2 (ACE2), and aminopeptidase A (APA) were expressed in tumor cells whilst Angiotensin-converting enzyme (ACE) was expressed in the endothelial cells of intratumor blood vessels. The expression of ACE, ACE2 and NEP/CD10 was highest in clear cell renal cell carcinoma (CCRCC) and papillary renal cell carcinoma (PRCC). The expression of these enzymes correlated with CCRCC aggressiveness. In addition, NEP/CD10 correlated with 15-year overall survival. On the other hand, APA expression was decreased in CCRCC with higher grade and stage. The loss of expression of APA independently correlated with a worse 15-year overall survival. Serum activity of ACE2, NEP/CD10 and APA was significantly higher in renal tumor patients than in healthy subjects. Serum ACE activity was lower in high grade and metastatic CCRCC patients, and NEP/CD10 activity was negatively correlated with UISS (UCLA Integrated Staging System) and SSIGN (Mayo Clinic stage, size, grade and necrosis model) scores and with overall survival of CCRCC patients. These results suggest a metabolic imbalance of iRAS in renal tumors. This finding should be taken into account in the search of new diagnostic, prognostic and therapeutic tools for this disease.

Background In clear cell renal cell carcinoma, 80% of cases have biallelic inactivation of the VHL gene, leading to constitutive activation of both HIF1α and HIF2α. As HIF2α is the driver of the disease promoting tumour growth and metastasis, drugs targeting HIF2α have been developed. However, resistance is common, therefore new therapies are needed. Methods We assessed the effect of the HIF2α antagonist PT2385 in several steps of tumour development and performed RNAseq to identify genes differentially expressed upon treatment. A drug screening was used to identify drugs with antiproliferative effects on VHL- mutated HIF2α-expressing cells and could increase effectiveness of PT2385. Results PT2385 did not reduce cell proliferation or clonogenicity but, in contrast to the genetic silencing of HIF2α, it reduced in vitro cell invasion. Many HIF-inducible genes were down-regulated upon PT2385 treatment, whereas some genes involved in cell migration or extracellular matrix were up-regulated. HIF2α was associated with resistance to statins, addition to PT2385 did not increase the sensitivity. Conclusions: this study shows key differences between inhibiting a target versus knockdown, which are potentially targetable.

Metabolic heterogeneity within the cell microenvironment is a key driver of cancer progression and resistance to therapy. However, current approaches lack the spatial and temporal resolution required to capture its dynamics in living systems. While recent advances in 3D cell culture models and metabolomic profiling have improved our understanding of the tumor niche, their integration with real-time optical sensing remains underdeveloped. Here, we present an integrated platform combining a 3D-printed microreactor culture chamber with Raman spectroscopy to enable non-invasive, spatially resolved metabolic monitoring of living cell cultures. Our microreactor platform generates controlled oxygen and nutrient cues while simultaneously acquiring label-free Raman spectra, revealing extracellular metabolic fingerprints linked to cell catabolism (e.g., glucose and lactate shifts) and acidification. Analysis across four cell lines uncovered temporal evolution as the dominant source of metabolic variance, while spatial heterogeneity along oxygen gradients is a secondary factor. In particular, diffusion-limited regions exhibited localized acidification and accumulation of stress biomarkers—such as the release of nucleotides—features that cannot be detected using conventional bulk assays. By providing a versatile platform for real-time mapping, this work enables the mechanistic dissection of cell adaptation to microenvironmental stress and supports the prediction of metabolic signatures underlying drug response and treatment outcomes.

Patient stratification has been instrumental for the success of targeted therapies in breast cancer. However, the molecular basis of metastatic breast cancer and its therapeutic vulnerabilities remain poorly understood. Here we show that PML is a novel target in aggressive breast cancer. The acquisition of aggressiveness and metastatic features in breast tumours is accompanied by the elevated PML expression and enhanced sensitivity to its inhibition. Interestingly, we find that STAT3 is responsible, at least in part, for the transcriptional upregulation of PML in breast cancer. Moreover, PML targeting hampers breast cancer initiation and metastatic seeding. Mechanistically, this biological activity relies on the regulation of the stem cell gene SOX9 through interaction of PML with its promoter region. Altogether, we identify a novel pathway sustaining breast cancer aggressiveness that can be therapeutically exploited in combination with PML-based stratification. Targeting PML in acute promyelocytic leukaemia has changed the outcome of patients with this disease. Here, the authors demonstrated that PML is also a potential therapeutic target in breast cancer where it specifically regulates cancer initiating cells and tumour progression through the transcriptional regulation of SOX9 .