EVI1-rearranged acute myeloid leukemia (AML) with inv(3)(q21q26) or t(3;3)(q21q26) represents a distinct and aggressive subtype characterized by poor prognosis and limited treatment options. However, the optimal strategy to overcome resistance to conventional therapy remains elusive. Building upon observations correlating EVI1 overexpression with reduced sensitivity to venetoclax, a BH3-mimetic BCL-2 inhibitor, we investigated the mechanisms of resistance to venetoclax in combination with hypomethylating agents in inv(3)/t(3;3) AML cells. Utilizing novel murine models recapitulating inv(3) AML with concomitant SF3B1 mutations, we conducted comprehensive phenotypic and transcriptomic analyses in the presence or absence of venetoclax-containing therapy. Despite initial therapeutic responses, manifested as partially prolonged survival and myeloid differentiation, resistant leukemic cells demonstrated enhanced dependency on BRD4 and MYB pathways with a dormant phenotype. Notably, inhibition of either BRD4 or MYB significantly augmented the efficacy of venetoclax and hypomethylating agents in both murine and patient-derived AML models harboring inv(3) and SF3B1 mutations. These findings elucidate the transcriptional dynamics underlying venetoclax resistance and propose alternative therapeutic strategies targeting BRD4 and MYB as promising avenues for improving outcomes in patients with EVI1-rearranged AML. Our work highlights the necessity for innovative combination therapies to address the multifaceted mechanisms of resistance in this high-risk leukemia subtype.

Depression in patients with prostate cancer (PC) has become a significant public health issue. Given the high treatment failure rate and short life expectancy of patients with castration-resistant prostate cancer (CRPC), their risk of developing major depressive disorder (MDD) is significantly increased. However, the exact mechanisms of comorbidity between CRPC and MDD are not yet clear, and there is a lack of standardized intervention strategies to address this clinical issue. This study used bioinformatics methods combined with Mendelian randomization (MR) analysis to explore the molecular mechanisms of CRPC/MDD comorbidity and predict potential therapeutic drugs for this comorbidity. Three hub genes of the comorbidity (AUTS2, AOC1, ANKRD37) were identified, which have excellent diagnostic value in both diseases. AOC1 and ANKRD37 showed prognostic significance in CRPC, and the risk association of AUTS2 with MDD was also validated through MR analysis. The study also found that immune, inflammatory, androgen response pathways are key mechanisms of comorbidity, but the role of apoptosis should not be overlooked. The study further suggested that the JAK/STAT inhibitor WP1066 may be a potential drug for treating CRPC/MDD comorbidity, and this was validated through molecular docking. These findings not only provide a new perspective on the relationship between CRPC and MDD but also offer important clues for the development of treatment strategies.

Despite advances in cancer treatments, epithelial ovarian cancer (EOC) remains the leading cause of death among gynecologic cancers. EOC is stratified into five main histopathological subtypes: high-grade serous carcinoma (HGSC), low-grade serous carcinoma (LGSC), endometrioid carcinoma (EC), clear cell carcinoma (CCC), and mucinous carcinoma (MC). However, personalized treatment strategies and reliable biomarkers for all histotypes remain elusive. Building on our previous work with early-stage EOC, we aim to explore diagnostic and prognostic biomarkers in advanced-stage EOC, updated to the latest World Health Organization classification guidelines from 2020, using comprehensive transcriptomic profiling from total RNA sequencing of 146 EOCs. Differential expression analysis identified top 9 histotype-specific gene panels for HGSC, CCC, MC, and EC, including S100A1 (HGSC), ARID3A (CCC), LGALS4 (MC), and PAX9 (EC). We also identified gene candidates associated with overall survival and disease-specific survival, reflecting both favorable (e.g., OTOF, EEF1E1-BLOC1S5, and STAC3) and unfavorable (e.g., SMOC1, GDPGP1, EPRS1) clinical outcome. Additionally, enrichment analysis revealed tumor progression-related pathways unique to each histotype, offering insights into the molecular mechanisms underlying disease progression and potential therapeutic targets. These findings provide valuable insights into the molecular landscape of advanced-stage EOC, paving the way for more effective diagnostic and prognostic tools across diverse histotypes.

Merkel cell carcinoma (MCC) is an aggressive skin cancer with neuroendocrine differentiation marked by high cellular plasticity, often manifesting as rapid therapy resistance. Although the cell-of-origin is presumed to be epithelial, epidermal localization of MCC is rarely observed, largely because in situ MCC is typically an incidental finding. Nevertheless, a subset of MCC tumors exhibits epidermotropism, wherein tumor cells are present in the epidermis. The behavior of cancer cells is profoundly influenced by the tumor microenvironment and interactions with neighboring cells. Notably, the normal counterparts of the cancer's cell-of-origin have been shown to attenuate tumor aggressiveness. Thus, epidermotropic MCC presents a unique opportunity to explore the potential role of epidermal microenvironment in modulating tumor cell behavior. While the epidermotropic tumor nests share histological resemblance with their dermal counterparts, their transcriptomic profiles remain unexplored. Here, we employed high-definition spatial and single-cell transcriptomics to dissect the gene expression profiles of epidermotropic MCC cells, comparing them to MCC cells in the tumor core and those adjacent to blood vessels. Notably, epidermotropic MCC cells exhibit a transcriptomic signature reminiscent of cutaneous squamous cell carcinoma, characterized by upregulation of genes encoding keratins, S100A proteins, as well as calmodulin-like proteins 3 and 5. Mechanistically, this keratinocytic differentiation is associated with enhanced p63 activity, leading to the upregulation of PERP. Collectively, our study demonstrates that MCC cells can adopt a keratinocytic differentiation program in response to microenvironmental cues, underscoring the remarkable phenotypic plasticity of this malignancy and the importance of the microenvironment for tumor cell characteristics.

Hepatocellular carcinoma (HCC) is a biologically and clinically heterogeneous malignancy, whose initiation and progression are increasingly recognized to be driven by the aberrant regulation of programmed cell death (PCD) pathways. To elucidate this association, we systematically integrated gene signatures from 21 distinct PCD types to characterize their expression patterns in HCC and construct a prognostic model for survival and therapeutic response prediction. Based on the TCGA-LIHC, GSE14520, and GSE116174 datasets, 85 candidate genes were identified through differential expression analysis and random survival forest algorithms. A 10-gene PCD-based risk score model was developed using machine learning including key genes such as KIF20A (associated with ferroptosis) and SLC2A1 (associated with anoikis), which demonstrated robust prognostic performance across three independent cohorts by stratifying patients into high- and low-risk groups. The risk score significantly correlated with immune infiltration, immune evasion potential, and predicted sensitivity to multiple anticancer agents. Consensus clustering based on model gene expression revealed two molecular subtypes with distinct survival outcomes and immune characteristics. A nomogram integrating the risk score exhibited favorable calibration and clinical applicability. Collectively, these findings propose a novel PCD-based molecular framework for prognosis assessment and personalized therapy in HCC.

In children, rhabdomyosarcoma is the most common tumor originating in soft connective tissue. The PAX3/PAX7-FOXO1 fusion-positive alveolar subtype has poor clinical outcomes, with frequent recurrence, metastasis, and low survival. Current therapies may be limited by the tumor microenvironment containing cancer, immune, and fibroblast cells. In cancer, cells that transform into cancer-associated fibroblasts support growth and other malignant properties of the tumor. To study the role of cancer-associated fibroblasts, we isolated cells from the lung metastases of a patient with rhabdomyosarcoma that are positive for fibroblast biomarkers. Compared to normal lung fibroblasts, these cancer-associated fibroblasts secreted distinct factors that specifically supported the growth and migration of fusion-positive rhabdomyosarcoma cells. The cancer-associated fibroblasts also promoted expression of immune checkpoints and conferred resistance to cyclophosphamide, a chemotherapy commonly used to treat this disease. We further characterized the secretory phenotype of cytokines and growth factors produced by these cancer-associated fibroblasts and targeted CXCR4 expression inhibition, which induced cytotoxicity at increased sensitivity. This study establishes a model of cancer-associated fibroblasts from metastatic fusion-positive rhabdomyosarcoma. Altogether, our results describe tumor-promoting mechanisms of growth, migration, and treatment resistance supported by the tumor microenvironment, and offer a novel therapeutic strategy for the treatment of rhabdomyosarcoma.

Metabolism operates under physico-chemical constraints that result in multireaction dependencies. Understanding how multireaction dependencies affect metabolic phenotypes remains challenging, hindering their biotechnological applications. Here, we propose the concept of a forcedly balanced complex that allows to efficiently determine the effects of specific multireaction dependencies on metabolic network functions in constrained-based models. Using this concept, we found that the fraction of multireaction dependencies induced by forcedly balanced complexes in genome-scale metabolic networks followed power law with exponential cut-off. We identified forcedly balanced complexes that are lethal in cancer but have little effect on growth in healthy tissue models. In addition, these forcedly balanced complexes are largely specific to models of particular cancer types. Therefore, multireaction dependencies resulting from forced balancing of complexes represent an innovative means to control cancers that, we argue, can be implemented via transporter engineering. The presented constraint-based approaches pave the way for using multireaction dependencies in metabolic engineering for diverse biotechnological applications.

Tumor thrombus (TT) worsens prognosis and complicates surgery in renal cell carcinoma (RCC), yet its formation mechanisms remain unclear. Here, we perform integrative single-cell and spatial transcriptomic analyses on 71 tissues and 48 sections from RCC patients with or without TT. The cellular and spatial atlas reveals distinct TT-associated tumor microenvironment remodeling characterized by the enrichment of FAP+ fibroblasts. These FAP+ fibroblasts are spatially contiguous to aggressive cancer cells and promote their malignant phenotypes in vitro. Their abundance inversely correlates with functional NK cells, suggesting roles in tumor invasion and immune evasion. Furthermore, single-cell multiomics analysis identifies tumor pericytes as a source of FAP+ fibroblasts and delineates transcription factor dynamics underlying pericyte-fibroblast transition. Finally, high levels of FAP+ fibroblasts are associated with poor prognosis and predict a weaker response to anti-VEGF-based therapy. In conclusion, our study highlights FAP+ fibroblasts as drivers of aggressive RCC with TT, suggesting potential therapeutic targets.

Protein folding is a fundamental process ensuring that polypeptide chains acquire the correct three-dimensional structures required for biological function. This complex journey from nascent polypeptides to mature proteins is tightly regulated by the cellular proteostasis network-an integrated system of molecular chaperones, folding enzymes, and degradation machineries. Disruptions in this network lead to dysproteostasis, a pathological state implicated in a growing list of human diseases, including neurodegenerative disorders, metabolic syndromes, and cancer. In this review, we provide a comprehensive and multidimensional analysis of protein folding biology, tracing its evolution from early theoretical foundations to cutting-edge biophysical and computational techniques that now permit near-atomic-resolution modeling of folding dynamics. We explore the historical progression of protein folding research, including landmark discoveries of secondary structure, chaperone biology, and energy landscape theory. We detail the roles of key molecular chaperones across cytosolic, mitochondrial, and endoplasmic reticulum compartments, emphasizing their collaborative actions in protein folding and quality control. We also discuss the multifactorial causes of protein misfolding-from genetic mutations to aging and oxidative stress-and examine the pathological consequences, paying special attention to diseases characterized by toxic protein aggregation and loss of proteome fidelity. We then examine therapeutic innovations targeting proteostasis, including chaperone modulators, proteostasis pathway inhibitors, and emerging strategies to increase proteome resilience. By consolidating insights at the molecular, cellular, and systems levels, this review underscores the central role of protein folding homeostasis in health and disease and highlights novel opportunities for therapeutic intervention through the modulation of the proteostasis network.

Pathogenic or likely pathogenic (P/LP) CDH1 germline genetic variants are causally linked to early onset diffuse gastric cancer and prophylactic total gastrectomy (PTG) is a recommended intervention for (P/LP) CDH1 variant carriers. However, PTG introduces fundamental challenges to a patient's quality of life (QOL) and psychological well-being. There is a growing need for evidence-based recommendations to address the psychosocial needs of PTG patients. The present review summarizes published literature on psychosocial sequelae and quality of life reported post-PTG in germline (P/LP) CDH1 variant carriers.

This study aimed to evaluate whether pretreatment circulating tumor DNA (ctDNA) is a predictive biomarker for recurrence in patients with early-stage non-small cell lung cancer (ES-NSCLC), including those with pathologically unproven (PU) who received ablative radiotherapy.

Objectives: Cases from our hospital and a systematic review were performed in this paper to get a better understanding on the diagnosis and therapies for primary pulmonary NUT carcinoma (PPNC) patients. Methods: The clinical features, pathological diagnosis, treatment and outcomes of PPNC patients from 2020-2025, including four cases from the First Affiliated Hospital of Soochow University, were collected delicately. The Kaplan-Meier method and Cox proportional hazard regression model were used to calculate cumulative survival and prognostic factors. Results: The male-to-female ratio of PPNC was 18∶15, the left to right ratio was 14∶19, the median age was 36 years old and the median tumor diameter was 6.1 cm. Most patients were already at an advanced stage with the clinical features-cough (16/33) and chest or back pain (13/33) when they first came to the hospital. The tumor cells were arranged in nest pattern with small-medium size, round to oval shape, and nuclei were deeply stained. The high positive staining of NUT (32/32) and CK-pan (16/19) was observed, NUTM1 gene translocation in 24 cases was detected by fluorescence in situ hybridization (FISH), and different gene rearrangements were located by NGS-NUTM1-BRD4 (8/12), NUTM1-BRD3 (2/12), NUTM1-BRD2 (1/12) and NUTM1-ZNF532 (1/12). Most patients accepted different chemotherapy regimens (25/29), including paclitaxel albumin and platinum (13/25), etoposide and platinum (8/25). Meanwhile, 12 cases were treated with PD-1/PD-L1 antibody during the therapy. The median follow-up time was 7 months in 28 cases tracked from 2-90 months. Univariate Cox regression analysis showed that metastasis of this disease affected patient prognosis (HR=2.55, 95% CI: 0.974-6.677, P=0.057) and the cumulative survival rate was lower in the older ones. Conclusions: PPNC, more often found in middle-aged patients, no difference in sex, can be diagnosed by pathmorphology and immunophenotype, while NUTM1 molecular test is highly suggested for the accurate therapy. Metastasis can be recognized as the prognostic risk factor. Early detection of the cancer improves the chances of successful treatment, especially in patients with older age.

Breast cancer is one of the most common malignancies among women in China. According to GLOBOCAN 2022, more than 350,000 new breast cancer cases were diagnosed in China, ranking second among all newly diagnosed cancers in women. Although breast cancer has entered an era of chronic disease management and overall survival has improved substantially, the prognosis of metastatic breast cancer (MBC) remains unsatisfactory. The genome of MBC is characterized by spatiotemporal heterogeneity and may undergo dynamic evolution. With the continuous identification of actionable alterations, targeted therapies guided by genomic testing have emerged as an important approach to improving patient outcomes. Therefore, the implementation of standardized genomic testing in clinical practice has become an urgent priority. While several international and domestic guidelines have recommended genomic testing for MBC, China still lacks detailed technical specifications and clinical pathways tailored to advanced disease in the local healthcare context. Accordingly, it is imperative to establish a guideline for genomic testing in advanced breast cancer that reflects national realities, ensures strong clinical operability, unifies testing standards, and optimizes workflows, thereby expanding access to precision therapy and improving patient prognosis. Against this background, the Breast Cancer Committee of the Chinese Anti-Cancer Association convened a multidisciplinary working group experts. Following predefined methodological procedures-including clinical question prioritization, systematic evidence retrieval, graded evaluation, and formulation of recommendations-the guideline was developed. It integrates the latest evidence with multidisciplinary expert consensus, providing specific recommendations on key aspects of genomic testing for MBC, including patient eligibility, specimen selection, testing methodologies, and prioritization of target genes. In addition, the guideline systematically summarizes available targeted therapeutic strategies for different genomic alterations, and provides graded recommendations based on both levels of evidence and drug accessibility, thereby ensuring clarity and facilitating clinical implementation. This guideline is closely aligned with the realities of clinical practice and drug accessibility in China, with a strong emphasis on the feasibility of testing and the actionability of results. It establishes a multidisciplinary consensus on standardized pathways for genomic testing in patients with MBC, aiming to bridge precision diagnostics and individualized targeted therapy, and to provide practical guidance for improving the standardization of advanced breast cancer care nationwide.

Circulating tumor DNA (ctDNA) has emerged as a critical noninvasive biomarker for cancer diagnosis and monitoring. To effectively capture tumor heterogeneity, we developed a rapid, homogeneous, and label-free method for the simultaneous detection of EGFR L858R and 19 del mutations in lung cancer, employing a filter-membrane-assisted separation strategy coupled with inductively coupled plasma mass spectrometry (ICP-MS). The assay utilized functional Y-shaped DNA nanospheres, self-assembled through T-Hg2+-T and C-Ag+-C coordination, enabling highly specific target recognition and efficient release of metal reporters. Following filtration, free Hg2+ and Ag+ ions were quantitatively measured by ICP-MS, facilitating multiplexed ctDNA detection with high sensitivity. The method demonstrated a wide linear range from 10 aM to 10 pM, with detection limits as low as 4.3 aM for L858R and 3.7 aM for 19 del. Clinical validation using 42 plasma samples revealed 100% specificity and 96.9% sensitivity, closely aligning with the pathological findings. Receiver operating characteristic (ROC) analysis achieved an area under the curve (AUC) of 0.94, highlighting the excellent diagnostic accuracy of this approach. This strategy provides a robust, noninvasive platform for precise lung cancer diagnosis and treatment monitoring.

Craniopharyngiomas (CPs) are rare brain tumors, categorized into 2 distinct types: adamantinomatous craniopharyngiomas (ACs) and papillary craniopharyngiomas (PCs). Their proximity to critical brain structures and high recurrence rates pose therapeutic challenges. Advances in cancer genomics have uncovered key molecular drivers, including BRAF V600E mutations in papillary and CTNNB1 mutations in ACs. These discoveries have prompted updates in tumor classification and the development of novel targeted therapies. B-Raf proto-oncogene, serine/threonine kinase (BRAF) and mitogen activated protein kinase (MEK) inhibitors have shown remarkable efficacy in treating PCs, while systemic therapeutic options for ACs remain limited. This article highlights the pathogenesis, molecular profiles, and emerging targeted therapies for these challenging tumors.

Regulated cell death (RCD) is a fundamental biological process essential for tissue homeostasis, and the elimination of damaged or malignant cells. In cancer, dysregulation of RCD is closely linked to tumor initiation, progression, therapeutic resistance, and remodeling of the tumor microenvironment (TME). In this review, we classify RCD in cancer into three broad groups. Classical cell death types include apoptosis, autophagy, necroptosis, and pyroptosis, which have well-established roles in controlling cell fate. Metal-dependent pathways, represented by ferroptosis, and cuproptosis, highlight vulnerabilities linked to iron and copper metabolism. Emerging modalities such as entosis, NETosis, disulfidptosis, and parthanatos, further expand the conceptual landscape of RCD, revealing diverse mechanisms by which cancer cells respond to stress. We synthesize the molecular mechanisms and signaling networks governing these processes, emphasizing their intricate crosstalk, shared regulators, and context-dependent dual roles in tumor suppression and promotion. Finally, we discuss translational strategies to exploit RCD, including pharmacologic modulators, nanomaterial-based approaches, and early clinical evidence, outlining future directions for precision oncology. Together, these insights establish RCD as a dynamic and targetable network that provides both mechanistic understanding and opportunities for novel therapeutic interventions in cancer.

Prostaglandin F2 receptor negative regulator (PTGFRN) is a transmembrane protein that has been linked to the metastatic behavior of certain cancers. However, its specific function and underlying regulatory mechanisms in lung cancer remain unclear. In this research, we observed that PTGFRN expression was markedly increased in lung cancer tissues compared to normal tissues, and patients with high PTGFRN levels exhibited poorer survival outcomes. Silencing PTGFRN significantly inhibited non-small cell lung cancer cell proliferation, tumor formation, and metastatic capacity. Mechanistically, PTGFRN was found to interact with signal transducer and activator of transcription 3 (STAT3)and inhibit its degradation. The resulting accumulation of STAT3 enhanced its binding to the BCAT1 gene promoter, thereby boosting branched-chain amino acid transaminase 1 (BCAT1) expression. This subsequently elevated branched-chain amino acid (BCAA) metabolism in lung cancer cells. Overall, our findings highlight the tumor-promoting role of PTGFRN in non-small cell lung cancer and demonstrate that PTGFRN accelerates cancer progression by enhancing the STAT3/BCAT1 signaling axis and reprogramming BCAA metabolism.

Serous ovarian carcinoma (SOC) is an aggressive disease, characterized by advanced-stage tumors that are often associated with relapse and poor outcomes. Although platinum-based chemotherapy is a cornerstone of the treatment, most of the relapsed tumors become resistant to these agents. We explored organoids derived from SOC malignant effusions to identify targets actionable by epigenetic drugs (epi-drugs) to enhance platinum response. Tumor-derived organoids (TDOs) were established using malignant effusions of SOC patients. Histological and transcriptomic (RNA-Seq) characterization (18 TDOs versus 7 normal ovarian samples) was performed, followed by cross-validation with external RNA-Seq datasets (337 SOC samples, 4 TDOs, and 180 normal tissues). Predicted interactions between long noncoding RNAs (lncRNAs) and epigenetic effectors were investigated. We selected the epi-drugs decitabine and tazemetostat, whose targets were overexpressed in SOC, to treat carboplatin-resistant SOC cell lines and TDOs. Subsequently, these models were challenged with carboplatin. Twelve lncRNAs and 168 protein-coding genes differentially expressed were involved in epigenetic regulation. Abnormal expression levels of lncRNA MEG3 and epigenetic effectors DNMT3B and EZH2 were confirmed in external datasets. Increased carboplatin sensitivity and MEG3 upregulation were observed after treating the cell lines and TDOs with epi-drugs. Altogether, our findings provide novel insights into using organoids derived from malignant effusions as preclinical models and hint at potential targets for overcoming platinum resistance in SOC.

BRAF/MEK inhibitor induction therapy (BRAF/MEK-i) followed by ipilimumab/nivolumab (IPI/NIVO) did not show benefit over upfront IPI/NIVO in unselected advanced melanoma patients in clinical trial setting. We investigated BRAF/MEK-i in subgroups of patients with advanced melanoma and poor prognostic characteristics.

Pancreatic ductal adenocarcinoma (PDAC) has limited therapeutic options and frequent resistance to standard treatments. This study evaluates the feasibility and clinical impact of comprehensive tumor molecular profiling in PDAC patients aged ≤ 60 years.