Paralogs often exhibit functional redundancy, allowing them to effectively compensate for each other's loss. However, this buffering mechanism is frequently disrupted in cancer, exposing unique paralog-specific vulnerabilities. Here, we identify a selective dependency on the splicing factor TRA2A. We find that TRA2A and its paralog TRA2B are synthetic lethal partners that function as widespread and largely redundant activators of both alternative and constitutive splicing. While loss of TRA2A alone is typically neutral due to compensation by TRA2B, we discover that a subset of cancer cell lines are highly TRA2A-dependent. Upon TRA2A depletion, these cell lines exhibit a lack of paralog buffering specifically on shared splicing targets, leading to defects in mitosis and cell death. Notably, TRA2B overexpression rescues both the aberrant splicing and lethality associated with TRA2A loss, indicating that paralog compensation is dosage-sensitive. Together, these findings reveal a complex dosage-dependent relationship between paralogous splicing factors, and highlight how dysfunctional paralog buffering can create a selective dependency in cancer.

Endometrial cancer (EC) is the most common pelvic gynecologic malignancy in developed countries, and its incidence is also increasing in developing countries. Endometrioid endometrial carcinoma (EEC) is the most frequent subtype. EEC is often associated with favorable clinicopathological features and a good prognosis, especially when diagnosed in stage I. Although some patients have no signs to predict locally advanced or metastatic disease, they may present tumor relapse in the future. There is no biomarker capable of predicting the relapse of stage I EEC. The present study applied a transcriptome analysis to identify differentially expressed genes in stage I EEC, comparing relapsed with non-relapsed tumors. The estrogen receptor 1 gene (ESR1) was overexpressed in EEC stage I samples from patients who developed relapse by 4.3-fold compared to non-relapsed tumors. Subsequently, an independent set of 64 stage I EEC samples was used to validate ESR1 gene overexpression in relapsed tumors and assess estrogen receptor alpha (ERα) protein levels. ESR1 was confirmed to be overexpressed in samples from relapsed tumors, and its expression level was an independent prognostic variable for disease-free (hazard ratio=7.25) and overall survival (hazard ratio=5.15). In contrast, Erα did not show different values between relapsed and non-relapsed tumors. We concluded that ESR1 overexpression is a biomarker for poor prognosis in stage I EEC.

The primary objective of the present study was to identify differentially expressed genes (DEGs) associated with castration-resistant prostate cancer (CRPC) to verify the potential mechanism of CRPC progression. DEGs from CRPC datasets were filtered with a P<0.05 and Spearman correlation coefficient ≥0.3. Serpin peptidase inhibitor, clade A member 3 (SERPINA3), was uniquely present in three CRPC datasets, and its low expression in CRPC was confirmed in cell lines and tissues. Colony formation, transwell assays, and subcutaneous tumor formation experiments in mice demonstrated that overexpression of SERPINA3 may significantly inhibit the proliferation and invasion of PC3 cells. Mechanistic studies revealed that, in prostate cancer (PCa), SERPINA3 can activate the interleukin (IL)-17 and tumor necrosis factor (TNF)α signaling pathways by promoting the expression of CXC chemokine ligand 2 (CXCL2), thereby increasing the recruitment of M1 macrophages into the tumor microenvironment and inhibiting the progression of PCa. The current results indicated that the expression of SERPINA3 may be negatively correlated with CRPC, and it could promote the M1 polarization of macrophages and inhibit the progression of CRPC by increasing the expression of CXCL2.

Bladder cancer is the most prevalent malignancy of the urinary tract, with significant advancements in treatment achieved over recent decades. Nonetheless, the immunological mechanisms underlying bladder cancer progression remain elusive, and only a limited number of patients derive benefit from current immune checkpoint inhibitors. Here, we conducted a single-cell RNA sequencing analysis of 44,022 cells from peripheral blood mononuclear cell samples of bladder cancer patients and a healthy donor. Our findings indicated that the proportions of T cells and neutrophils are higher in bladder cancer patients than in the healthy donor. LAG3, HAVCR2, and CTLA4 had elevated expression levels in CD8-T2-GZMK cell clusters from patients. CD8-T7-STMN1 cells highly expressed ITGAE, CD38, and STMN1. Furthermore, NK3-CMC1, more prevalent in patients, showed a high expression of TIGIT. Additionally, Bcell2-TCL1A and Bcell3-MS4A1 were characterized by the high expression of inhibitory receptor marker genes. Gene set variation analysis suggested that Mono4-THBS1 may play a role in promoting tumor hypoxia and angiogenesis. Neu-FCGR3B exhibited high levels of IL4R and CD274 expression. Our study indicated that LAG-3 and TIM-3 may serve as novel potential immune checkpoint inhibitors in bladder cancer treatment. The phenotypes of NK3-CMC1, Bcell2-TCL1A, and Bcell3-MS4A1 might be altered by tumor progression. Mono4-THBS1 could potentially be a source of tumor-enriched monocyte-like cells. Neu-FCGR3B may play a detrimental role in the anti-tumor response and could emerge as a predictive marker for bladder cancer. Overall, these high-resolution transcriptomic data offer invaluable insights for identifying new therapeutic targets and biomarkers in bladder cancer immunotherapy.

Truly understanding the cancer biology of heterogeneous tumors in precision medicine requires capturing the complexities of multiple omics levels and the spatial heterogeneity of cancer tissue. Techniques like mass spectrometry imaging (MSI) and spatial transcriptomics (ST) achieve this by spatially detecting metabolites and RNA but are often applied to serial sections. To fully leverage the advantage of such multi-omics data, the individual measurements need to be integrated into 1 dataset.

Durable clinical responses to immune checkpoint inhibitors (ICI) are limited to a minority of patients, and molecular pathways that modulate their efficacy remain incompletely defined. We have recently shown that activation of the innate RNA-sensing receptor RIG-I and associated apoptotic tumor cell death can facilitate tumor immunosurveillance and -therapy, but the mechanism that drives its immunogenicity remained unclear. We here show that intratumoral activity of the pore-forming protein gasdermin E (GSDME) links active RIG-I signaling and apoptotic cell death in tumor cells to inflammatory pyroptosis. Activation of tumor-intrinsic RIG‑I triggered cleavage of GSDME, pore formation, loss of cell membrane integrity and leakage of cytosolic components from dying tumor cells. Tumor antigen cross-presentation by dendritic cells and subsequent expansion of cytotoxic T cells strongly relied on tumor-intrinsic GSDME activity. In preclinical murine cancer models, defective GSDME signaling rendered tumors resistant to ICI therapy. Epigenetic reprogramming with upregulation of Gdsme enhanced the susceptibility of tumor cells to inflammatory cell death and immunotherapy. In humans, transcriptome analysis of melanoma samples showed strong correlation between genetic activity of the RIG-I and pyroptosis pathways. In melanoma patients, high transcriptional activity of a pyroptosis gene set was associated with prolonged survival and beneficial response to ICI therapy. In summary, our data show that GSDME links RIG-I and apoptotic signaling to inflammatory cell death, thereby driving its immunogenicity and responsiveness to ICI. A deeper understanding of these pathways may allow for the development of novel combined modality approaches to improve ICI treatment responses in cancer patients.

Accurate prediction of patient survival rates in cancer treatment is essential for effective therapeutic planning. Unfortunately, current models often underutilize the extensive multimodal data available, affecting confidence in predictions. This study presents MMSurv, an interpretable multimodal deep learning model to predict survival in different types of cancer. MMSurv integrates clinical information, sequencing data, and hematoxylin and eosin-stained whole-slide images (WSIs) to forecast patient survival. Specifically, we segment tumor regions from WSIs into image tiles and employ neural networks to encode each tile into one-dimensional feature vectors. We then optimize clinical features by applying word embedding techniques, inspired by natural language processing, to the clinical data. To better utilize the complementarity of multimodal data, this study proposes a novel fusion method, multimodal fusion method based on compact bilinear pooling and transformer, which integrates bilinear pooling with Transformer architecture. The fused features are then processed through a dual-layer multi-instance learning model to remove prognosis-irrelevant image patches and predict each patient's survival risk. Furthermore, we employ cell segmentation to investigate the cellular composition within the tiles that received high attention from the model, thereby enhancing its interpretive capacity. We evaluate our approach on six cancer types from The Cancer Genome Atlas. The results demonstrate that utilizing multimodal data leads to higher predictive accuracy compared to using single-modal image data, with an average C-index increase from 0.6750 to 0.7283. Additionally, we compare our proposed baseline model with state-of-the-art methods using the C-index and five-fold cross-validation approach, revealing a significant average improvement of nearly 10% in our model's performance.

This study aims to explore the effects of silencing Zic family member 5 (ZIC5) on glucose metabolism and disulfidptosis in lung adenocarcinoma (LUAD) cells.

The use of multigene panels has significantly increased the likelihood that genetic testing will leave patients with uncertainties regarding test interpretation, implications, and recommendations, which will change over time. Effective longitudinal care models are needed to provide patients with updated information and to obtain patient and family history updates.

Patients with sporadic breast cancer have comparable prognoses after undergoing either breast-conserving treatment (BCT) or mastectomy. However, there are limited and inconsistent data on the assessment of oncologic outcomes between BCT and mastectomy in patients with pathogenic variants in BRCA1 or BRCA2.

SMARCB1-deficient and SMARCA4-deficient sinonasal carcinomas are rare, with only a few systematic studies available in the literature. Secondary EWSR1 gene abnormalities have been reported in SMARCB1-deficient tumors. This study aimed to systematically investigate SWI/SNF complex-deficient sinonasal carcinomas in a single-institution cohort, perform clinicopathologic characterization, and explore the underlying molecular mechanisms.

Hepatocellular carcinoma (HCC) is prevalent globally, and the discovery of new targets is vital for the treatment of HCC. Mitochondrial pyruvate carrier 1 (MPC1) has been found to exhibit reduced expression and promote tumour progression in some cancers, although its role in HCC needs to be explored. Using GEO datasets and Kaplan‒Meier plotter, the clinicopathological features and patient prognosis were analysed by assessing the expression levels of MPC1 in HCC tissues. After MPC1-knockdown and MPC1-overexpressing cell lines were constructed, the effects of modulating MPC1 expression on the malignant phenotype of HCC cells were tested via CCK8, colony formation, and scratch assays and flow cytometry. The effects of MPC1 on HCC cells and mitochondria were examined via MitoTracker Red CMXRos staining, cytoskeleton staining and cellular energy metabolism assays. MPC1 expression was found to be reduced in HCC patients and correlated with prognosis and clinicopathological features. It was found that low expression of MPC1 promotes the malignant phenotype of HCC cells and affects the mitochondrial energy metabolism of HCC cells to support the tumour microenvironment, and that MPC1 may act through signal transducer and activator of transcription 3 (STAT3). MPC1 might play a tumor-suppressing role in HCC through its interaction with STAT3, and this discovery could offer novel perspectives for HCC treatment.

Dysregulation of circRNA expression is associated with increased metastasis and an adverse prognosis in non-small cell lung cancer (NSCLC). Herein, this study assessed the role and regulatory mechanism of circPVT1 in NSCLC development.

Hereditary lobular breast cancer (HLBC) is a distinct subset of hereditary breast cancer primarily associated with germline pathogenic variants in the CDH1 gene, which encodes E-cadherin, a crucial protein in cell adhesion. Loss of E-cadherin disrupts tissue architecture, contributing to the invasive growth pattern characteristic of lobular carcinoma. CDH1 mutations are also implicated in hereditary diffuse gastric cancer, predisposing some patients to both cancers. However, variable cancer risk is observed, as many HLBC patients with a family history of gastric cancer do not develop gastric malignancies, reflecting the complex interplay of E-cadherin's role in cell cohesion and tumorigenesis.

The appearance of hybrid epithelial-mesenchymal (E/M) cells expressing E-cadherin is favourable for the establishment of pro-invasive function. Although the potential role of E-cadherin in cancer invasion is now accepted, the molecular mechanisms involved in this process are not completely elucidated. To gain further insight, we focused our analysis on invadopodia formation, an early event in the invasion process. We used models of E/M hybrid cell lines, tissue sections and patient-derived xenografts from a multi-centre clinical trial. E-cadherin involvement in invadopodia formation was assessed using a gelatin-FITC degradation assay. Mechanistic studies were performed by using proteomic analysis, siRNA strategy and proximity ligation assay. We showed that E-cadherin is a critical component of invadopodia. This unexpected localization results from a synergistic trafficking of E-cadherin and MT1-MMP through a Rab vesicle-dependent pathway. Modulation of E-cadherin expression or activation impacted invadopodia formation. Moreover, colocalization of E-cadherin and Actin in "ring structures" as precursors of invadopodia reveals that E-cadherin is required for invadopodia structuration. E-cadherin, initially localised in the adherens junctions, could be recycled to nascent invadopodia where it will interact with several components enriched in invadopodia, such as Arp2/3, Cortactin or MT1-MMP. The trans-adhesive properties of E-cadherin are therefore essential for structuring invadopodia. This new localisation of E-cadherin and its unexpected role in cell invasion shine a new light on hybrid E/M transition features in tumoral invasion.

IntroductionThe objective of the current study was to examine the impact of Spanish-language patient outreach and navigation services on adherence to initial colorectal cancer (CRC) screening with multitarget stool DNA (mt-sDNA) testing in a predominantly Spanish-speaking patient population receiving care at Federally Qualified Health Centers (FQHCs).MethodThis study included patients aged 45 years or older who identified as Hispanic from FQHCs in a California Health System who were new to mt-sDNA testing and shipped a Cologuard® collection kit between 10-1-2022, and 1-1-2024. Patient outreach was provided only in English prior to 1-22-2023 (pre-intervention period). From 1-23-2023, onward, patient outreach was offered in either English or Spanish based on the patients' preferred language selection (post-intervention period). Patients were classified into two subgroups: Spanish language preference (SLP) or non-Spanish language preference (NSLP). It was hypothesized that adherence would be greater in SLP patients when patient outreach was provided in Spanish compared to the NSLP.ResultsThe final sample comprised 20 341 Hispanic patients who met the study criteria, comprising 15 702 patients with SLP and 4639 with NSLP, stratified across pre- and post-intervention periods. Overall, adherence to initial mt-sDNA testing within 180 days following the index date was 51.4% for SLP patients and 41.3% for NSLP patients, with a significant post-intervention improvement observed after the intervention for SLP patients (47.1% to 52.7%, P < .001), compared to a non-significant improvement (40.7% to 41.4%, P = .713) among NSLP patients.DiscussionFollowing the introduction of Spanish-language patient outreach, adherence to mt-sDNA testing improved significantly among SLP patients. The preference of Hispanic individuals for stool-based tests, combined with the non-invasive nature of mt-sDNA testing, supports its suitability as a CRC screening option for this population.

The HBV core protein (HBC) is crucial for the progression of HCC. WD repeat-containing (WDR) 46 (WDR46) is implicated in the development of different tumors. Nevertheless, whether WDR46 is controlled by HBC to drive hepatocarcinogenesis remains unclear.

Pancreatic cancer is a highly aggressive and lethal disease, characterized by a limited response to chemotherapy and overall poor prognosis. Pancreatic cancers with a distinct mismatch repair deficiency, although relatively rare, have been shown to be associated with markedly better outcomes in comparison. Furthermore, whereas pancreatic cancers are generally unresponsive to current immunotherapy, this specific group of tumors has been shown to have a notable susceptibility to immune checkpoint inhibitors.

Colorectal cancer (CRC) is a leading cause of cancer-related mortality globally, yet current therapies exhibit suboptimal efficacy with limited prognostic improvement. RNA 5-methylcytosine (m5C), a posttranscriptional modification, has been implicated in tumorigenesis and progression across malignancies. In our previous study, the m5C methyltransferase NOP2 has been shown to promote proliferation, migration, and invasion of CRC cells, however, the underlying mechanism is still elusive.

BRCA1/BRCA2 female pathogenic sequence variant (PSV) carriers in Israel are offered semiannual cancer antigen 125 (CA125) serum level determination and transvaginal ultrasound until performing risk reducing salpingo-oophorectomy (RRSO), even with the lack of proven efficacy of these procedures in providing adequate early detection of ovarian cancer.