Intratumoral low oxygen tension promotes cancer cell invasion and metastasis. Hypoxia-Inducible Factor 1-alpha (HIF1α) is the principal transcription factor orchestrating cellular responses to hypoxic stress, mediating the regulation of genes implicated in adapting to perturbations in oxygen homeostasis. Here, we describe our findings that functionally demonstrate a nucleolar localization domain in HIF1ɑ that enables HIF1ɑ to translocate to the nucleolus. Nucleolar HIF1ɑ binds the ribosomal DNA promoter and upregulates RNA Polymerase I activity leading to dysregulated ribosomal RNA transcription and consequently enhanced ribosome biogenesis. Ribosome biogenesis is important in supporting cellular metabolic processes and invasion and metastasis. Our findings are recapitulated in breast tumors wherein upregulated HIF1ɑ and rRNA biogenesis are associated with poor prognosis. Finally, our studies demonstrate that inhibition of RNA Polymerase I impedes aggressive traits of hypoxia-driven cancer progression, highlighting the potential of this approach as a therapeutic strategy in breast cancer. Cumulatively our work unravels an unprecedented role of HIF1ɑ in regulating rRNA biogenesis in breast cancer.

Recent evidence has highlighted immune checkpoint inhibitors as among the most promising immunotherapies for various malignancies. However, a significant proportion of HCC patients exhibit poor responses. Lipid metabolic heterogeneity is considered a key driver of cancer progression. However, the role of lipid metabolic reprogramming in HCC immunotherapy resistance remains poorly understood. Herein, we aimed to illuminate the potential relationship between lipid metabolic reprogramming and ICI resistance and provide novel strategies to increase the HCC immunotherapy response. Patients who received PD-1/PD-L1 inhibitors were enrolled. The effect of TACC3 on the tumor microenvironment was validated via single-cell RNA sequencing in HCC-bearing mouse models. Targeted metabolomics was performed to analyze the regulatory role of TACC3 in HCC metabolism. To address HCC immunotherapy resistance, we developed a targeted nucleic acid therapeutic utilizing N-acetylgalactosamine (GalNAc) to conjugate siTACC3. Through clinical cohort analysis, we found that TACC3 was overexpressed in HCC patients with poor response to immunotherapy. Furthermore, we demonstrated that silencing tumor-derived TACC3 optimizes the cytotoxicity of infiltrating CD8+ T lymphocytes. Both in vitro and in vivo assays suggested that TACC3 maintains ACSL4-mediated polyunsaturated fatty acid (PUFA) metabolism in HCC cells. Additionally, TACC3 accelerates ACSL4 expression by interacting with LARP1 and PABPC1, which stabilize ACSL4 mRNA. The results of preclinical models demonstrated the satisfactory efficacy of GalNAc-conjugated siTACC3 combined with PD-1 inhibitor therapy for HCC. In summary, tumor-derived TACC3 impairs the tumor-killing activity of CD8+ T lymphocytes through PUFA metabolism-associated crosstalk. Targeting TACC3 represents a novel and practicable strategy to augment ICI efficacy against HCC.

Mitosis is a critical phase of the cell cycle and a vulnerable point where cancer cells can be disrupted, causing cell death and inhibiting tumor growth. Challenges such as drug resistance persist in clinical applications. During mitosis, mRNA translation is generally downregulated, while non-canonical translation of specific transcripts continues. Here, we show that mitotic cancer cells redistribute ribosomes toward the 5' untranslated region (5' UTR) and beginning of the coding sequence (CDS), enhancing translation of thousands of upstream open reading frames (uORFs) and upstream overlapping open reading frames (uoORFs). This mitotic induction of uORF/uoORF enriches human leukocyte antigen (HLA) presentation of non-canonical peptides on the surface of cancer cells after mitotic inhibitor treatment. Functional assays indicate these epitopes provoke cancer-cell killing by T cells. Our findings highlight the therapeutic potential of targeting uORF/uoORF-derived epitopes with mitotic inhibitors to enhance immune recognition and tumor cell elimination.

Repeated oncogenic mutations and polyclonal proliferation are evident in cancers. However, little is known about the polyclonal principles governing the systemic cancerous lineage during immunotherapy. Here, we examine a unique autopsy case of metastatic urothelial carcinoma that exhibits different treatment responses to anti-PD-1 therapy at each tumor site. By performing in-depth analyses of different multiregional bulk tumor masses, we reveal that subsets of subclones acquire potential driver mutations under treatment selection pressure. Spatial transcriptomics analysis reveals that subclones resistant to immunotherapy form distinct immunosuppressive environments consistent with their habitats. Furthermore, different cancer hallmarks are identified in each of the subclones that expand under immunotherapy at single-cell level; for example, one subclone is more proliferative, and another is more stem-cell-like. In summary, this study provides an overall picture of the polyclonal competition and changes in the immune microenvironment that are related to resistance to immunotherapy in patients with malignancies.

Lymph node metastasis (LNM) is a crucial risk factor influencing an unfavorable prognosis in specific cancers. Fundamental research illuminates our understanding of tumor behavior and identifies valuable therapeutic targets. Nevertheless, the exploration of fundamental theories and the validation of clinical therapies hinge on preclinical experiments. Preclinical models, in this context, serve as the conduit connecting fundamental theories to clinical outcomes. In vivo models established in animals offer a valuable platform for comprehensively observing interactions between tumor cells and organisms. Using various experimental animals, including mice, diverse methods, such as carcinogen-induced tumorigenesis, tumor cell line or human tumor transplantation, genetic engineering, and humanization, have been used effectively to construct numerous models for tumor LNM. Carcinogen-induced models simulate the entire process of tumorigenesis and metastasis. Transplantation models, using human tumor cell lines or patient-derived tumors, offer a research platform closely mirroring the histology and clinical behavior of human tumors. Genetically engineered models have been used to delve into the mechanisms of primary tumorigenesis within an intact microenvironment. Humanized models are used to overcome barriers between human and murine immune systems. Beyond mouse models, various other animal models have unique advantages and limitations, all contributing to exploring LNM. This review summarizes existing in vitro and animal preclinical models, identifies current bottlenecks in preclinical research, and offers an outlook on forthcoming preclinical models.

T-cell activation and clonal expansion are essential to effective immunotherapy responses in non-small cell lung cancer (NSCLC). The distribution of T-cell clones may offer insights into immunogenic mechanisms and imply potential prognostic and predictive information.

Metastatic ovarian cancer patients who have recurrent disease after multiple lines of prior treatment have dismal prognosis. The Kristen rat sarcoma viral oncogene homologue (KRAS) G12C mutation is very rare in ovarian cancers and no approved KRAS G12C targeted treatment options exist for ovarian cancer. Here we present a case of metastatic ovarian serous adenocarcinoma in a female patient in her late 70s who was heavily pretreated with multiple lines of treatment before, showing an excellent durable response to KRAS G12C inhibitor sotorasib at reduced dose of 240 mg oral daily for over 26 months and ongoing. Our case highlights KRAS G12C as a driver mutation in ovarian cancer patients that is potentially targetable in certain subgroups of patients.

Cervical teratoblastoma in paediatric patients is an extremely rare and aggressive malignancy, with limited documentation in the medical literature. Teratoblastoma is a malignant variant of germ cell tumours, distinguished by its invasive growth pattern and poor cellular differentiation.A female child in early adolescence presented to our oncology hospital with complaints of persistent lower abdominal discomfort and abnormal uterine bleeding. These symptoms had been progressively worsening over time. On physical examination and imaging, pelvic ultrasonography and MRI revealed a complex cystic mass with hypoechoic features, located in the region between the cervix and the hymenal ring. Histopathological evaluation of a biopsy specimen confirmed the diagnosis of malignant cervical teratoblastoma. A multidisciplinary tumour board recommended surgical intervention. The patient underwent transvaginal excision of the cervical mass, with care taken to preserve reproductive anatomy.Postoperatively, adjuvant chemotherapy was initiated with the bleomycin, procarbazine (Natulan) and cisplatin regimen to reduce the risk of recurrence and metastasis. This case highlights the importance of early recognition, accurate diagnosis and a coordinated treatment approach in managing rare paediatric cervical malignancies.

Orbital metastasis is a rare manifestation of systemic malignancy, accounting for approximately 2%-5% of orbital tumours. The most common primary cancers associated with orbital metastases include breast carcinoma, malignant melanoma and prostate carcinoma. Hepatocellular carcinoma (HCC) is an uncommon source of all reported orbital metastases. We report the case of a man in his mid-50s with a history of alcoholic cirrhosis who presented with an acute onset of left periorbital pain, conjunctival injection, proptosis and restrictive ophthalmoplegia, in addition to abdominal discomfort. Orbital CT demonstrated a heterogeneously enhancing mass in the superolateral left orbit, associated with osseous erosion and displacement of adjacent orbital structures. Further imaging revealed multifocal hepatic lesions with evidence of portal vein invasion. A biopsy of the orbital mass confirmed metastatic HCC. The patient experienced rapid clinical deterioration before initiating treatment and ultimately passed away. This case highlights the importance of considering metastatic liver malignancy in the differential diagnosis of orbital masses, particularly in patients with risk factors for HCC.

This is a case of a man in his 60s initially diagnosed with gastric adenocarcinoma and treated with curative intent surgery and chemotherapy 6 years ago. Four years after initial treatment he had locoregional lymph node recurrence treated with curative chemoradiation and was on surveillance with no evidence of disease for 2 years. He presented to clinic with multiple 'bumps' on his head that had been increasing in size for the past 6 months. He has no other associated symptoms aside from 20 pounds of weight loss. The skin nodule was biopsied, and the pathology showed recurrence of his primary gastric adenocarcinoma. A positron emission tomography (PET)-CT showed a small area of metastasis in a single rib alongside this scalp lesion, without any areas of locoregional or intrathoracic recurrence. This is a rare case of cutaneous recurrence of primary gastric cancer without a high burden of intra-abdominal or visceral disease.

The RAPID-RT study is part of a large-scale research programme investigating the use of routinely collected real-world patient data to rapidly and prospectively evaluate and optimise the impact of changes in radiotherapy practice on clinical outcome, an approach often referred to as 'rapid learning'. As a proof of concept, a prospective, observational clinical study using realworld data is embedded within the programme. This study implements a new dose limit to a defined region of the heart in patients with stage I-III lung cancer treated with curative-intent radiotherapy at The Christie NHS Foundation Trust. The RAPID-RT study includes both methodological and clinical objectives. Its primary aim is to assess the feasibility and clinical acceptability of using rapid learning with real-world data to evaluate outcomes following modifications to standard-of-care radiotherapy protocols. This work has the potential to establish rapid learning as a robust, evidence-based approach for the continuous optimisation of radiotherapy workflows.

To describe long term risks of second non-breast primary cancers and contralateral breast cancers among women with early invasive breast cancer after primary surgery.

Epithelial ovarian cancer (EOC) remains one of the most lethal gynecological malignancies. Although treatment options for newly diagnosed advanced EOC include primary debulking surgery (PDS) or neoadjuvant chemotherapy (NACT) followed by interval debulking surgery (IDS), the comparative effectiveness of these strategies remains uncertain across different disease stages.

RPS20 is a proposed colorectal cancer (CRC) predisposition gene, with only four families with putative loss-of-function (pLoF) variants published. The prevalence, phenotypic spectrum, and clinical management recommendations for RPS20 heterozygotes remain unknown.

This Special Article provides a comprehensive review and expert commentary on the prospective clinical implementation of artificial intelligence (AI) in the detection of prostate cancer from digital prostate biopsies, as presented in the original research by Flach et al. It contextualizes the study within broader developments in digital pathology and AI, addressing barriers to adoption and the implications for diagnostic workflows and pathology practice.

Infection with tick-borne encephalitis virus (TBEV) can lead to severe neurological complications largely associated with the activation of innate immunity and inflammatory reactions in the tissues of the nervous system. In this regard, the study of factors, including viral factors, influencing these processes is underway. We analyzed the possible role of nonstructural protein 1 (NS1) of TBEV in the activation of innate immune response reactions in cells of the nervous system. SH-SY5Y neuroblastoma and DBTRG-05MG glioblastoma cells were transfected with a plasmid encoding NS1 or treated with extracellular vesicles of NS1-expressing HEK293T cells and then stimulated with polyinosinic-polycytidylic acid [poly(I:C)] to activate the innate immune response. It was found that poly(I:C) stimulation of NS1-expressing SH-SY5Y cells resulted in lower mRNA levels of the pro-inflammatory cytokines interleukin-1β(IL-1β) and tumor necrosis factor-α(TNF-α), as well as the innate immune response of the cytokine interferon-1β(IFN-β) and the interferon-stimulated gene 15 product (ISG15), compared to stimulated cells without NS1 expression. In addition, transcription of the sensor gene MDA5, which is responsible for activating gene transcription of these cytokines, was reduced in these cells. In NS1-expressing DBTRG-05MG stimulated cells, only the IL-1β mRNA content was reduced. Treatment of SH-SY5Y cells with extracellular vesicles from NS1-expressing cells followed by poly(I:C) stimulation resulted in increased mRNA levels of IL-6, TNF-α, and IFN-β, compared with stimulated cells treated with vesicles from non-NS1-expressing cells. No differences were detected in DBTRG-05MG cells with similar treatment. Based on these data, we can assume that TBEV NS1 plays a dual role in the formation of neuroinflammation during the infection, and we can consider this protein as a potential therapeutic target.

The discovery of a class of long noncoding RNAs (lncRNAs), including lncRNAs of the small nucleolar RNA (snoRNA) host gene family, SNHG, has led to growing interest in the study of both snoRNAs themselves and the genes encoding them. Currently, of the 232 known snoRNA genes, only 32 have been confirmed to have lncRNAs. At the same time, a positive correlation has been shown between the expression of lncRNAs and snoRNAs encoded by a common host gene of the SNHG family. Thus, lncRNA of the SNHG1 gene correlates with snoRNAs SNORD22 and SNORD25-31, and lncRNA of the SNHG16 gene, with snoRNAs SNORD1A, SNORD1B, and SNORD1C. There is evidence that SNHG lncRNAs can participate in oncogenesis both through regulatory functions inherent to lncRNAs and by influencing ribosome biogenesis. At the same time, information has accumulated on the "extraribosomal" functions of snoRNAs. In addition to a brief excursion into the biological functions of snoRNAs and SNHG lncRNAs, we present a comprehensive review of data on the role of these two types of noncoding RNAs in the pathogenesis of ovarian cancer, the most insidious cancer of the female reproductive system. The influence of these regulatory RNAs on the main processes of ovarian oncogenesis, such as apoptosis, epithelial-mesenchymal transition, cell cycle control, and DNA methylation mechanisms in this type of cancer is considered. The prospects for clinical application of regulatory RNAs due to their influence on the level of drug resistance are also discussed.

In single-cell datasets, patient labels indicating disease status (e.g., "sick" or "not sick") are typically available, but individual cell labels indicating which of a patient's cells are associated with their disease state are generally unknown. To address this, we introduce mixture modeling for multiple-instance learning (MMIL), an expectation-maximization approach that trains cell-level binary classifiers using only patient-level labels. Applied to primary samples from patients with acute leukemia, MMIL accurately separates leukemia from nonleukemia baseline cells, including rare minimal residual disease (MRD) cells; generalizes across tissues and treatment time points; and identifies biologically relevant features with accuracy approaching that of a hematopathologist. MMIL can also incorporate cell labels when they are available, creating a robust framework for leveraging both labeled and unlabeled cells. MMIL provides a flexible modeling framework for cell classification, especially in scenarios with unknown gold-standard cell labels.

Thyroid nodules are primarily diagnosed using ultrasound imaging (USI), but its low specificity leads to unnecessary fine-needle aspiration biopsies (FNABs). In particular, USI's limited ability to differentiate follicular neoplasms from benign nodules contributes to suboptimal biopsy decision-making. We propose a dual-modal imaging approach that combines multiparametric photoacoustic imaging (PAI) and USI to support smarter biopsy decisions. In 106 patients with 29 benign nodules, 45 papillary thyroid carcinomas, and 32 follicular neoplasms, three PAI-derived parameters-the photoacoustic spectral gradient, oxygen saturation, and skewness of the oxygen saturation distribution-were combined using a support vector machine. Following USI-based American Thyroid Association (ATA) guidelines, they were used to develop the ATA-Photoacoustic (ATAP) scoring system. The ATAP score achieved 97% sensitivity and 38% specificity in distinguishing nodules requiring FNAB. Our approach enabled better identification of benign nodules, reducing unnecessary FNAB in 11 of the 29 benign cases. This dual-modal strategy can assess thyroid nodules, effectively reducing unnecessary biopsies while maintaining high diagnostic accuracy.

Neurofibromin/NF1 is a RAS (rat sarcoma virus) GTPase-activating protein and estrogen receptor (ER) transcriptional corepressor. NF1low status, identified by copy number loss or low mRNA/protein expression, is associated with endocrine therapy resistance in ~20% of ER+/HER2- (human epidermal growth factor receptor 2) early-stage breast cancers. The identification of targeted treatments for NF1low ER+/HER2- breast cancer is therefore a priority. In this study, proteogenomic analysis of ER+/HER2- breast cancer demonstrated that NF1low tumors exhibited elevated cyclin-dependent kinase 4/6 (CDK4/6) activity. In cell lines, NF1 deletion had a dual effect on CDK4 activity: first, by promoting ER recruitment to CCND1 (cyclin D1), thereby increasing CDK4-cyclin D1 complex formation, and second, by activating C-RAF (rapidly accelerated fibrosarcoma), which drove phosphorylation of the CDK4 activation loop. Preclinical modeling demonstrated that NF1low ER+ cancer cells were more sensitive to fulvestrant combined with a CDK4/6 inhibitor versus fulvestrant alone, with the induction of cell death in vitro and durable tumor regressions in ER+ NF1low patient-derived xenograft models in vivo. Furthermore, NF1low ER+/HER2- tumors were more sensitive to neoadjuvant aromatase inhibitor (AI) plus palbociclib than to neoadjuvant AI alone, as indicated by suppression of mRNA-based proliferation scores. These data are consistent with a model whereby ER and RAS coactivation upon NF1 loss can drive CDK4/6 activity and endocrine therapy resistance but renders NF1low ER+ tumors susceptible to CDK4/6 inhibition. Development of clinical-grade NF1 diagnostics should be prioritized to determine whether NF1low ER+ breast cancers should receive adjusted adjuvant treatment recommendations that reflect increased responsiveness to CDK4/6 inhibition.