Choroid Plexus Tumors (CPT) are rare (2-4% of all pediatric CNS tumors), predominantly early childhood brain neoplasms. Due to their rarity and the lack of prospective clinical trials, evidence-based treatment guidelines remain limited. This review provides a comprehensive summary of the current knowledge.\n\nCPTs span a spectrum from mature Choroid Plexus Papillomas (CPP) to malignant Choroid Plexus Carcinomas (CPC), with Atypical Choroid Plexus Papillomas (aCPP) in between. A significant proportion of CPCs are driven by either somatic or germline TP53 mutations (Li-Fraumeni syndrome); however, other molecular drivers of CPT tumorigenesis remain poorly understood. CPTs exhibit distinct DNA methylation profiles, allowing for classification into clinically relevant subgroups. These tumors also display a chromosomal instability phenotype, characterized by multiple copy number alterations. \n\nAdvances in molecular profiling have revealed that TP53-mutated CPCs have significantly worse outcomes. Both retrospective and limited prospective data have shown 5-year event-free survival rates of 0-25% for TP53-mutant CPCs versus 70-80% for TP53-wild-type cases. The extent of surgical resection remains another established prognostic factor, while data on the roles of radiation therapy (RT) and myeloablative chemotherapy with stem cell rescue are still evolving. Preliminary evidence suggests that TP53-mutant patients may be getting less benefit from RT, but greater benefit from myeloablative chemotherapy approach with avoidance of RT.\n\n The emerging insights into CPC biology and long-term outcomes can direct the design of future clinical trials. A new international prospective study led by the Pediatric Neuro-Oncology Consortium is in development, with the goal to stratify patients by molecular subtype to receive different therapy based on individual molecular profiles and patient age.

Pediatric-type diffuse low grade glioma are a novel subgrouping of pediatric glioma defined in the updated WHO 2021 classification of central nervous system tumors. The newly recognized pediatric-type diffuse low grade glioma family is comprised of four distinct entities, including diffuse astrocytoma MYB or MYBL1-altered, angiocentric glioma, polymorphous low-grade neuroepithelial tumor of the young, and diffuse low grade glioma MAPK-altered. Due to significant overlap in histopathology and molecular alterations between pediatric-type diffuse low grade glioma, accurate diagnosis of these tumor subtypes requires integration of both histology and molecular findings. Herein, we describe the epidemiologic, imaging, and molecular features of these pediatric diffuse glioma. In addition, we review current knowledge regarding management approach and treatment outcomes, including potential therapeutic implications of prevalent molecular alterations within this family of tumors.

The 7-Dehydrocholesterol reductase (DHCR7), a critical enzyme catalyzing the final step of the cholesterol biosynthesis pathway, has gained attention for its potential role in tumorigenesis. This study systematically investigated the association between DHCR7 expression and oncogenic processes across multiple cancer types.

Tumor progression and therapeutic resistance depend not only on tumor cells but also on the tumor vasculature, a central component of the tumor microenvironment (TME). Accordingly, normalization and remodeling of tumor vessels represent a promising therapeutic strategy, highlighting the urgent need for approaches that selectively and efficiently modulate this compartment. Actrt1 (ArpT1) is an actin-related protein implicated in ciliogenesis, but its roles in the TME are unknown. Here, we show that Actrt1 drives tumor progression through non-hematopoietic cells, with endothelium as a principal site of action. Actrt1 knockout (Actrt1-/-) mice displayed significantly reduced growth of B16F1 and MC38 tumors and improved survival. Bone-marrow chimeras localized this phenotype to the host non-hematopoietic compartment; Actrt1-/- marrow in WT hosts did not confer protection, whereas WT marrow in Actrt1-/- hosts did. Immunofluorescence detected Actrt1 in CD31+ tumor vessels in vivo. Developmental retinal vascularization was preserved, but endothelial sprouting from Actrt1-/- aortic rings was reduced, and recovery after hindlimb ischemia was delayed. In Matrigel-tumor plugs, gross vascular ingrowth was decreased. Single-cell RNA-seq of the GFP- CD45- stromal fraction resolved 14 clusters; the endothelial fraction was unchanged in proportion, yet Actrt1 deficiency shifted its transcriptome toward immaturity. Histology showed shorter, discontinuous CD31+ vessels. Together, our data indicate that Actrt1 promotes tumor growth through non-hematopoietic endothelium by sustaining sprouting and vessel maturation, while developmental angiogenesis remains intact. Targeting Actrt1 may therefore restrain tumor growth by impairing maladaptive angiogenesis and could complement strategies for vascular normalization.

DNA damage response (DDR), a highly complicated regulatory network that detects and repairs DNA lesions, serves as an indispensable guardian of genomic integrity. Targeting aberrant DNA repair pathway has emerged as a promising therapeutic approach for cancer, which includes double-strand break repair (DSBR), nucleotide and base excision repair (NER/BER) and mismatch repair (MMR). Elucidating precise molecular mechanisms of DNA damage repair and their synthetic lethal effects will facilitate the development of novel therapeutic targets and strategies for cancer. Deubiquitinases (DUBs) modulate the subcellular localization, protein activity and stability of DDR molecules, thereby playing a critical role in dynamically orchestrating DNA damage repair process. Furthermore, DUBs are highly attractive drug targets in cancer therapies due to their catalytic domains. This review provides a comprehensive overview of the multifaceted roles and mechanisms of DUBs in DNA damage responses and their anticancer potential.

The atlas of immune microenvironment at single-cell level in BRCA1/2-mutated breast cancer is largely unknown and whether an immune signature on the basis of single-cell atlas is associated with response to neoadjuvant chemotherapy remains to be investigated.

Renal cell carcinoma (RCC) that metastasizes to the pancreas (RCC-PM) is a rare but known phenomenon. These patients have been described to have indolent disease and longer overall survival than patients with metastasis to other sites. We investigated the genomic landscape and outcomes for patients with RCC-PM.

Sturge-Weber syndrome and encephalocraniocutaneous lipomatosis (ECCL) are neurocutaneous syndromes with unique presentations.

Epithelial-mesenchymal transition (EMT) plays a key role in cancer metastasis by promoting changes in adhesion and motility. RNA-binding proteins (RBPs) regulate alternative splicing (AS) during EMT, enabling a single gene to produce multiple protein isoforms that affect tumor progression. Disruption of RBP-AS interactions may disrupt the progress of diseases like cancer. Despite the importance of RBP-AS relationships in EMT, few computational methods predict these associations. Existing models struggle in sparse settings with limited known associations. To improve performance, we incorporate both sparsity constraints and heterogeneous biological data to infer RBP-AS associations.

Genetic abnormalities in ion channels that regulate the depolarization of adrenal glomerular cell plasma membranes have been identified as a cause of primary aldosteronism (PA) due to aldosterone-producing adenoma (APA). This study aimed to evaluate somatic variants in the KCNJ5, CACNA1D, CLCN2, ATP1A1, ATP2B3, GNAQ, GNA11, and CTNNB1 genes, assess the genotype-phenotype correlation, and analyze the outcomes in patients with APA from a heterogenic ethnic population.

Coiled-coil domain-containing protein 86 (CCDC86) expression is correlated with the occurrence of lymphoma. However, the expression of CCDC86 in solid tumors such as nasopharyngeal carcinoma (NPC) and the effects of CCDC86 on tumorigenesis remains unclear. Here we studied both problems using tumor tissue samples from NPC patients, NPC cell lines (in vivo), and a model of transplanted tumor in BALB/c nude mice (in vitro). We found that CCDC86 protein was expressed in all studied cell lines, but its expression in CNE1, CNE2, CNE-2Z, 5-8F, and 6-10B cell lines was higher than in nasopharyngeal epithelium cell lines NP69 and NP460. In tumor tissues obtained from patients with NPC, CCDC86 expression was higher than in normal (adjacent) tissues. Knockdown of CCDC86 gene inhibited colony formation and cell proliferation, but increased apoptosis. In BALB/c nude mice transplanted with CCDC86-knockdown CNE-2Z cells, tumors barely grew in comparison with the controls transplanted with CNE-2Z cells transfected with an empty vector lentivirus. In conclusion, CCDC86 is expressed in NPC tissues and NPC cell lines and is closely associated with NPC tumorigenesis. Our study may provide insights into exploring the novel therapeutic targets for NPC.

Prostate cancer (PCa) is a leading cause of cancer-related mortality, with significant racial disparities in outcomes. Long non-coding RNAs (lncRNAs) MALAT1 and TUG1 are implicated in oncogenic pathways. Aberrant RNA splicing, a hallmark of cancer, is often driven by dysregulation of serine-arginine protein kinase 1 (SRPK1), a key spliceosome regulator. The relationship between lncRNAs of splicing factors in cancer pathways remains underexplored, and thus, this study aimed to elucidate the roles of MALAT1 and TUG1 lncRNAs in relation to the SRPK1 inhibitor SPHINX31 in PCa.

Cervical cancer is a common cancer among women worldwide. It has been revealed that hypoxia contributes to the progression of cervical cancer. In our study, we discovered that hypoxia indeed promoted the malignant phenotypes of cervical cancer cells by enhancing glycolysis. Loss-of-function experiments showed that hypoxia treatment upregulated the octamer-binding transcriptional factor 4 (OCT4) expression via glycolysis. Through the RNA-sequence and enrichment analyses, we found that hypoxia induced the enrichment of the calcium signaling pathway and upregulation of Calcium Release-Activated Calcium Modulator 3 (ORAI3), which could be abrogated by silencing OCT4. Notably, overexpressing ORAI3 has similar effects on the malignant phenotypes of HeLa and SiHa cells as those of hypoxia. Furthermore, silencing ORAI3 or inactivating calcium signals significantly reversed OCT4-induced malignant progression of cervical cancer both in vitro and in vivo. ChIP and dual-luciferase reporter results confirmed that OCT4 contributed to the transcription of ORAI3. Mechanically, hypoxia upregulated OCT4 expression by facilitating glycolysis, and OCT4 overexpression enhanced the transcription of ORAI3, activating the calcium signaling pathway and ultimately promoting the malignant progression of cervical cancer. Our study reveals novel molecular mechanisms by which hypoxia induces the progression of cervical cancer, providing a new strategy for treating cervical cancer.

Mismatch repair-deficient (dMMR) or microsatellite instability-high (MSI-H) tumors represent a biologically and immunologically distinct subset of solid malignancies. Defective DNA mismatch repair mechanisms in these tumors lead to the accumulation of insertion-deletion mutations, a hypermutated phenotype, and abundant tumor-specific neoantigens. These features drive robust T cell responses, explaining the remarkable sensitivity of dMMR/MSI-H tumors to immune checkpoint inhibitors (ICIs). Emerging evidence from clinical trials across resectable dMMR/MSI-H colorectal, gastric and gastroesophageal junction, and other solid tumors indicate that ICI therapy can induce profound pathological responses, including high rates of pathological complete response. These responses may permit organ preservation and reduce treatment-associated morbidity, offering a compelling alternative to conventional surgery-based approaches. Despite this promise, several challenges remain. Critical areas warranting further investigation include the refinement of patient selection strategies, clarification of the role of surgery in patients achieving a clinical complete response, and the identification of reliable predictive biomarkers for therapeutic response and resistance. In addition, the long-term oncologic outcomes associated with non-operative management remain to be elucidated. This review comprehensively summarizes the biological basis and emerging clinical evidence for immunotherapy in resectable dMMR/MSI-H solid tumors. We discuss current opportunities and ongoing challenges in refining curative-intent strategies, with the aim of improving outcomes and quality of life for patients with these immunologically distinct cancers.

Cancer cells harbor somatic mutations that generate novel amino acid sequences that are absent in the self-proteome. These mutation-derived cancer-specific peptides are defined as "neo-peptides". Neo-peptides eliciting immune responses, i.e. immunogenic neo-peptides, are defined as "neo-epitopes". Given their relevance to cancer immunotherapy, we conducted a meta-analysis to examine how experimental evidence informs our understanding of neo-epitopes. Our study is the largest reported to date. Using the cancer epitope database and analysis resource (CEDAR), we analyzed over 16,000 neo-peptides tested in more than 20,000 T cell assays across 180 studies. We found that validated neo-epitope frequencies varied across cancer types, with the highest rates in skin and lung and the lowest in colorectal cancer. Neo-epitopes were enriched in driver genes such as TP53 and KRAS. However, testing frequency correlated with mutation prevalence, revealing bias toward recurrent mutations. Despite the high sequence similarity among RAS family members, validated neo-epitope overlap was minimal, challenging pan-RAS strategies. Shared neo-epitopes across cancer types are rare, with only 16 validated in more than one cancer type. While most assays involved HLA class I, class II alleles presented a higher proportion of validated neo-epitopes. Specific alleles, including HLA-B*40:01 and HLA-DRB1*11:01, were enriched for neo-epitopes, whereas others, like HLA-A*02:01, were enriched for non-immunogenic neo-peptides. Finally, amino acid substitutions that altered hydrophobicity or charge were more common in neo-epitopes. Together, these findings define key features of neo-epitopes, expose methodological and biological biases in the literature, and highlight opportunities to improve the selection and prioritization of neo-epitopes for cancer immunotherapy.

The MEK-ERK pathway is a key driver of hepatocellular carcinoma (HCC) pathogenesis, and BRAF mutations, particularly BRAFV600E, can contribute to its activation. Although BRAFV600E mutations are rare in human HCC, they do occur, yet their physiologic impact in liver cells, especially when combined with frequent comutations in tumor suppressor genes, remains poorly understood. Moreover, the effect of BRAF inhibitors on HCC progression and metastasis is not well-defined. Therefore, we developed mouse models with hepatocyte-specific BRAFV600E expression and Trp53 or Cdkn2a deletion to assess tumor development, subtypes, and metastatic patterns. We found that BRAFV600E expression caused hepatomegaly, vascular congestion, and ductal reactions, and led to reduced liver function and early mortality. Codeletion of Trp53 or Cdkn2a markedly increased primary liver tumor incidence and enabled sarcomatoid metastasis. While the BRAF inhibitor PLX4720 effectively reduced primary tumors and extended survival, it paradoxically increased sarcomatoid metastases. Mechanistically, PLX4720 and other RAF inhibitors induced TGFβ2 expression which promoted epithelial-to-mesenchymal transition (EMT) and enhanced tumorigenicity. The effects of RAF inhibitors on TGFβ2 expression were validated in BRAFV600E-mutant human melanoma cells. We conclude that BRAFV600E drives diverse primary tumors but only one type of metastasis and that RAF inhibition, while effective against primary tumors, may promote metastasis through TGFβ2-mediated EMT. Although RAF inhibitors remain promising therapies, their unintended role in enhancing metastasis raises concerns that may extend beyond liver cancer to other BRAFV600E-driven malignancies.

Benign and malignant (cancerous) tumors differ markedly in their impact on organismal fitness, yet studies in comparative oncology rarely distinguish between them. Using a Bayesian phylogenetic framework across birds and mammals, we show that while both tumor types increase in prevalence with body mass, only the prevalence of malignant tumors is negatively associated with the rate of body size evolution-suggesting that adaptive mechanisms of cancer defense are associated with rapidly evolving lineages. Additionally, the rate of lineage diversification is positively associated with the prevalence of both tumor types in birds but not mammals, potentially reflecting differences in genome architecture and speciation dynamics. Together, these results highlight distinct macroevolutionary drivers of benign versus malignant tumor prevalence and underscore the value of treating tumor types separately in comparative oncology.

Metabolic pathways are typically dysregulated in cancer to support critical cellular processes. In response to metabolic disturbances, cancer cells preferentially manipulate stress sensors to enhance their adaptability. Sestrin 2 (SESN2), a highly conserved protein induced by various stressors, is implicated in this adaptation. Mutations and alterations of SESN2 are prevalent among cancer patients, suggesting a potential role in tumor progression. However, the functions and regulation of SESN2 in cancer, particularly in virus-induced cancer, remain largely unknown. In this study, we demonstrate that latent infection with Kaposi's sarcoma-associated herpesvirus (KSHV) stabilizes and upregulates SESN2 by inhibiting its proteasomal degradation across multiple cell lines. Notably, KSHV-encoded vCyclin, a homolog of cellular Cyclin D, directly interacts with SESN2 and promotes its stabilization by recruiting the deubiquitinase OTUB1, thereby blocking SESN2 polyubiquitination and proteasomal degradation. Moreover, vCyclin- and OTUB1-mediated stabilization of SESN2 activates AMP-activated protein kinase (AMPK), which supports the survival and growth of KSHV-driven primary effusion lymphoma cells. Importantly, the lysine at residue 74 of vCyclin is crucial for its cytosolic localization, OTUB1 recruitment, and subsequent SESN2 upregulation and AMPK activation. These findings unveil a regulatory mechanism for SESN2 involving vCyclin and OTUB1, positioning them as potential therapeutic targets for diseases associated with AMPK dysregulation.

Thyroid nodules are common, and the majority are of benign nature, however the main clinical aim remains to discriminate malignant ones. Despite that, the actual routine workup for thyroid nodules including hormonal testing, ultrasound scan, scintigraphy, and Fine needle aspiration cytology (FNAC) is still deficient, often necessitating surgical intervention for a conclusive histopathological examination and diagnosis. Therefore, searching for molecular tools that help in differentiating benign and malignant thyroid nodules gains an increasing interest.

Secretory breast carcinoma (SBC) is a rare tumour defined by ETV6-NTRK3 rearrangement, but its clinicopathological spectrum and potential for aggressive behaviour remain incompletely characterised. We retrospectively reviewed 29 SBCs diagnosed between 2014 and 2024, including 28 females and one male aged 12-63 years (median 44). Twenty-eight tumours arose in the breast parenchyma and one in axillary accessory breast tissue. Histologically, microcystic and tubular patterns predominated and carcinoma in situ was common. Most tumours were nuclear grade 1 with rare mitoses (0-1/10 high-power fields, HPF). A single patient with distant metastasis harboured a solid-predominant tumour showing nuclear grade 2-3, brisk mitoses (6/10 HPF), and multifocal necrosis. All tumours demonstrated diffuse S100 and pan-TRK expression. Oestrogen and/or progesterone receptor staining was observed in 16 of 29 cases (2-30% of tumour cells), and all were HER2 negative or low (0-1+). Ki-67 ranged from 3% to 20% (mean 7%). Fluorescence in situ hybridisation (FISH) was positive in 17 of 17 tested tumours (14 ETV6-NTRK3 dual-fusion; 3 NTRK3 break-apart). In the metastatic case, RNA sequencing confirmed canonical ETV6-NTRK3 fusion, while targeted DNA sequencing identified additional variants of uncertain significance (VUS) - RANBP2 p.S1843R, NUP107 p.K382Q, NCOR1 p.A1947V (missense), and PREX2 p.G606G (synonymous). All patients underwent surgery, and 14 received adjuvant chemotherapy. During follow-up ranging from 6 to 135 months (median 76), one patient developed lung metastasis and was alive with disease at 88 months; the remaining 28 patients were alive without recurrence or metastasis. In summary, SBC is typically indolent and characterised by ETV6-NTRK3 rearrangement with diffuse pan-TRK/S100 positivity. A solid-predominant pattern with increased cytological atypia, mitotic activity, and necrosis may indicate aggressive potential. Routine NTRK testing supports diagnosis and may help identify patients who could benefit from TRK-inhibitor therapy in advanced disease.