Human epidermal growth factor receptor 2 (HER2), mismatch repair (MMR) proteins, claudin-18 isoform 2 (CLDN18.2), and the programmed cell death ligand-1 combined positive score (PD-L1 CPS) are predictive biomarkers for the efficacy of combination chemotherapy in patients with locally advanced unresectable or metastatic gastric or gastroesophageal junction cancer. However, only a small proportion of these patients are positive for at least two of these predictive biomarkers.

In this issue of Molecular Cell, Cuneo et al.1 propose an equilibrium between two quaternary states of SPOP that can become dysregulated in cancer. SPOP oligomers form inactive double donuts or active linear filaments, as seen in gain-of-function cancer mutations.

The generation of highly plastic cell states in colorectal cancer that are prone to metastatic dissemination involves complex epigenetic reprogramming, rather than new genetic traits. Goto et al.1 implement a serial orthotopic organoid transplantation framework to uncover the idea that losing Gata6, a guardian of the colonic lineage, promotes metastatic competence.

Chondrosarcoma is a common bone sarcoma in adults with limited therapeutic options due to frequent chemoresistance. Cisplatin (CDDP) is a key chemotherapeutic agent, but resistance often develops. This study investigated the role and mechanism of circular RNA HMGB2 (circHMGB2) in cisplatin resistance of chondrosarcoma. Clinically, circHMGB2 was upregulated in chondrosarcoma tumors and associated with cisplatin resistance and poor patient survival. Functionally, exogenous overexpression of circHMGB2 elevated cisplatin resistance in chondrosarcoma cells (SW1353, OUMS-27) in vitro, while its silencing re-sensitized resistant cells. Mechanistically, circHMGB2 did not function as a miRNA sponge but acted as a competitive molecular decoy for the RNA-binding protein IGF2BP1. We demonstrated that circHMGB2 directly binds IGF2BP1, competitively impairing IGF2BP1's binding to and stabilization of Grb10 mRNA, leading to its destabilization and subsequent downregulation of Grb10 protein. This suppression of Grb10, a known negative regulator of the PI3K/Akt pathway, resulted in constitutive Akt phosphorylation, driving resistance. Crucially, co-overexpression of IGF2BP1 rescued circHMGB2-induced Grb10 downregulation, Akt activation, and cisplatin resistance, validating the decoy mechanism. Furthermore, in a cisplatin-resistant xenograft model, silencing circHMGB2 synergized with cisplatin to significantly inhibit tumor growth, improve host survival, and upregulate intratumoral Grb10 while suppressing Akt phosphorylation. Our results delineate a novel circHMGB2/IGF2BP1/Grb10/Akt axis that drives cisplatin resistance in chondrosarcoma. Targeting circHMGB2 could therefore serve as a promising therapeutic strategy to overcome chemoresistance and enhance treatment efficacy.

To analyze the results of the 15-gene expression profile/preferentially expressed antigen in melanoma (15-GEPP) prognostic classifier and associated survival outcomes in a series of Brazilian patients with posterior uveal melanoma.

Endometrial cancer is the most common gynecologic malignancy in developed countries. Currently, there are no reliable screening methods available for the early diagnosis or prognostic evaluation of the disease. MicroRNAs are small non-coding ribonucleic acid molecules primarily involved in the regulation of gene expression. The aim of this study was to evaluate and compare serum levels of microRNA-204 and microRNA-652-3p between patients diagnosed with endometrial cancer and healthy controls in order to determine their potential diagnostic and prognostic value as candidate biomarkers.

Breast cancer is one of the most distressing cancers affecting women, and early detection is considered the most effective way to reduce breast cancer mortality. However, the benefits of early detection vary among different risk groups. Therefore, using a combination of genetic information, family history, and other factors to stratify populations by risk can help more people benefit from early detection. Traditional polygenic risk score (PRS) is essentially a weighted sum calculation method that has achieved some success, but it neglects the interactions between genes-genes, genes-environment, and their potential impact on breast cancer risk. In this context, we developed a new deep learning-based method called wide, deep, and cross network (WDCN). Experimental results show that our algorithm outperforms PRS and other machine learning baseline methods and achieves an area under the receiver operating characteristic curve (AUROC) of 0.6439 when using 286 single nucleotide polymorphism (SNP) features and 0.8865 when incorporating environmental features with genetic data. Increasing the SNP set to 317 further raised the performance to 0.6464 and 0.8872, both with and without non-genetic factors. Risk stratification shows that individuals in the top 30% have a relative risk of 7.85 (95% CI: 6.98-8.83) compared with those in the bottom 30%. We also identified an interaction between rs2588809 and age. This novel approach has shown promise for initial risk stratification of populations, potentially providing better decision-making support for individuals and clinicians.

Diffuse Gastric Cancer (DGC) is an aggressive subtype with a poor prognosis and a lack of specific biomarkers, representing a critical unmet need in oncology. This study aimed to elucidate the key molecular drivers of DGC by integrating RNA-seq data with a multi-faceted bioinformatics approach.

As the most common malignant renal tumor in children, the progression of Wilms' tumor is frequently driven by abnormal alternative splicing (AS), cell death imbalance, and an immunosuppressive microenvironment. However, the precise regulatory chain connecting these three critical elements remains largely unexplored. This study aimed to systematically construct and characterize an "AS-cell death-immunity" regulatory network in Wilms' tumor.

Dedifferentiated liposarcoma (DDLPS) typically presents as a solitary retroperitoneal mass; diffuse granular and nodular peritoneal sarcomatosis as the inaugural manifestation is exceptional. We report such a case to highlight a critical diagnostic consideration: distinguishing primary sarcomatous peritoneal dissemination from the more common epithelial peritoneal carcinomatosis.

Uterine corpus endometrial carcinoma (UCEC) ranks as the 6th most common malignancy among women. Emerging evidence indicates that the dysregulation of tRNA-derived fragments (tRFs) is involved in the pathogenesis of multiple cancer types, including UCEC; however, the molecular mechanisms underlying the roles of tRFs in UCEC remain poorly characterized. Desmocollin3 (DSC3), a transmembrane protein, is predominantly expressed in the basal and suprabasal layers of normal stratified epithelia. While accumulating evidence has implicated DSC3 in the pathogenesis of multiple disease entities, its functional role in UCEC remains elusive. The present study is designed to investigate the functional significance and underlying molecular mechanisms of tRF-19-79MP9PJZ in the progression of UCEC. In this study, tRF-19-79MP9PJZ was found to be significantly upregulated in UCEC tissues and cell lines, with its elevated expression correlating with unfavorable prognostic outcomes in UCEC patients. Furthermore, tRF-19-79MP9PJZ knockdown was observed to suppress the proliferative and migratory capacities of UCEC cells, while concurrently enhancing apoptotic processes. At the mechanistic level, tRF-19-79MP9PJZ was demonstrated to facilitate UCEC progression through targeted regulation of DSC3. Collectively, this study elucidates a previously uncharacterized mechanism whereby tRF-19-79MP9PJZ drives UCEC development, thereby highlighting the potential of the tRF-19-79MP9PJZ/DSC3 axis as a therapeutic target for UCEC intervention.

Esophageal cancer (EC) ranks 11th in incidence and 7th in mortality among malignancies globally. The role of eukaryotic translation initiation factor 6 (eIF6) in esophageal squamous cell carcinoma (ESCA) progression, including its involvement in tumor development, invasion, and epithelial-mesenchymal transition (EMT), remains to be fully characterized.

In acute myeloid leukemia (AML), therapeutic resistance is intimately linked to vascular microenvironment remodeling; however, the initiating molecular determinants remain elusive. Here, we identified exosomal pyruvate kinase M2 (PKM2) as a pivotal mediator of this pathogenic process. PKM2 was abundantly present in AML-derived exosomes and transferred to human umbilical vein endothelial cells (HUVECs), eliciting metabolic reprogramming characterized by enhanced glycolysis and angiogenic activation. Mechanistically, PKM2 knockdown in AML cells substantially attenuated exosome-induced endothelial migration and tube formation, whereas ectopic PKM2 overexpression in endothelial cells potentiated pro-angiogenic phenotypes. In NOD/SCID mouse xenograft, AML-derived exosomes promoted microvascular remodeling and accelerated disease progression, effects that were abrogated by the angiogenesis inhibitor endostatin. This vascular remodeling coincided with diminished cytarabine (Ara-C) sensitivity, indicative of a chemoprotective microenvironment. Consistently, in a systemic AML model, pharmacological PKM2 inhibition disrupted the vascular niche, suppressed angiogenesis, and restored Ara-C chemosensitivity. Clinically, PKM2 expression correlated positively with VEGFA and HIF-1α levels, and exosomes derived from AML patients with elevated PKM2 conferred enhanced tube-forming capacity upon endothelial cells. Collectively, these findings establish exosomal PKM2 as a critical regulator of the chemoprotective vascular niche in AML and underscore its translational potential as a therapeutic target.

Oxaliplatin resistance remains a major obstacle in the treatment of colorectal cancer (CRC). This study aimed to determine whether MYC contributes to oxaliplatin resistance by regulating ferroptosis and to clarify the downstream mechanisms involving FTH1 and GPX4.

Emerging evidence suggests that viral integration into non-coding and genomically vulnerable regions may represent one of several mechanisms contributing to oncogenesis, warranting further investigation through long-read whole-genome sequencing (WGS).

Olaparib has demonstrated clinical benefit in patients with metastatic castration-resistant prostate cancer (mCRPC) harboring BRCA pathogenic or likely pathogenic variants (PVs) in randomized clinical trials; however, multicenter real-world data in Japanese patients remain limited.

TRIB3 is upregulated in non-small cell lung cancer (NSCLC) and associates with worse survival, yet targeted therapeutics remain lacking. Calcium phosphate (CaP) nanoparticles offer biocompatible, serum-stable delivery for siRNA therapy. Here, we developed CaP nanoparticles loading siRNA targeting TRIB3 (NPCaP/siTrib3) and evaluated antitumor efficacy and mechanisms in vitro and in vivo.

Polybromo-1 (PBRM1) modulates chromatin accessibility and transcription via six bromodomains that bind acetyl-lysine residues on nuclear proteins. PBRM1 variants exist in ~40% of clear cell renal cell carcinoma (ccRCC) cases. PBRM1 loss correlates with improved responses to antiangiogenics and immune checkpoint blockade, which are the standard of care for ccRCC therapy. Missense variants cluster within PBRM1 bromodomains and are present in 16% of ccRCC cases, with unknown impacts on therapeutic response. Since in-depth biophysical and cellular testing of the hundreds of PBRM1 missense variants reported in ccRCC and other cancer types is intractable, computational approaches can provide actionable variant impact assessments. We employed an integrated structural genomics analysis at the levels of protein sequence (2D), structure (3D), and molecular dynamics (4D) to evaluate the effects of all reported ccRCC-associated missense variants in the second and fourth bromodomains of PBRM1 (33 total) on molecular fitness (i.e., stability, structural integrity, and ligand binding). We also evaluated the concordance between molecular fitness and biophysical parameters of variant structural integrity (differential scanning fluorimetry, circular dichroism, and 1H-NMR spectroscopy) and ligand binding (AlphaScreen and electrophoretic mobility shift assays). Integrated molecular fitness scores correlated with measures of acetylated histone binding, while 3D and integrated molecular fitness scores correlated with measures of thermal stability. This integrated structural genomics analysis accelerates mechanistic understanding of how ccRCC missense variants impact PBRM1 bromodomain structure and function. This knowledge supports future studies correlating specific missense variants with PBRM1 tumor-suppressive functions and patient responses to antiangiogenics and immune checkpoint blockade to inform ccRCC personalized medicine approaches.

Triple negative breast cancer (TNBC) and ovarian cancer share many molecular features and are primarily treated with surgical resection and aggressive chemotherapy regimens. Unfortunately, survival rates for patients with advanced metastatic disease are poor, highlighting the need for innovative therapeutic approaches.

Recent advances in molecular and immunologic profiling have substantially refined the understanding of mycosis fungoides (MF) and Sézary syndrome (SS), the two most prominent subtypes of cutaneous T-cell lymphomas (CTCL). CTCL comprise a heterogeneous group of lymphoid malignancies characterized by clonal proliferation of malignant T-cell with cutaneous tropism. The pathogenesis of MF and SS appears to be driven by convergent oncogenic programs involving dysregulated JAK/STAT, NF-κB, PI3K/AKT/mTOR, and MAPK signaling, epigenetic reprogramming, apoptosis resistance, immune escape, and microenvironmental support. In parallel, altered surface phenotypes and chemokine receptor programs shape tissue tropism across skin, blood, and lymph nodes, while the tumor microenvironment promotes tumor persistence and Th2-skewed immune polarization. These insights have translated into novel targeted and immune-based therapies. This review summarizes current insights into the cell-intrinsic and microenvironmental biology of MF and SS and discusses emerging approaches aimed at achieving more durable and personalized disease control.