bims-necame 2026-06-07 papers

Issue of 2026–06–07
four papers selected by
Grigor Varuzhanyan, UCLA

Front Oncol. 2026 ;16 1807289

Morphologic mimicry in high-grade lung carcinoma: a case report of RB1-intact, MYC-amplified, and NFE2L2-mutated pseudo-small cell lung cancer.

Furong Wang, Yaxian Yang, Zhijian Luo, Weiquan Luo, Jian Huang.

Small cell lung cancer (SCLC) is historically defined by distinct neuroendocrine morphology and the obligate bi-allelic inactivation of TP53 and RB1. However, the advent of comprehensive molecular profiling has revealed a subset of high-grade tumors that morphologically mimic SCLC but lack its canonical genomic signatures. These "pseudo-SCLC" cases present significant diagnostic and therapeutic challenges. A 58-year-old male presented with a scapular lytic lesion and pulmonary opacities. Histopathology of the bone biopsy revealed small round blue cells with nuclear molding, crush artifact, and a Ki-67 index of 90%, strongly suggestive of SCLC. Paradoxically, immunohistochemistry (IHC) demonstrated a "null" neuroendocrine phenotype (CD56-, CgA-, Syn focal+) while retaining TTF-1 expression. Next-Generation Sequencing (NGS) identified a pathogenic TP53 mutation (p.V173L) and high-level MYC amplification (CNV: 5×). Crucially, the tumor retained wild-type RB1. Furthermore, a pathogenic NFE2L2 mutation (p.D29V)-a genetic hallmark typically associated with oxidative stress response in non-small cell lung cancer (NSCLC) was identified. This case suggests a potential association with MYC-driven lineage plasticity, where a solid-type adenocarcinoma may undergo de-differentiation into an SCLC-like phenotype. The retention of RB1 and the presence of the NFE2L2 mutation distinguish this entity from classic SCLC, supporting a reclassification as high-grade NSCLC. Recognition of this molecular subset is vital, as NFE2L2 mutations are theoretically linked to resistance to standard platinum-based regimens, potentially necessitating therapeutic strategies distinct from standard SCLC algorithms.

Keywords: MYC amplification; NFE2L2; RB1; lineage plasticity; precision medicine; small cell lung cancer

DOI: https://doi.org/10.3389/fonc.2026.1807289

Aging Male. 2026 Dec 31. 29(1): 2680719

Ubiquitination-anchored signature defines neuroendocrine prostate cancer: hub genes and single-cell ecosystem insights from integrated bioinformatics analysis of public transcriptomic datasets.

Zhenkun Zhao, Lei Qiu, Ziang Li, Jialong Wu, Qianyang Ni, Sijie Li, Hongyin Wang, Chengdong Shi, Xiushi Lin, Yixiao Liu, Jian Lu.

BACKGROUND: Neuroendocrine prostate cancer (NEPC) is an aggressive, treatment-refractory state that often emerges under androgen-receptor pathway inhibition. We hypothesized that dysregulated ubiquitination underpins NEPC lineage plasticity and that integrating bulk and single-cell transcriptomes would define a ubiquitination-centered signature and tumor microenvironment (TME) circuits of diagnostic and therapeutic relevance.
METHODS: Public bulk transcriptomic datasets were combined to compare NEPC with prostate adenocarcinoma, including a GEO discovery cohort of 49 tissue samples from GSE32967 and GSE104786, and intersected with a curated ubiquitination-related gene universe to derive ubiquitination-related differentially expressed genes (URDEGs). Co-expression networks, functional enrichment, and protein-protein interaction (PPI) network topology analyses were used to identify and prioritize candidate hub genes. An independent scRNA-seq cohort was integrated for biological contextualization to map cellular lineages, hub gene localization, and intercellular communication.
RESULTS: We identified 317 URDEGs that clearly segregated NEPC from conventional prostate cancer and clustered into NEPC-associated modules enriched for cell-cycle and mitotic programs. Network integration yielded an 11-gene hub panel, including AURKA, CCNA2, EZH2, FGFR1, and TTK. In the single-cell dataset, 25,325 cells were retained after quality control, and UMAP resolved 17 clusters annotated into 8 major lineages. Single-cell mapping further revealed lineage-biased hub gene expression and highlighted a prominent stromal-vascular as well as immune MIF-CD74/CXCR4 signaling axis.
CONCLUSIONS: This integrative analysis identifies a ubiquitination‑anchored transcriptomic signature and associated hub‑gene network that are consistently associated with NEPC in public bulk datasets and supported by cell‑type-resolved patterns in an independent scRNA‑seq cohort; these findings nominate candidate biomarkers and therapeutic hypotheses that warrant external validation in prospectively collected, clinically annotated cohorts with protein‑level assessment.

Keywords: Neuroendocrine prostate cancer; single-cell RNA sequencing; tumor microenvironment; ubiquitination; weighted gene co-expression network analysis (WGCNA)

DOI: https://doi.org/10.1080/13685538.2026.2680719

Cancer. 2026 Jun 01. 132 Suppl 1 e70418

The future promise of antibody-drug conjugates in extensive-stage small cell lung cancer.

Nan Sethakorn, Anne C Chiang.

Small cell lung cancer (SCLC) is an aggressive subtype of lung cancer with poor long-term survival. It is highly sensitive to chemotherapy and radiation therapy upfront, but rapidly develops acquired treatment resistance, even with the addition of checkpoint inhibitor therapies. Antibody-drug conjugates (ADCs) are a rapidly emerging class of therapeutics consisting of a targeting antibody linked to a cytotoxic payload, which can deliver these potent chemotherapies directly to the tumor sites. This review will discuss promising targets and ADCs in SCLC, address current challenges, and future opportunities for the next generation of ADCs.

Keywords: SCLC; antibody–drug conjugates; clinical trials; transcriptional subtypes

DOI: https://doi.org/10.1002/cncr.70418

Neoplasia. 2026 May 30. pii: S1476-5586(26)00051-5. [Epub ahead of print]78 101321

Systematic analysis of hippo pathway signaling identifies TEAD1 as a transcriptional regulator of neuroendocrine prostate cancer.

Treatment-induced neuroendocrine prostate cancer (NEPC) represents an aggressive form of castration-resistant prostate cancer (CRPC) associated with lineage plasticity and therapeutic resistance. In this study, we investigated the role of the Hippo signaling axis in the transdifferentiation from androgen receptor-positive prostate cancer (ARPC) to NEPC. RNA sequencing analyses of CRPC metastases revealed coordinated alterations in Hippo pathway components, with decreased expression of YAP1, LATS2, and TEAD2 and increased expression of LATS1, TEAD1, and the RNA splicing regulator RBFOX2 in NEPC. These transcriptional alterations were consistently observed across multiple model systems and patient samples. Epigenetic analyses demonstrated that reduced expression of YAP1, TEAD2, and LATS2 was associated with increased DNA methylation, whereas elevated TEAD1 expression correlated with DNA hypomethylation in NEPC. NEPC selectively retained TEAD1 expression, including a spliced isoform not detected in ARPC. Proteomic interactome analyses revealed that TEAD1 associated with RNA splicing factors and DNA repair proteins. Functional studies showed that TEAD1 knockdown led to the reversion of gene programs associated with epithelial differentiation. These findings indicate that the conversion of ARPC to NEPC involves coordinated loss of AR, YAP1, and REST activity alongside sustained TEAD1 expression and altered RNA processing. Our data identify TEAD1 as a transcriptional regulator associated with the NEPC state and suggest a role for TEAD1-linked transcriptional and post-transcriptional mechanisms in prostate cancer lineage plasticity.

Keywords: Neuroendocrine; Prostate; RBFOX2; TEAD1; YAP

DOI: https://doi.org/10.1016/j.neo.2026.101321