bims-necame 2026-01-11 papers

bims-necame

Biomed News

on Metabolism in small cell neuroendocrine cancers

Issue of 2026–01–11
twenty-two papers selected by
Grigor Varuzhanyan, UCLA

A MYC Family Switch: L-MYC Drives and Maintains Neuroendocrine Lineage Programs in Prostate Cancer.
Esophageal neuroendocrine carcinoma: molecular insights, diagnostic advances, and emerging treatment strategies.
The Olive Phenolic S-(-)-Hydroxyoleocanthal Attenuates Neuroendocrine Prostate Cancer via Modulation of EPHA3-Centered Oncogenic Network.
KDM7B-mediated demethylation of RNF113A regulates small cell lung cancer sensitivity to alkylation damage.
Relationship Between Metabolic Parameters and Asphericity Derived from 18F-FDG PET/CT and Stage in Small Cell Lung Cancer.
Molecular Deconvolution of Circulating "Other Cells": A Reliable Predictive Marker of Therapy Response and Survival in Neuroendocrine Tumor Patients Receiving 177Lu-DOTATATE PRRT.
SMARCA4 loss promotes late-stage tumor progression in non-neuroendocrine small-cell lung cancer.
Extracellular matrix regulates lineage plasticity in prostate cancer through YAP/TEAD.
Malignancy Detection Rates of [68Ga]Ga-SSO120 PET/CT in Patients with Small Cell Lung Cancer and Large Cell Neuroendocrine Lung Cancer.
Improved somatic mutation profiling in small-cell lung cancer using RNA-sequencing and the T2T-CHM13 genome reference.
Relative survival of large cell to small cell neuroendocrine carcinoma of the uterine cervix.
Lineage Plasticity and Histologic Transformation in EGFR-TKI Resistant Lung Cancer.
Epigenetics and the Tumor Microenvironment in Neuroendocrine Tumors.
Targeting DHODH Reveals a Metabolic Vulnerability in AR-positive and AR-negative Prostate Cancer Cells via Pyrimidine Synthesis and Metabolic Crosstalk with the TCA and Urea Cycles.
Analysis of SCLC subtype markers (ASCL1, NEUROD1, POU2F3, YAP1), DLL3, OTP, and TTF1 in 300 lung carcinoids and enteropancreatic neuroendocrine tumours.
Regulation of INSM1 Gene Expression and Neuroendocrine Differentiation in High-Risk Neuroblastoma.
Safety and efficacy of the HilumDirect uVATS for small cell lung cancer: a retrospective study.
LASSO-based nomograms predict early death in small cell lung cancer (SCLC) patients with brain metastasis.
Conserved Neuronal-like and Secretory Programs Define the Spatial Architecture of Gastroenteropancreatic Neuroendocrine Tumors.
Diagnosis and management of pituitary neuroendocrine tumors: recent advances.
CCT3 Facilitates the Malignant Progression of NSCLC and SCLC via PI3 K/AKT-EMT Axis and Emerges as a Novel Serum Diagnostic Biomarker.
Molecular reprogramming in thymic neuroendocrine tumors: a narrative review.

bioRxiv. 2025 Dec 26. pii: 2025.12.25.696507. [Epub ahead of print]

A MYC Family Switch: L-MYC Drives and Maintains Neuroendocrine Lineage Programs in Prostate Cancer.

Jeyaluxmy Sivalingam, Kyung Hyun Cho, Yingli Shi, Preston Barron, Michael Lan, Omar Franco, Xiuping Yu.

Neuroendocrine prostate cancer (NEPC) is an aggressive, therapy-resistant subtype that emerges through lineage plasticity following androgen receptor (AR) pathway inhibition. Although MYC family oncogenes are central to prostate cancer progression, the role of MYCL (L-MYC) in NEPC has remained unclear. Here, we show that MYCL is selectively and robustly upregulated in NEPC patient samples and cell line models, whereas MYC is downregulated and MYCN remains low, revealing a lineage-associated MYC family switch. MYCL expression strongly correlates with the neuroendocrine lineage regulators ASCL1 and INSM1 and inversely with adenocarcinoma-associated genes. Mechanistically, MYCL activation is not driven by genomic amplification but reflects a permissive epigenetic landscape. Functionally, MYCL overexpression suppresses AR signaling and induces neuroendocrine-like transcriptional reprogramming, whereas MYCL knockdown disrupts neuroendocrine lineage identity and restores adenocarcinoma-associated gene expression, including MYC. We further identify ASCL1 and INSM1 as upstream regulators of MYCL, establishing a conserved neuroendocrine transcriptional axis. Together, these findings define MYCL as a lineage-specific regulator that drives neuroendocrine identity and plasticity in advanced prostate cancer.

DOI: https://doi.org/10.64898/2025.12.25.696507
Clin Transl Oncol. 2026 Jan 08.

Esophageal neuroendocrine carcinoma: molecular insights, diagnostic advances, and emerging treatment strategies.

Xi-Wen Wu, Yu Du, Yan Jiao.

  Esophageal neuroendocrine carcinoma (ENEC) is a rare and aggressive malignancy, characterized by its high-grade, poorly differentiated nature. Despite advancements in understanding neuroendocrine tumors (NETs), ENEC remains an under-researched and poorly understood entity, presenting significant challenges in both diagnosis and treatment. Molecular studies have revealed frequent mutations in TP53 and RB1, along with genetic profiles paralleling small cell lung cancer (SCLC), suggesting shared oncogenic pathways that may guide targeted therapeutic approaches. However, the rarity of ENEC has limited the development of standardized treatment regimens, with most strategies borrowed from other malignancies such as SCLC. Current treatments, including platinum-based chemotherapy, show moderate success, yet response rates remain variable, particularly in advanced stages. The role of immunotherapy and targeted therapies is under investigation, with promising case reports but limited clinical evidence. Emerging diagnostic technologies, such as molecular profiling and liquid biopsy, offer enhanced precision in early detection and personalized treatment plans. Prognostic factors, such as Ki-67 proliferation index, serum biomarkers, and tumor stage, have shown significant associations with survival outcomes, though they remain under-explored in prospective clinical trials. Given the unique molecular features of ENEC, including high tumor mutational burden and distinct immune profiles, further research is essential to develop effective biomarkers, refine prognostic models, and create personalized, targeted therapies. This review aims to consolidate current knowledge on ENEC's molecular biology, diagnosis, and treatment, while identifying gaps in research and suggesting directions for future investigation to improve patient outcomes.

Keywords:  Chemotherapy; Esophageal neuroendocrine carcinoma; Immunotherapy; Molecular profiling; Targeted therapy

DOI:  https://doi.org/10.1007/s12094-025-04191-7
Cancers (Basel). 2025 Dec 21. pii: 26. [Epub ahead of print]18(1):

The Olive Phenolic S-(-)-Hydroxyoleocanthal Attenuates Neuroendocrine Prostate Cancer via Modulation of EPHA3-Centered Oncogenic Network.

Md Towhidul Islam Tarun, Hassan Y Ebrahim, Khalid A El Sayed.

  Background/Objectives. Prostate cancer (PCa) is the second leading cause of cancer-related mortality among men in the United States. Treatment with second-generation androgen receptor (AR) inhibitors, such as enzalutamide, can trigger lineage plasticity, promoting the transdifferentiation of PCa cells into an AR-independent, poorly differentiated neuroendocrine phenotype (NEPC). The receptor tyrosine kinase EPHA3 is a critical driver for NEPC. It is overexpressed in PCa, particularly in androgen-independent and neuroendocrine subtypes. EPHA3 activates c-Myc signaling to enhance EZH2 expression, promoting histone H3K27 trimethylation. The neural transcription factor BRN2 functions upstream of both EZH2 and ASCL1. The latter regulates the Notch pathway ligand DLL3, thereby orchestrating neuroendocrine differentiation. Elevated expression of classical neuroendocrine markers CHGA and SYP is characteristic of the NEPC phenotype. This study reports the novel usage of the olive phenolic S-(-)-hydroxyoleocanthal (HOC, oleacein) to effectively control NEPC by targeting the EPHA3-BRN2-EZH2-ASCL1-DLL3-SYP-CHGA oncogenic network. Methods. Cell viability assays were conducted to assess in vitro effects. To model NEPC progression and recurrence, NCI-H660-Luc cells were xenografted into male athymic nude mice. RNA-sequencing was performed to compare the differentially expressed genes between placebo control and treated tumors. Results. HOC significantly attenuated the proliferation of NEPC NCI-H660 cells in vitro. Daily oral administration of HOC at 10 mg/kg body weight markedly suppressed the progression of NEPC NCI-H660-Luc tumors. Continued HOC treatments after surgical excision of the primary tumors substantially reduced locoregional recurrence. HOC significantly downregulated the expression of EPHA3, BRN2, EZH2, ASCL1, DLL3, SYP, and CHGA in treated primary and recurrence tumors versus placebo control. Conclusions. These findings establish HOC as a multifaceted therapeutic entity capable of disrupting key NEPC oncogenic networks, highlighting its potential as a novel lead intervention for aggressive NEPC.

Keywords:  EPHA3–BRN2–EZH2–ASCL1–DLL3–SYP–CHGA axis; RNA-sequencing; S-(-)-hydroxyoleocanthal; neuroendocrine prostate cancer; olive phenolics; progression; recurrence

DOI:  https://doi.org/10.3390/cancers18010026
bioRxiv. 2026 Jan 03. pii: 2026.01.03.697470. [Epub ahead of print]

KDM7B-mediated demethylation of RNF113A regulates small cell lung cancer sensitivity to alkylation damage.

Tanveer Ahmad, Xiaojie Yang, Anne-Emmanuelle Foucher, Lingnan Ren, Ning Tsao, Natasha Flores, Jinkai Wan, Lucid Belmudes, Etienne Dubiez, Monika Chandan Bhowmik, Jessica Vayr, Simone Hausmann, Florent Chuffart, Xiaoyin Lu, Sandrine Blanchet, Tourkian Chasan, Faycal Boussouar, Yohann Couté, Nima Mosammaparast, Fei Lan, Jan Kadlec, Pawel K Mazur, Nicolas Reynoird.

Chemoresistance remains a major obstacle to effective cancer treatment, often driven by enhanced DNA repair mechanisms that enable tumor cells to withstand genotoxic therapies. One such pathway involves the atypical DNA damage repair complex ALKBH3-ASCC, activated by the E3 ligase RNF113A in response to alkylation damage. We previously showed that SMYD3-dependent methylation of RNF113A stimulates this pathway, enhancing DNA repair and promoting resistance. Here, we identify KDM7B/PHF8 as the bona fide RNF113A demethylase, establishing one of the first functional examples of a dynamic, reversible non-histone methylation event regulating genome integrity. KDM7B antagonizes SMYD3 activity by maintaining low levels of methylated RNF113A, thereby limiting ASCC activation and sensitizing cancer cells to alkylating agents. To dissect this regulation in depth, we focused on small cell lung cancer (SCLC), a particularly aggressive malignancy characterized by limited therapeutic options and rapid acquisition of resistance. In SCLC, high KDM7B levels correlate with improved patient prognosis, whereas xenografts with reduced expression exhibit diminished responses to alkylating treatment. Moreover, CRISPR-based on/off modulation of KDM7B in genetically engineered SCLC mouse models demonstrates its central role in determining tumor response to chemotherapy. Our findings position the RNF113A-ASCC axis as a central modulator of chemoresistance, regulated through a post-translational methylation switch representing an innovative therapeutic vulnerability that could be exploited to enhance the efficacy of alkylating agents. Targeting this pathway may provide new opportunities to overcome chemoresistance, with KDM7B levels serving as a predictive biomarker to guide treatment in SCLC.

DOI: https://doi.org/10.64898/2026.01.03.697470
Rev Esp Med Nucl Imagen Mol (Engl Ed). 2026 Jan 02. pii: S2253-8089(25)00181-8. [Epub ahead of print] 500276

Relationship Between Metabolic Parameters and Asphericity Derived from 18F-FDG PET/CT and Stage in Small Cell Lung Cancer.

K Şeker, Ö Ulaş, Z Hasbek.

   PURPOSE: This study retrospectively evaluated the relationship between disease stage and metabolic parameters, along with asphericity, derived from 18F-FDG PET/CT images in patients with Small Cell Lung Cancer (SCLC).
METHODS: We analyzed primary tumor metabolic parameters, including maximum and mean standardized uptake values (SUVmax, SUVmean), metabolic tumor volume (MTV), and total lesion glycolysis (TLG), as well as Asphericity (ASP). Disease staging was determined from 18F-FDG PET/CT images as either limited-stage (LS) or extensive-stage (ES). Statistical analyses assessed the correlation among these metabolic parameters and ASP, their relationship with disease stage, their ability to predict disease stage.
RESULTS: The study included 134 SCLC patients (mean age: 62.3; 112 males, 22 females). Of these, 61.2% had ES and 38.8% had LS disease. MTV, TLG, and ASP values were significantly higher in the ES group than in the LS group (p < 0.001). In the multivariate binary logistic regression analysis, Age (p = 0.025), Gender (p = 0.033), and ASP (p = 0.001) were identified as independent predictors of disease stage. Notably, a one-unit increase in ASP was associated with a 6.35-fold increase in the likelihood of Extensive-Stage disease (OR = 6.350). In ROC analysis, MTV, TLG, and ASP significantly distinguished disease stages (p < 0.001) with optimal cut-off values of 45.05, 382.81, and 0.536, respectively.
CONCLUSION: Relying solely on SUVmax for SCLC patient evaluation may be insufficient. Incorporating other metabolic parameters like MTV and TLG, in addition to ASP, which was identified as a strong independent predictor, may enhance the understanding of tumor behavior during staging. These additional parameters can significantly aid in comprehensive patient assessment.

Keywords:  PET/CT; PET/TC; cáncer de pulmón de células pequeñas(18)F-FDG; estadio extenso; estadio limitado; extensive stage; limited stage; small cell lung cancer (18)F-FDG

DOI:  https://doi.org/10.1016/j.remnie.2025.500276
Cancer Med. 2026 Jan;15(1): e71444

Molecular Deconvolution of Circulating "Other Cells": A Reliable Predictive Marker of Therapy Response and Survival in Neuroendocrine Tumor Patients Receiving 177Lu-DOTATATE PRRT.

Mahesh K Padwal, Rahul V Parghane, Sandip Basu, Bhakti Basu.

   PURPOSE: To assess the prognostic impact of pre-treatment circulating other cells on treatment response and survival in neuroendocrine tumor (NET) patients receiving Peptide Receptor Radionuclide Therapy (PRRT) with 177Lu-DOTATATE.
METHODS: Healthy donors (HDs, n = 81) and NET patients (n = 137) were analyzed. Baseline circulating other cells proportions (OC%) were deconvoluted from RNA-Seq profiles using the Kassandra-B algorithm. Associations of OC% with demographic and clinicopathologic characteristics, tumor response to PRRT, and survival outcomes were evaluated.
RESULTS: NET patients had a significantly higher OC% compared to HDs (median = 0.26 vs. 0.18, p = 0.0018). A positive correlation was observed between OC% and the tumor grade (G3 tumors: median = 0.47, G1 tumors: median = 0.22, p = 0.029) or disease burden (high: median = 0.32, low: median = 0.23, p = 0.016). The OC% was negatively associated with 68Ga-DOTATATE avidity (high: median = 0.22, low: median = 0.32, p = 0.0026). Patients with progressive disease had high OC% (median = 0.41, IQR = 0.25-0.56), significantly higher than those with stable disease (median = 0.24, IQR = 0.12-0.36, p = 0.0024) or complete/partial response (median = 0.22, IQR = 0.08-0.32, p = 0.0067). NET patients in the OCLow group (OC% ≤ 0.18%) had > 90% disease control rate on PRRT, independent of tumor characteristics. Patients in the OCHigh group (OC% > 0.18%) had a significantly higher risk of early disease progression [HR = 3.2, 95% CI = 1.32-7.75, p = 0.01]. After adjusting for demographic and tumor characteristics, the association of OC% with progression-free survival retained marginal significance [HR = 2.08, 95% CI = 0.78-5.54, p = 0.14], in a multivariate model. Integration of OC% with established risk variables identified a specific subgroup of NET patients at an increased risk of PRRT failure and poor prognosis.
CONCLUSIONS: Pre-treatment OC%, in conjunction with critical risk factors, is predictive of treatment response and survival in NET patients receiving 177Lu-DOTATATE PRRT. This RNA-Seq-based test may evolve as a dependable adjunct for clinicians in the risk stratification of NET patients, in the PRRT setting.

Keywords:  177Lu‐DOTATATE PRRT; disease control rate; neuroendocrine tumors; other cell proportions; prognosis

DOI:  https://doi.org/10.1002/cam4.71444
Mol Cancer Res. 2025 Jan 05.

SMARCA4 loss promotes late-stage tumor progression in non-neuroendocrine small-cell lung cancer.

Nicole A Kirk, Jin Ng, Kate-Lin Ly, Miae Choi, Young Ho Ban, Godfrey A Dzhivhuho, Jinho Jang, Kyung-Pil Ko, Michael S Kareta, Jae-Ll Park, Anthony N Karnezis, Anish Thomas, Kate D Sutherland, Kwon-Sik Park.

Role of SMARCA4, a core component of the SWI/SNF chromatin remodeling complex, remains unclear in small-cell lung cancer (SCLC). Using genetically engineered mouse models, we found that Smarca4 deletion markedly reduced tumor formation and decreased expression of ASCL1, a key neuroendocrine lineage factor. However, Smarca4-deficient tumors, though smaller, exhibited aggressive features, including variant histology and loss of neuroendocrine differentiation. In established tumor cells, Smarca4 knockdown did not affect proliferation in vitro but unexpectedly promoted tumor growth in vivo, accompanied by reduced expression and cell-surface display of PVR, a ligand critical for T and NK cell activation. Although the contribution of these immune cells to SMARCA4 tumor-suppressor activity remains unknown, these findings suggest distinct roles of SMARCA4 in promoting early tumor development but restraining progression of late-stage, neuroendocrine-low tumors. Implications: This study underscores the importance of tumor context and timing in understanding and targeting SMARCA4 and other chromatin regulators in SCLC.

DOI: https://doi.org/10.1158/1541-7786.MCR-25-0592
bioRxiv. 2025 Dec 31. pii: 2025.12.30.697072. [Epub ahead of print]

Extracellular matrix regulates lineage plasticity in prostate cancer through YAP/TEAD.

Teng Han, Zhen Sun, Matthew Lange, Y Zoe Cho, Patrick Mcgillivray, Maren Büttner, Nathaniel R Kastan, Subhiksha Nandakumar, Huiyong Zhao, Sanyukta Oak, Linda Fong, Wenfei Kang, Ning Fan, Jimmy Zhao, Nazifa Salsabeel, Harmanpreet Kaur, Ninghui Mao, Qing Chang, Eric Rosiek, Eric Chan, Murray Tipping, Nikolaus Schultz, Pierre-Jacques Hamard, Elisa DeStanchina, Dana Pe'er, Richard Koche, Zhenghao Chen, A James Hudspeth, Charles L Sawyers.

Treatment-related neuroendocrine prostate cancer (NEPC) is an increasingly frequent mechanism of resistance to androgen receptor pathway inhibitor (ARPI) therapy in prostate adenocarcinoma (PRAD). This lineage transition is dependent on upregulation of the NE-specifying transcription factor ASCL1, typically in a genetic background of RB1 and TP53 loss. Here we identify extracellular matrix-integrin-YAP1/TEAD signaling as a critical brake on NEPC lineage transition. Deletion of Itgb1 , the shared B1 subunit required for collagen and laminin-mediated integrin activation, is sufficient to induce ASCL1 and NE lineage gene expression, by activating LATS1/2 kinases with subsequent inactivation of YAP1/TEAD signaling. Conversely, restoration of YAP1/TEAD signaling by pharmacological LATS1/2 inhibition, or by expression of constitutively active YAP1/TAZ mutants, prevents or reverts NEPC lineage transition. NOTCH and AR cooperate with YAP/TEAD to repress ASCL1, such that combined inhibition leads to complete reprograming of PRAD into NEPC in vitro , providing a dynamic platform to dissect the molecular events responsible for lineage transition over time. We find that lineage transition is accompanied by a redistribution of FOXA1 and TEAD cistromes from PRAD to NEPC-specific enhancers and requires the pioneering activity of FOXA1. Thus, extracellular matrix/integrin signaling in the PRAD tumor microenvironment restrains NE lineage plasticity, highlighting a potential path for pharmacological inhibitors in modulating treatment-induced lineage change.

DOI: https://doi.org/10.64898/2025.12.30.697072
J Nucl Med. 2026 Jan 08. pii: jnumed.125.270233. [Epub ahead of print]

Malignancy Detection Rates of [68Ga]Ga-SSO120 PET/CT in Patients with Small Cell Lung Cancer and Large Cell Neuroendocrine Lung Cancer.

Tine N Christensen, Seppo W Langer, Danijela Dejanovic, Nicholas Gillings, Jacob Madsen, Gitte Persson, Sune H Keller, Elisabeth Albrecht-Beste, Barbara M Fischer.

  The primary aim of this study was to investigate the malignancy detection rate of [68Ga]Ga-SSO120 ([68Ga]Ga-satoreotide trizoxetan) PET/CT in patients with small cell lung cancer (SCLC) and large cell neuroendocrine lung cancer (LCNEC). Secondary aims included investigations of lesion-based detection rates and quantification. Methods: In this prospective, phase 2, cross-sectional imaging trial, 21 [68Ga]Ga-SSO120 PET/CTs were performed for 19 patients. Overall detection rates, lesion-based detection rates, and number of identified lesions were compared between [68Ga]Ga-SSO120 PET and CT. The [68Ga]Ga-SSO120 SUVmax, SUVpeak, SUVmean, and tumor-to-liver ratios in malignant lesions and selected normal tissue were quantified. Results: Nineteen patients (16 with SCLC, 2 with LCNEC, and 1 with combined SCLC/LCNEC) were scanned during palliation chemotherapy (n = 11) or surveillance (n = 8). [68Ga]Ga-SSO120-detectable lesions were identified in 18 patients (95%). Sensitivity in the lungs, regional lymph nodes, and extrathoracic regions was 82%, 83%, and 93%, respectively. [68Ga]Ga-SSO120 PET detected significantly fewer lesions than did CT (P = 0.037), particularly small lung lesions, regional lymph nodes, and liver lesions. In contrast, [68Ga]Ga-SSO120 PET identified 10 additional metastases in 5 patients (bone, 7; cerebellum, 1; subcutaneous, 2). SUVmax (median, 7.4; range, 4.6-26.4) was not significantly associated with time since diagnosis, time since last chemotherapy, number of treatment cycles, or current progression. Conclusion: [68Ga]Ga-SSO120 PET/CT successfully visualized SCLC and LCNEC lesions during and after chemotherapy. Therapeutic studies with [177Lu]Lu-SSO110 ([177Lu]Lu-satoreotide tetraxetan), the theranostic companion of [68Ga]Ga-SSO120, PET are warranted.

Keywords:  LCNEC; SCLC; SSTR2; [177Lu]Lu-SSO110 radiopharmaceutical therapy; [68Ga]Ga-SSO120 PET/CT

DOI:  https://doi.org/10.2967/jnumed.125.270233
Comput Biol Chem. 2025 Dec 30. pii: S1476-9271(25)00538-9. [Epub ahead of print]121 108874

Improved somatic mutation profiling in small-cell lung cancer using RNA-sequencing and the T2T-CHM13 genome reference.

Pragya Kashyap, Dinesh Kumar Ahirwar, Pankaj Yadav.

  Comprehensive identification of somatic mutations (SMs) is essential for understanding the molecular landscape of small cell lung cancer (SCLC). While DNA-sequencing remains a prevalent method for SMs detection, RNA-sequencing (RNA-seq) offers a powerful complementary strategy by focusing on mutations in actively transcribed regions. Despite its potential, the utility of RNA-seq for somatic variant discovery in SCLC remains underexplored. Here, we present a robust RNA-seq analysis pipeline that integrates a two-pass HISAT2 alignment with somatic variant calling using MuTect2 from the Genome Analysis Toolkit (GATK). Variant annotation using COSMIC and dbSNP databases revealed a predominance of G > A and C > T transitions, consistent with mutational signature of tobacco exposure and oxidative stress. Our analysis identified six key oncogenes (COL4A1, FN1, AKT1, TRAF4, MYC, PTK2) implicated in SCLC signaling pathways, alongside 259 previously unreported high-impact mutations. Leveraging the complete T2T-CHM13 reference genome improved variant resolution, capturing more SNPs, MNPs, and Indels compared to GRCh38. Integration with CancerVar tool prioritized putative driver genes, including UBC, TSC1, ADGRL1, and ATN1. Notably, these driver mutations showed a negative association with the SCLC-inflamed subtype, which is characterized by increased immune infiltration and prolonged survival. Our findings highlight the untapped potential of RNA-seq for somatic mutation profiling in SCLC and unveil novel molecular targets with implications for patient stratification, immunotherapy, and precision treatment strategies.

Keywords:  RNA sequencing; Small cell lung cancer; Somatic variants; T2T-CHM13 reference

DOI:  https://doi.org/10.1016/j.compbiolchem.2025.108874
Int J Gynecol Cancer. 2025 Dec 05. pii: S1048-891X(25)01976-0. [Epub ahead of print]36(2): 102852

Relative survival of large cell to small cell neuroendocrine carcinoma of the uterine cervix.

Mariya Kobayashi, Jennifer A Yao, Matthew W Lee, Satoshi Nakagawa, Kae Hashimoto, Shinya Matsuzaki, Lynda D Roman, Koji Matsuo.

  This retrospective study compared clinico-pathological characteristics and survival of large cell to small cell neuroendocrine carcinomas of the uterine cervix identified in the Commission-on-Cancer's National Cancer Database from 2004 to 2022 (n = 2051). Large cell neuroendocrine carcinoma, reported in 16.3%, was more likely to be T1 classification (37.1% vs 29.5%) and have smaller cervical tumor (median size, 47 and 59 mm) but less likely to be T3 classification (15.6% vs 22.4%) and N1 classification (36.8% vs 45.1%) than small cell neuroendocrine carcinoma (all, p < .05). In propensity score inverse probability of treatment weighting, large cell neuroendocrine carcinoma had overall survival comparable to small cell neuroendocrine carcinoma (5-year rates, 33.8% vs 30.9%, hazard ratio 1.02, 95% confidence interval 0.86 to 1.20). This survival association was consistent across stage I, II, III, and IV diseases. In the secondary cohort of the National Cancer Institute's Surveillance, Epidemiology, and End Results Program, cause-specific survival from cervical cancer was similar between large cell and small cell neuroendocrine carcinomas (5-year rates, 36.1% vs 39.1%, hazard ratio 1.25, 95% confidence interval 0.88 to 1.76). In conclusion, these data suggest that large cell neuroendocrine carcinoma represents less than 20% of neuroendocrine carcinomas of the uterine cervix, and although tumor characteristics appear to be less aggressive, oncologic outcomes are dismal and similar to small cell neuroendocrine carcinoma.

Keywords:  Cervical Cancer; Large Cell; Neuroendocrine Carcinoma; Small Cell; Survival

DOI:  https://doi.org/10.1016/j.ijgc.2025.102852
Int J Mol Sci. 2025 Dec 31. pii: 445. [Epub ahead of print]27(1):

Lineage Plasticity and Histologic Transformation in EGFR-TKI Resistant Lung Cancer.

Li Yieng Eunice Lau, Anders Jacobsen Skanderup, Aaron C Tan.

  Lineage plasticity, the ability of cancer cells to alter their differentiated state through transcriptional and epigenetic reprogramming, has emerged as a key mechanism of therapeutic resistance across cancers. This adaptive process can manifest in multiple ways, including epithelial-mesenchymal transition, acquisition of stem-like features, and histological transformation, the most striking and clinically apparent example. In EGFR-mutant lung adenocarcinoma (LUAD), lineage plasticity is increasingly recognized as a prevalent mechanism of acquired resistance to tyrosine kinase inhibitors (TKIs). Among its visible manifestations, histologic transformation into small-cell lung cancer (SCLC) is the most frequent, while squamous transformation and other phenotypic shifts also occur. Transformed tumors typically retain the initiating EGFR mutation but lose EGFR dependence, acquire neuroendocrine features, and display aggressive clinical behavior with poor clinical outcomes compared with both de novo SCLC and non-transformed LUAD. Recent studies show that plasticity arises through combined genomic, transcriptomic, and epigenetic reprogramming, often foreshadowed by molecular alterations before overt histological change. Spatial and single-cell profiling reveal heterogeneous trajectories and intermediate states, while functional models and multi-omics approaches have begun to identify therapeutic vulnerabilities distinct from both de novo EGFR-mutated SCLC and classical EGFR-mutated LUAD. Thus, lineage plasticity, whether manifested as histologic transformation or through more subtle epigenetic reprogramming, represents a formidable resistance mechanism in NSCLC. Defining its molecular basis and temporal dynamics will be essential for early detection, prognostication, and the development of tailored therapies.

Keywords:  EGFR-TKI; acquired resistance; epigenetic reprogramming; histologic transformation; lineage plasticity; lung adenocarcinoma; lung cancer; targeted therapy; transcriptional reprogramming

DOI:  https://doi.org/10.3390/ijms27010445
Cancers (Basel). 2025 Dec 25. pii: 69. [Epub ahead of print]18(1):

Epigenetics and the Tumor Microenvironment in Neuroendocrine Tumors.

Alice Castenetto, Teresa Gagliano.

  Background: Neuroendocrine neoplasms (NENs) represent a heterogeneous group of malignancies arising from neuroendocrine cells and are most commonly localized in the gastroenteropancreatic and pulmonary systems. Overall, most NENs are characterized by a low mutational burden. Consequently, increasing research attention has focused on epigenetic mechanisms and the tumor microenvironment, which may actively contribute to tumor pathogenesis. Moreover, epigenetic modifications represent plausible mediators of communication in the crosstalk between neuroendocrine cancer cells and components of the tumor microenvironment, as observed in other non-neuroendocrine malignancies. Objectives: The aim of this review is to summarize current knowledge on the role of epigenetic regulation and the tumor microenvironment in the pathogenesis of neuroendocrine tumors and to discuss their potential as targets for more effective therapeutic strategies. Methods: We reviewed research articles published over the past decades that investigated the involvement of epigenetic mechanisms and the tumor microenvironment in NENs. Results: Several studies highlight the pivotal role of epigenetic alterations and tumor microenvironment interactions in NEN biology, influencing tumor development, progression, and therapeutic response. Conclusions: Further studies are warranted to deepen understanding in this field, as this may lead to the development of more effective therapies and improved clinical outcomes for patients with neuroendocrine neoplasms.

Keywords:  crosstalk; epigenetics; neuroendocrine neoplasms; targets; therapeutic strategies; tumor microenvironment

DOI:  https://doi.org/10.3390/cancers18010069
Mol Metab. 2026 Jan 06. pii: S2212-8778(25)00223-6. [Epub ahead of print] 102316

Targeting DHODH Reveals a Metabolic Vulnerability in AR-positive and AR-negative Prostate Cancer Cells via Pyrimidine Synthesis and Metabolic Crosstalk with the TCA and Urea Cycles.

Maxime Labroy, Marc-Oliver Paré, Line Berthiaume, Mélissa Thomas, Cynthia Jobin, Alain Veilleux, Martin Pelletier, Frédéric Pouliot, Jean-Yves Masson, Étienne Audet-Walsh.

  Following recurrence, the cornerstone clinical therapy to treat prostate cancer (PCa) is to inhibit the androgen receptor (AR) signaling. While AR inhibition is initially successful, tumors will eventually develop treatment resistance and evolve into lethal castration-resistant PCa. To discover new anti-metabolic treatments for PCa, a high-throughput anti-metabolic drug screening was performed in PC3 cells, an AR-negative PCa cell line. This screening identified the dihydroorotate dehydrogenase (DHODH) enzyme as a metabolic vulnerability, using both AR-positive and AR-negative models, including the neuroendocrine cell line LASCPC-01 and patient-derived organoids. DHODH is required for de novo pyrimidine synthesis and is the sole mitochondrial enzyme of this pathway. Using extracellular flux assays and targeted metabolomics, DHODH inhibition was shown to impair the pyrimidine synthesis pathway, as expected, along with a significant reprogramming of mitochondrial metabolism, with a massive increase in fumarate (>10-fold). Using 13C6-glucose, it was shown that following DHODH inhibition, PCa cells redirect carbons from glucose toward biosynthetic pathways rather than the TCA cycle. In parallel, using 13C5-glutamine, it was shown that PCa cells use this amino acid to fuel a reverse TCA cycle. Finally, 13C1-aspartate and 15N1-glutamine highlighted the connection between pyrimidine synthesis and the urea cycle, redirecting pyrimidine synthesis intermediates toward the urea cycle as a stress response mechanism upon DHODH inhibition. Consequently, combination therapies targeting DHODH and glutamine metabolism were synergistic in impairing PCa cell proliferation. Altogether, these results highlight DHODH as a metabolic vulnerability of AR-positive and AR-negative PCa cells by regulating central carbon and nitrogen metabolism.

Keywords:  BAY-2402234; DHODH; NEPC; androgen receptor; aspartate; cancer metabolism; castration-resistant prostate cancer; glucose; glutamine; mitochondria; neuroendocrine differentiation; neuroendocrine prostate cancer; nucleotide synthesis; prostate cancer

DOI:  https://doi.org/10.1016/j.molmet.2025.102316
Histopathology. 2026 Jan 05.

Analysis of SCLC subtype markers (ASCL1, NEUROD1, POU2F3, YAP1), DLL3, OTP, and TTF1 in 300 lung carcinoids and enteropancreatic neuroendocrine tumours.

Jonathan Willner, Irfan Khan, Zeynep Tarcan, Rania Aly, Prithviraj Solanki, Olca Basturk, Andrew M Bellizzi, Marina K Baine, Susan M Armstrong, William D Travis, Laura H Tang, Christina Wilson, Francis Bodd, Rohit Thummalapalli, Alissa J Cooper, Jake June-Koo Lee, Charles M Rudin, Natasha Rekhtman.

   AIMS: ASCL1, NEUROD1, POU2F3 and YAP1 are recently described markers of transcriptional subtypes in small cell lung carcinoma (SCLC), while DLL3, regulated by ASCL1, is a target of novel therapeutic agents in various neuroendocrine neoplasms. The expression of these markers in lung carcinoids is not well established.
METHODS AND RESULTS: We examined these markers in 109 lung carcinoids and compared their expression with that in 191 enteropancreatic neuroendocrine tumours (EP-NETs) and with lung carcinoid markers (OTP, TTF1). ASCL1, NEUROD1, OTP and TTF1 were positive in 56%, 0%, 84% and 35% of lung carcinoids, respectively. Of the OTP-negative lung carcinoids (n = 18), 4 (22%) were ASCL1-positive, of which one was TTF1-positive. In contrast, 59% of EP-NETs were NEUROD1-positive, whereas only rare tumours focally expressed ASCL1 (1.1%) and OTP (0.5%) and none expressed TTF1. DLL3 was positive in 57 (52%) lung carcinoids versus 5 (2.6%) EP-NETs. All lung carcinoids and EP-NETs were completely negative for POU2F3 and YAP1. We also analysed clinicopathologic correlates of ASCL1, OTP, TTF1 and DLL3 expression in lung carcinoids, expanding on several previously suggested associations, including ASCL1 and TTF1 with peripheral location, OTP with low Ki67 (P = 0.002) and low stage (P = 0.002) and DLL3 with high Ki67 (P = 0.002).
CONCLUSION: Unlike SCLC, lung carcinoids and EP-NETs completely lack the expression of POU2F3 and YAP1, which offers diagnostic applications. Our findings also nominate ASCL1 and NEUROD1 as site of origin markers for lung versus digestive NETs/carcinoids, respectively. Finally, the divergent expression of DLL3 in lung carcinoids and EP-NETs has therapeutic implications.

Keywords:  ASCL1; DLL3; NEUROD1; OTP; TTF1; carcinoid tumour; neuroendocrine tumour

DOI:  https://doi.org/10.1111/his.70081
Biology (Basel). 2025 Dec 22. pii: 22. [Epub ahead of print]15(1):

Regulation of INSM1 Gene Expression and Neuroendocrine Differentiation in High-Risk Neuroblastoma.

Chiachen Chen, Siyuan Cheng, Xiuping Yu, Yisheng Lee, Michael S Lan.

  Neuroblastoma (NB), a pediatric cancer of sympatho-adrenal (SA) lineage, is marked by disrupted differentiation and cellular heterogeneity. INSM1, a zinc-finger transcription factor, is highly expressed in NB and developing SA tissues, where it regulates neuroendocrine differentiation, especially in chromaffin cells. We investigated INSM1's role in maintaining an undifferentiated, progenitor-like state in NB and its regulation via metabolic and epigenetic mechanisms. Transcriptomic profiling, promoter assays, and metabolic flux analysis revealed that INSM1 expression correlates with methionine cycle activity, particularly the S-adenosylmethionine (SAM)/S-adenosylhomocysteine (SAH) ratio. Disruption of SAM/SAH balance altered INSM1 promoter activity and histone methylation, implicating epigenetic control in NB cell fate. Retinoic acid-induced differentiation downregulated INSM1 and N-Myc, linking INSM1 to tumor cell immaturity. INSM1 overexpression in SH-SY-5Y cells upregulated neuroendocrine and thyroid hormone-related genes (CHGA, CHGB, DDC, NCAM1, DIO3, TH), while suppressing genes involved in cell cycle (RRM, CDC25A), methionine metabolism (AHCY, MAT2A), transcriptional regulation (MYBL2, EZH2), and oncogenic signaling (ALK, LINC011667). These findings suggest that INSM1 promotes NB aggressiveness by sustaining a neuroendocrine progenitor-like phenotype through metabolic-epigenetic coupling.

Keywords:  5′-iodotubercidin; INSM1; N-Myc; SAH; SAM; methionine cycle signaling; neuroblastoma; neuroendocrine differentiation; sympatho-adrenal lineage

DOI:  https://doi.org/10.3390/biology15010022
Front Surg. 2025 ;12 1666087

Safety and efficacy of the HilumDirect uVATS for small cell lung cancer: a retrospective study.

Xining Zhang, JingWei Liu, Shijie Zhang, Jian Li.

   Background: Despite advancements in multidisciplinary treatments, long-term survival rates for small cell lung cancer (SCLC) patients remain poor, and the role of surgical resection has been debated since the late 20th century. A more comprehensive surgical approach is necessary to enhance local control and improve outcomes.
Method: The records of the patients who received surgical treatment between January 2015 and December 2020 were collected and analyzed with propensity-score matching. The preoperative characteristics, short-term outcomes, and long-term survival were analyzed and compared between the HilumDirect uVATS and the conventional uVATS groups.
Results: Preoperative variables were well-balanced between the two groups. The HilumDirect uVATS group showed a numerically higher lymph node yield. Patients in the HilumDirect uVATS group pointed toward a numerical difference in cancer-specific survival (CSS) and recurrence-free survival (RFS) compared to the Conventional resection group (CSS, 50.82% vs. 44.09%, p = 0.890, RFS, 42.86% vs. 38.46%, p = 0.904). This numerical difference was consistent in both lymph node-negative (CSS: 72.70% vs. 51.60%, p = 0.287, RFS: 58.30% vs. 47.60%, p = 0.654) and node-positive subgroups (CSS: 35.70% vs. 33.30%, p = 0.869, RFS: 31.20% vs. 22.22%, p = 0.833). Competing risks analysis suggested a non-significant difference in the lower risk of distal metastasis of the HilumDirect uVATS (Subdistribution hazard ratio of Conventional uVATS: 2.164, 95% CI 0.741-6.318, p = 0.158).
Conclusion: The HilumDirect uVATS resection can be safely performed by experienced surgeons with minimal invasiveness. Our findings suggest that selected SCLC patients, particularly those with positive lymph nodes, may benefit from this approach. However, further studies are warranted to confirm these results.

Keywords:  multidisciplinary approach; small cell lung cancer (SCLC); surgery; surgical techinque; uVATS

DOI:  https://doi.org/10.3389/fsurg.2025.1666087
Transl Cancer Res. 2025 Dec 31. 14(12): 8526-8541

LASSO-based nomograms predict early death in small cell lung cancer (SCLC) patients with brain metastasis.

Xiaohao Liu, Long Wang, Linkuan Huangfu, Jiayin Ding, Dandan Wang, Jiayao Xu, Tianqi Li, Yahang Liu, Yue Yu, Yingjuan Zheng.

   Background: Small cell lung cancer with brain metastasis (SCLC-BM) is associated with a poor prognosis and a high probability of death. However, to date, few models exist to predict early death (ED) in patients with SCLC-BM. This study aimed to construct nomograms to predict ED in patients diagnosed with SCLC-BM.
Methods: The data of SCLC-BM patients were extracted from the Surveillance, Epidemiology, and End Results (SEER) database (2010-2015). The patients were randomly divided into training and test cohorts at a 7:3 ratio. Univariate regression was first performed to assess the significance of each variable. Least absolute shrinkage and selection operator (LASSO) regression was then applied to identify the most critical and minimum prognostic factors. Subsequently, a multivariate analysis was conducted to develop two nomograms to predict all-cause early death (ACED) and cancer-specific early death (CSED). The calibration and discriminative abilities of these nomograms were evaluated using receiver operating characteristic (ROC) curves and calibration curves. A decision curve analysis (DCA) was employed to assess the clinical applicability of the models.
Results: Primary site, regional lymph node stage (N stage), race, age, tumor size, radiotherapy, and chemotherapy were identified as independent predictors of ACED, while race, age, tumor size, radiotherapy, and chemotherapy were identified as independent predictors of CSED. Nomograms were developed based on these variables. The area under the curve (AUC) values of the ROC curves for ACED were 0.837 in the training cohort and 0.813 in the test cohort, while those for CSED were 0.794 and 0.783, respectively. Based on the performance of the ROC, calibration, and DCA curves, these predictive models demonstrated favorable efficacy.
Conclusions: This study developed nomograms to predict ACED and CSED in patients with SCLC-BM. The nomograms demonstrated clinical utility in ED prediction in the post-treatment planning period, and thus could assist oncologists in identifying high-risk patients after initial treatment planning has been established.

Keywords:  Small cell lung cancer (SCLC); brain metastasis (BM); early death (ED); least absolute shrinkage and selection operator (LASSO); nomogram

DOI:  https://doi.org/10.21037/tcr-2025-1269
bioRxiv. 2025 Dec 29. pii: 2025.12.28.696762. [Epub ahead of print]

Conserved Neuronal-like and Secretory Programs Define the Spatial Architecture of Gastroenteropancreatic Neuroendocrine Tumors.

Julie Karam, Samantha E Hoffman, Amanda Garza, Dan Gui, Hannah I Hoffman, Breanna M Titchen, Yutaro Tanaka, Erica Pimenta, Theodora Pappa, Laura Valderrabano, Kevin Bi, Riaz Gillani, Lauren Brais, Erin Shannon, Jason L Hornick, Jihye Park, Jennifer Chan, Eliezer M Van Allen.

Gastroenteropancreatic neuroendocrine tumors (GEP-NETs) are clinically heterogeneous malignancies whose biology and microenvironmental organization remain poorly understood. Here, we integrated single-nucleus multiomic (snRNA-seq and snATAC-seq) and spatial transcriptomic profiling across 38 well-differentiated pancreatic (pNET) and small-intestinal (siNET) tumors to define conserved malignant programs, their regulatory circuits, and spatial niches. We observed two conserved malignant cell programs spanning a continuous transcriptional spectrum: a neuronal-like program (si-cNMF1/p-cNMF1), and a secretory neuroendocrine program (si-cNMF2/p-cNMF2). Matched chromatin accessibility profiles uncovered distinct, tissue-specific regulatory networks, including MAX::MYC and MITF transcription factor binding motifs in siNETs versus ISL1 and TFAP4 in pNETs, indicating organ-specific epigenetic control. Spatial transcriptomic analyses revealed that si/p-cNMF1-high regions localized to high cell density, immune-rich tumor areas, whereas si/p-cNMF2-high regions occupied stromal and vascularized niches and co-occured with fibroblast and endothelial compartments enriched for TGFB1-ITGB1 , VEGFA-FLT1 , and LAMA2-ITGA1 signaling. Across both tumor types, the cNMF2 program was enriched in metastatic lesions and was enrichedfor pro-fibrotic and pro-angiogenic gene signatures. Thus, GEP-NETs are organized along a conserved neuronal-to-secretory axis defined by distinct epigenetic programs and spatially coupled to specific microenvironmental niches. This framework unifies NET heterogeneity across organ sites and identifies pathway-specific, microenvironment-linked vulnerabilities for therapeutic targeting.

DOI: https://doi.org/10.64898/2025.12.28.696762
Pol Arch Intern Med. 2026 Jan 07. pii: 17191. [Epub ahead of print]

Diagnosis and management of pituitary neuroendocrine tumors: recent advances.

Aina Raventos, Mari Minasyan, Carmín Puente de la Vega, Elena Valassi, Manel Puig Domingo.

Pituitary neuroendocrine tumors (PitNETs) are a heterogeneous group of neoplasms originating from anterior pituitary cells, encompassing a spectrum from indolent microadenomas to highly invasive, aggressive tumors. Their clinical presentation varies from classic endocrine hyper or hyposecretory syndromes to mass effect symptoms or incidental imaging findings. The 2022 World Health Organization classification has redefined PitNETs, emphasizing their neuroendocrine nature and the central role of transcription factor-based immunohistochemistry. Recent years have witnessed rapid progress in molecular characterization, multiomics, radiomics, and theragnostic approaches, which are reshaping the approach to these tumors either in their diagnosis, risk stratification, and management. This review provides a comprehensive and practical synthesis of current evidence, focusing on the integration of biomarkers, advanced imaging, and personalized therapies that could be useful for clinical practice, and discusses future directions in precision management of PitNETs.

DOI: https://doi.org/10.20452/pamw.17191
Technol Cancer Res Treat. 2026 Jan-Dec;25:25 15330338251412203

CCT3 Facilitates the Malignant Progression of NSCLC and SCLC via PI3 K/AKT-EMT Axis and Emerges as a Novel Serum Diagnostic Biomarker.

Guobin Song, Kexin Han, Lin Xiang, Tian Peng, Hailong Chen, Anqi Tang, Yanan Li, Tianqi Lan, Houqun Ying, Xuexin Cheng.

  IntroductionIdentifying therapeutic targets and early screening biomarkers is essential for improving the prognosis of lung cancer. CCT3 has been linked to tumor progression; however, its role in lung cancer proliferation and invasion, as well as its diagnostic significance remain poorly understood.MethodsCCT3 expression and its clinical correlations in lung cancer were analyzed utilizing data from the TCGA and GEO databases. The impact of CCT3 on cell proliferation, migration, and invasion was evaluated through CCK-8, colony formation, and Transwell assays. Western blotting was employed to assess the regulation of the PI3 K/AKT pathway and markers associate with epithelial-mesenchymal transition (EMT). Serum CCT3 levels in 714 participants were measured via ELISA, with diagnostic efficacy analyzed using receiver operating characteristic (ROC) curve analysis.ResultsCCT3 was over-expressed in lung cancer tissues, which was correlated with the stage of non-small lung cancer (NSCLC). CCT3 promotes cell proliferation, migration, and invasion by activating the PI3 K/AKT pathway and modulating EMT. In vivo, CCT3 knockdown significantly suppressed tumor growth in xenograft models. Elevated serum levels of CCT3 have been observed in patients with lung cancer, exhibiting high diagnostic efficacy for distinguishing NSCLC from benign nodules (AUC=0.873) and enhancing performance for small cell lung cancer when combined with proGRP.ConclusionCCT3 facilitates the progression of lung cancer through the PI3 K/AKT-EMT axis, positioning it as a potential therapeutic target and biomarker.

Keywords:  CCT3; EMT; NSCLC; PI3 K/AKT pathway; SCLC; biomarker

DOI:  https://doi.org/10.1177/15330338251412203
Mediastinum. 2025 ;9 32

Molecular reprogramming in thymic neuroendocrine tumors: a narrative review.

Jing Di, Yijia Zhou, Jingjing Hu.

   Background and Objective: Thymic neuroendocrine tumors (tNETs) are rare and heterogeneous neoplasms with limited evidence to guide diagnosis and management. Traditional classifications rely heavily on morphology, but recent advances in molecular profiling have begun to reshape understanding of their biology and clinical behavior. This narrative review synthesizes recent molecular findings in tNETs and proposes an integrated framework that combines traditional morphology with molecular stratification to guide precision oncology.
Methods: We performed a narrative review of the current literature on tNETs, focusing on histologic classification, molecular taxonomy, diagnostic algorithms, and therapeutic strategies. Special emphasis was placed on integrating emerging evidence from genomic, epigenetic, and clinical studies published between 2010 and 2025.
Key Content and Findings: Molecular frameworks such as copy number instability (CNI)-based classification, together with recurrent alterations in MEN1, TP53, and RB1, are refining risk stratification and linking tNETs to neuroendocrine neoplasms in other organ systems. Therapeutic advances include the use of everolimus and temozolomide, while PRRT appears less effective in this subgroup. Epigenetic dysregulation and novel trial designs, including basket and adaptive studies, represent promising avenues for future research.
Conclusions: This review integrates current knowledge of tNETs with recent advances in molecular diagnostics and therapeutic strategies. By highlighting key genetic and epigenetic alterations, as well as future directions such as liquid biopsy, artificial intelligence, and novel trial designs, we emphasize the need for biomarker-driven approaches to improve outcomes in this ultra-rare disease.

Keywords:  Thymic neuroendocrine tumors (tNETs); copy number instability (CNI); epigenetic alterations; molecular taxonomy; precision oncology

DOI:  https://doi.org/10.21037/med-25-40