Weiß Annika, Teply-Szymanski Julia, Schmitt Maxime, Foersch Sebastian, Jank Paul, Griger Joscha, Wagner Uwe, Bartsch Detlef K, Denkert Carsten, Jesinghaus Moritz
Institute of Pathology, Philipps University Marburg und University Hospital Marburg, Marburg, Germany.
Institute of Pathology, University Hospital Mainz, Mainz, Germany.
Endocr Pathol. 2025 Aug 20;36(1):29. doi: 10.1007/s12022-025-09869-w.
Mixed neuroendocrine-nonneuroendocrine neoplasms (MiNEN) are usually highly aggressive tumors characterized by marked histological heterogeneity, most commonly represented by mixed adenocarcinoma and poorly differentiated neuroendocrine carcinoma (NEC). However, beyond morphological observations, the biological basis and implications of this heterogeneity remain incompletely understood. In this study, we combined component-specific next-generation sequencing and spatial transcriptomics to investigate three mixed adenocarcinoma-NEC cases from different anatomical sites (ileocecal, ovarian, gastric), tracing tumor progression from precursor lesions to invasive NEC. Genomic analyses revealed a shared trunk of driver mutations across all tumor compartments, confirming their clonal origin, while also uncovering additional compartment-specific alterations. Spatial transcriptomics, together with gene set enrichment analysis (GSEA), revealed distinct transcriptional profiles aligned with histologically annotated compartments (e.g., adenocarcinoma, NEC, precursor). In NECs, GSEA consistently showed downregulation of immune-related pathways and upregulation of proliferation-associated pathways compared to non-neuroendocrine tumor areas. Moreover, distinct transcriptomic subclusters were identified within morphologically homogeneous NEC regions in two of the three cases. These subclusters exhibited significant differences in immune regulation, proliferation signaling, and cell-cycle control, and were associated with divergent predicted chemotherapy-response signatures, suggesting clinically relevant implications for treatment sensitivity and resistance. In summary, our findings indicate that despite a shared clonal origin, MiNEN develop distinct genetic and transcriptomic features across tumor compartments. The inconsistent presence of transcriptomic subclusters within morphologically similar regions underscores the complexity of intratumoral heterogeneity in these aggressive neoplasms. By connecting morphological and molecular layers of tumor architecture, spatial profiling may aid in translating biological complexity into more targeted clinical strategies.
混合性神经内分泌-非神经内分泌肿瘤（MiNEN）通常是高度侵袭性肿瘤，其特征为显著的组织学异质性，最常见的表现是腺癌与低分化神经内分泌癌（NEC）混合。然而，除了形态学观察外，这种异质性的生物学基础和影响仍未完全明确。在本研究中，我们结合成分特异性的下一代测序和空间转录组学，对来自不同解剖部位（回盲部、卵巢、胃）的三例腺癌-NEC混合病例进行研究，追踪肿瘤从前体病变到侵袭性NEC的进展。基因组分析揭示了所有肿瘤区域存在共同的驱动基因突变主干，证实了它们的克隆起源，同时也发现了其他区域特异性改变。空间转录组学与基因集富集分析（GSEA）显示，不同的转录谱与组织学注释区域（如腺癌、NEC、前体）一致。在NEC中，与非神经内分泌肿瘤区域相比，GSEA始终显示免疫相关通路下调，增殖相关通路上调。此外，在三例中的两例形态学上均一的NEC区域内鉴定出不同的转录组亚群。这些亚群在免疫调节、增殖信号传导和细胞周期控制方面表现出显著差异，并与不同的预测化疗反应特征相关，提示对治疗敏感性和耐药性具有临床相关意义。总之，我们的研究结果表明，尽管MiNEN有共同的克隆起源，但在肿瘤区域间会出现不同的遗传和转录组特征。形态学相似区域内转录组亚群的不一致存在突出了这些侵袭性肿瘤瘤内异质性的复杂性。通过连接肿瘤结构的形态学和分子层面，空间分析可能有助于将生物学复杂性转化为更具针对性的临床策略。
