以 L1CAM / FOXI1 引导的空间转录组，解析 BHD 相关 FLCN 突变肾肿瘤（FMT）中两类形态组分的分子差异。Unpaywall 标 hybrid OA，但 Elsevier/ScienceDirect 常被本站出口 Cloudflare 拦截；本文仅据 PubMed 摘要。
摘要
Birt-Hogg-Dubé（BHD）综合征是由卵泡素（FLCN）基因致病性变异引起的遗传性肿瘤易感综合征，与多灶性肾肿瘤风险增高相关。FLCN 突变肿瘤（FMT）常呈现形态异质性，混合类似肾嗜酸细胞瘤（RO）与嫌色细胞肾细胞癌（chRCC）的形态特征，但其异质性形态与形态—基因组关联的分子基础仍不清楚。此前工作中，我们识别出 L1 细胞黏附分子（L1CAM）与叉头框 I1（FOXI1）在 BHD 相关 FMT 中对两类形态不同细胞群体的互斥表达，据此假设这两个肿瘤组分可能具有不同的分子特征，并反映不同的肾单位上皮分化状态。本随访研究以 L1CAM 与 FOXI1 作为形态引导标记，用 NanoString GeoMX 数字空间分析仪（DSP）对 FMT 中不同肿瘤组分进行空间转录组分析。分析了来自 3 例 BHD 患者的 6 个 FMT，以及 3 例正常肾组织。自 L1CAM+ 主导、FOXI1+ 主导及混合型肿瘤区域采集 L1CAM+ 与 FOXI1+ 感兴趣区（AOI）。空间转录组分析显示，L1CAM+ 与 FOXI1+ FMT 组分具有彼此不同的基因表达特征，且独立于局部肿瘤组成。FOXI1+ 肿瘤细胞显著富集闰细胞（IC）相关基因签名。相比之下，L1CAM+ 肿瘤细胞转录谱呈异质性，与多种肾小管上皮细胞类型部分重叠，而非明确的主细胞样身份。尽管组分间存在差异，两组分共享一组肿瘤签名基因（包括糖蛋白 nmb [GPNMB]）以及核心的肿瘤相关生物学功能与信号通路。这些发现细化了既往关于 BHD 相关肾肿瘤的二分模型，并支持如下模型：L1CAM+ 与 FOXI1+ 肿瘤组分代表在共同 FLCN 突变肿瘤转录程序下的不同进化或分化状态。该空间转录组分析为 FMT 的形态异质性提供了分子证据，并加深对 BHD 相关 FMT 肿瘤生物学的认识。
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Abstract
Birt-Hogg-Dubé (BHD) syndrome is a hereditary cancer predisposition syndrome caused by pathogenic variants in the folliculin (FLCN) gene and is associated with an increased risk of multifocal renal tumors. FLCN-mutated tumors (FMTs) often exhibit morphological heterogeneity with mixed morphological features resembling renal oncocytoma (RO) and chromophobe renal cell carcinoma (chRCC), yet the molecular basis underlying the heterogeneous morphologic features and the morphologic-genomic correlations remain poorly defined. In our prior work, we identified mutually exclusive expressions of L1 cell adhesion molecule (L1CAM) and forkhead box I1 tboxI1 (FOXI1) labeling the two morphologically distinct cellular populations in BHD-associated FMTs, leading to the hypothesis that these two tumor compartments may have distinct molecular features and may reflect different nephron epithelial differentiation states. In this follow-up study, we tested this hypothesis using L1CAM and FOXI1 as morphology-guided markers for spatial transcriptomic profiling of the distinct tumor compartments in FMTs with the NanoString GeoMX Digital Spatial Profiler (DSP). Six FMTs from three patients with BHD and three normal kidney tissues were analyzed. L1CAM+ and FOXI1+ area of interest (AOI) were collected from tumor areas with various tumor compositions, including L1CAM+ dominant, FOXI1+ dominant, and mixed tumor areas. Spatial transcriptomic analysis identified distinct gene expression signatures in L1CAM+ and FOXI1+ FMT compartments independent of the local tumor compositions. FOXI1+ tumor cells showed robust enrichment for intercalated cells (IC)-associated gene signatures. In contrast, L1CAM+ tumor cells exhibited a heterogeneous transcriptional profile, with partial overlap across a spectrum of renal tubular epithelial cell types rather than a definitive principal cell-like identity. Despite this compartment-specific differences, both compartments share expression of a panel of tumor signature genes, including glycoprotein nmb (GPNMB) gene, and a core of cancer related biological functions and signaling pathways. Together, these findings refined the prior dichotomous model of BHD-associated renal tumors and support a model in which L1CAM+ and FOXI1+ tumor compartments represent divergent evolutionary or differentiation states with a common FLCN-mutant neoplastic transcriptional program. This spatial transcriptomic profiling provides molecular evidence for the morphological heterogeneity of FMTs and insights on the tumor biology of BHD-associated FMTs.