Laboratory investigation; a journal of technical methods and pathology · 2026
Spatial Transcriptomics of Micropapillary, Plasmacytoid, and Sarcomatoid Urothelial Carcinoma Reveals Distinct Molecular Landscapes.
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Zhao Ting, Nawrocki Cole, Xiong Linjie, Nieman Linda T, Saylor Philip J, Blute Michael L, Miyamoto David T, Ting David T, Dahl Douglas M, Wu Chin-Lee
Аннотация
PURPOSE: Consensus molecular classes of urothelial carcinoma (UC) include basal/squamous (Ba/Sq), luminal papillary, luminal nonspecified, luminal unstable, stroma-rich, and neuroendocrine-like. We aimed to determine the consensus molecular classifications of micropapillary (MP), plasmacytoid (PC), and sarcomatoid (SM) subtypes of bladder UC and characterize their spatial transcriptomic profiles.
MATERIALS AND METHODS: A tissue microarray of 17 formalin-fixed, paraffin-embedded cores (5 MP, 6 PC, and 6 SM) was profiled for expression of 18,676 messenger RNAs using the Bruker GeoMx Digital Spatial Profiler. Thirty-eight areas of interest were selected based on hematoxylin and eosin staining and fluorescence markers. Each area of interest was assigned to a consensus molecular class using a published approach, and pathway analysis was performed using Reactome gene sets.
RESULTS: Most MP and PC demonstrated luminal molecular classes, whereas SM was predominantly Ba/Sq. Adjacent mixed histological components within the same tumor frequently corresponded to distinct consensus molecular classes. Ba/Sq tumors upregulated invasion-associated and extracellular matrix (ECM) remodeling-associated genes, whereas luminal classes demonstrated distinct differentiation-associated signatures. MP demonstrated a predominantly luminal epithelial transcriptional program characterized by increased expression of luminal/urothelial differentiation markers (KRT20, UPK1A, PSCA, and FOXA1), secretory-associated genes (LCN2, MUC1, MUC20, and SPINK1), and relative ERBB2 enrichment, with suppression of Ba/Sq-associated genes (KRT5, KRT6A, KRT14, and TP63). In contrast, SM demonstrated a predominantly mesenchymal/stromal transcriptional program characterized by enrichment of mesenchymal/ECM-associated genes (FN1, VIM, COL6A1, and TGFB1) and reduced expression of luminal/epithelial and adhesion-associated genes (TACSTD2, PSCA, NECTIN4, and CDH1). PC appeared to demonstrate an intermediate phenotype between MP and SM, with partial preservation of epithelial differentiation and secretory programs, reduced adhesion programs, and moderate stromal-associated features. The therapeutic target NECTIN4 was relatively enriched in MP and PC compared with SM. FGFR3 was relatively downregulated in MP and PC compared with conventional invasive UC. Pathway analysis demonstrated relative enrichment of IGF/IGFBP signaling across MP, PC, and SM, with MP enriched for protein secretory programs, PC for RTK/MAPK and WNT/β-catenin signaling, and SM for ECM remodeling.
CONCLUSIONS: Adjacent histological components frequently corresponded to different consensus molecular classes in UC. MP, PC, and SM demonstrated distinct transcriptomic profiles, with PC exhibiting an intermediate phenotype between MP and SM.
MATERIALS AND METHODS: A tissue microarray of 17 formalin-fixed, paraffin-embedded cores (5 MP, 6 PC, and 6 SM) was profiled for expression of 18,676 messenger RNAs using the Bruker GeoMx Digital Spatial Profiler. Thirty-eight areas of interest were selected based on hematoxylin and eosin staining and fluorescence markers. Each area of interest was assigned to a consensus molecular class using a published approach, and pathway analysis was performed using Reactome gene sets.
RESULTS: Most MP and PC demonstrated luminal molecular classes, whereas SM was predominantly Ba/Sq. Adjacent mixed histological components within the same tumor frequently corresponded to distinct consensus molecular classes. Ba/Sq tumors upregulated invasion-associated and extracellular matrix (ECM) remodeling-associated genes, whereas luminal classes demonstrated distinct differentiation-associated signatures. MP demonstrated a predominantly luminal epithelial transcriptional program characterized by increased expression of luminal/urothelial differentiation markers (KRT20, UPK1A, PSCA, and FOXA1), secretory-associated genes (LCN2, MUC1, MUC20, and SPINK1), and relative ERBB2 enrichment, with suppression of Ba/Sq-associated genes (KRT5, KRT6A, KRT14, and TP63). In contrast, SM demonstrated a predominantly mesenchymal/stromal transcriptional program characterized by enrichment of mesenchymal/ECM-associated genes (FN1, VIM, COL6A1, and TGFB1) and reduced expression of luminal/epithelial and adhesion-associated genes (TACSTD2, PSCA, NECTIN4, and CDH1). PC appeared to demonstrate an intermediate phenotype between MP and SM, with partial preservation of epithelial differentiation and secretory programs, reduced adhesion programs, and moderate stromal-associated features. The therapeutic target NECTIN4 was relatively enriched in MP and PC compared with SM. FGFR3 was relatively downregulated in MP and PC compared with conventional invasive UC. Pathway analysis demonstrated relative enrichment of IGF/IGFBP signaling across MP, PC, and SM, with MP enriched for protein secretory programs, PC for RTK/MAPK and WNT/β-catenin signaling, and SM for ECM remodeling.
CONCLUSIONS: Adjacent histological components frequently corresponded to different consensus molecular classes in UC. MP, PC, and SM demonstrated distinct transcriptomic profiles, with PC exhibiting an intermediate phenotype between MP and SM.