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Spatial Transcriptomics of Aggressive Micropapillary, Plasmacytoid, and Sarcomatoid Urothelial Carcinoma Reveals Distinct Molecular Landscapes
Ting Zhao, MD1, Cole Nawrocki, BA2, Alfred Anthony Barney, IV, MS1, Linjie Xiong, MD1, Linda T. Nieman, PhD3, Philip J. Saylor, MD1, Michael L. Blute, MD1, David T. Miyamoto, MD, PhD1, David T. Ting, MD1, Douglas M. Dahl, MD1, Chin-Lee Wu, MD, PhD1.
1Massachusetts General Hospital, Boston, MA, USA, 2Mass General Bringham Cancer Institute, Boston, MA, USA, 3Mass General Brigham Cancer Institute, Boston, MA, USA.
BACKGROUND: Consensus molecular classes of urothelial carcinoma (UC) include basal/squamous (Ba/Sq), luminal papillary (LumP), luminal nonspecified (LumNS), luminal unstable (LumU), stroma-rich, and neuroendocrine (NE)-like.
METHODS: We determined the consensus molecular classifications of MP, PC, and SM subtypes of bladder UC and characterized their transcriptomic profiles using spatial transcriptomics (ST). A tissue microarray of 17 FFPE cores (5 MP, 6 PC, 6 SM) was profiled for expression of 18,676 mRNAs using Bruker GeoMx Digital Spatial Profiler. 38 areas of interest (AOIs) were selected based on H&E and fluorescence markers. Each AOI was assigned to a consensus molecular class using a published approach, and gene set enrichment analysis was performed for Reactome gene sets.
RESULTS: Patients (88% male) had a median age of 69 years (range, 56-87). All tumors were high-grade. 11 patients (79%) had ≥pT3 disease. At median follow-up (18 months) (range, 1-135), 76% died of disease. 70% of adjacent AOIs had different molecular classes. MP/PUC/UCIS were luminal. PC was luminal-predominant, whereas SM was Ba/Sq-predominant. Molecular class distributions were most similar between MP (2 LumU/1 LumP/1 LumNS) and PC (2 LumU/1 LumP/1 LumNS/2 stroma-rich). Two SM were NE-like: one adjacent to neuroendocrine carcinoma, the other lacking NE morphology in the entire tumor. Ba/Sq upregulated
NRP1/P4HA2/CTSC/MSN/PRNP/IGF2BP2. Besides shared luminal identity, LumP upregulated
TMPRSS4/MECOM; LumNS upregulated
LEMD1/OR10R2; and LumU upregulated
ACSL1/SPNS2. Stroma-rich upregulated
IGF1/CD24/AEBP1. NE-like upregulated
NES/PKD1. MP downregulated androgen receptor signaling versus CIUC/PUC/PC/SM and upregulated IGF/IGFBP activity and protein secretory programs versus CIUC/PUC. PC showed reduced adhesion and increased IGF/IGFBP activity versus CIUC/PUC and upregulated WNT/β-catenin signaling versus MP. SM showed reduced adhesion versus CIUC/PUC and enrichment of SLIT/ROBO signaling versus CIUC.
CONCLUSIONS: In conclusion, adjacent histological components frequently correspond to different consensus molecular classes. MP was transcriptomically most similar to PC, whereas MP, PC, and SM each exhibited distinct ST profiles.
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