Spatially-resolved analyses of muscle invasive bladder cancer microenvironment unveil a distinct fibroblast cluster associated with prognosis

Our plain-English summary of Spatially-resolved analyses of muscle invasive bladder cancer microenvironment unveil a distinct fibroblast cluster associated with prognosis, by C. Feng, Y. Wang, W. Song, et al (Frontiers in Immunology, 2024).

The study

• Authors: C. Feng, Y. Wang, W. Song, T. Liu, H. Mo, H. Liu, S. Wu, Z. Qin, Z. Wang, Y. Tao, L. He, S. Tang, Y. Xie, Q. Wang, T. Li
• Journal: Frontiers in Immunology
• Published: 2024;15:1522582
• Cited by: 9 articles, as counted by NIH iCite
• Read it: PubMed · Publisher · Free full text

Abstract

Background: Muscle-invasive bladder cancer (MIBC) is a prevalent cancer characterized by molecular and clinical heterogeneity. Assessing the spatial heterogeneity of the MIBC microenvironment is crucial to understand its clinical significance.

Methods: In this study, we used imaging mass cytometry (IMC) to assess the spatial heterogeneity of MIBC microenvironment across 185 regions of interest in 40 tissue samples. We focused on three primary parameters: tumor (T), leading-edge (L), and nontumor (N). Cell gating was performed using the Cytobank platform. We calculated the Euclidean distances between cells to determine cellular interactions and performed single-cell RNA sequencing (scRNA-seq) to explore the molecular characteristics and mechanisms underlying specific fibroblast (FB) clusters. scRNA-seq combined with spatial transcriptomics (ST) facilitated the identification of ligand-receptor (L-R) pairs that mediate interactions between specific FB clusters and endothelial cells. Machine learning algorithms were used to construct a prognostic gene signature.

Results: The microenvironments in the N, L, and T regions of MIBC exhibited spatial heterogeneity and regional diversity in their components. A distinct FB cluster located in the L region-identified as S3-is strongly associated with poor prognosis. IMC analyses demonstrated a close spatial association between S3 and endothelial cells, with S3-positive tumors exhibiting increased blood vessel density and altered vascular morphology. The expression of vascular endothelial growth factor receptor and active vascular sprouting were significant in S3-positive tumors. scRNA-seq and ST analyses indicated that the genes upregulated in S3 were associated with angiogenesis. NOTCH1-JAG2 signaling pathway was identified as a significant L-R pair specific to S3 and endothelial cell interactions. Further analysis indicated that YAP1 was a potential regulator of S3. Machine learning algorithms and Gene Set Variation Analysis were used to establish an S3-related gene signature that was associated with the poor prognosis of tumors including MIBC, mesothelioma, glioblastoma multiforme, lower-grade glioma, stomach adenocarcinoma, uveal melanoma, kidney renal clear cell carcinoma, kidney renal papillary cell carcinoma, and lung squamous cell carcinoma.

Conclusions: We assessed the spatial landscape of the MIBC microenvironment and revealed a specific FB cluster with prognostic potential. These findings offer novel insights into the spatial heterogeneity of the MIBC microenvironment and highlight its clinical significance.

Copyright © 2024 Feng, Wang, Song, Liu, Mo, Liu, Wu, Qin, Wang, Tao, He, Tang, Xie, Wang and Li.

In plain English

This laboratory study from China examined tumor tissue from 40 patients with muscle-invasive bladder cancer who had not received tumor treatment before. It does not study asbestos. Using a method that maps 33 proteins in tissue, the authors analyzed 185 regions: 100 tumor-core, 62 leading-edge (where the tumor invades muscle) and 23 non-tumor regions. They described four types of fibroblasts (connective-tissue cells). One type, called S3, made up nearly 75% of the fibroblasts in leading-edge regions. Patients whose tumors contained S3 had shorter overall survival than those whose tumors did not, but the article's text gives no survival figures. S3-positive tumors showed more blood vessels. Vessel-lining (endothelial) cells made up 8.39% of the neighbors of S3 cells, compared with 1.43% to 2.79% for the other fibroblast types. Using public gene data, the authors built an S3-based score. High scores were linked to poorer overall survival in bladder cancer datasets and in eight other cancer types, including mesothelioma. The mesothelioma data came from a public dataset, and the article does not describe its type or any asbestos exposure. The authors concluded that the S3 cluster has prognostic potential.

We wrote this plain-English summary from the full article with the help of AI, and a second AI model checked each sentence against the article. It is not the authors' wording; the abstract and the article are their own account.

What the study did and found

• Design: Laboratory tissue study combining imaging mass cytometry of patient tumor sections with analysis of publicly available single-cell RNA, spatial transcriptomic and bulk gene-expression datasets
• Who was studied: Tissue sections from 40 patients with muscle-invasive bladder cancer (MIBC) at the First Affiliated Hospital of Guangxi Medical University, untreated before enrolment. There were 185 regions of interest: 100 tumor-core, 62 leading-edge and 23 nontumor. Public data were also used: single-cell RNA data from eight bladder cancer patients, and TCGA and GEO cohorts, including TCGA-MESO.
• Exposure: No asbestos or other occupational or environmental exposure was studied. The factor compared was the presence of fibroblast cluster S3 (a-SMA+ Collagen I+ Vimentin+ CD90+) and a high versus low S3-based gene score (FCS3S).
• Main results:
  • Stromal cell frequencies decreased progressively from nontumor to leading-edge to tumor regions. Immune cells (B cells, macrophages, CD4+ and CD8+ T cells) were more frequent in leading-edge regions.
  • Four fibroblast clusters were identified. Leading-edge regions mainly contained two types, nearly 75% of them S3. Tumor regions contained all four types, and nontumor regions contained only FB S4.
  • MIBC patients with S3-positive tumors had shorter overall survival than those with S3-negative tumors. No numbers are given in the text.
  • S3-positive tumors had a higher density of blood vessels, including more extensive and distorted vessels, than S3-negative tumors.
  • Endothelial cells made up 2.38%, 1.43%, 8.39% and 2.79% of the neighbors of fibroblast clusters S1, S2, S3 and S4 respectively.
  • In public spatial gene data, the NOTCH1–JAG2 ligand–receptor pair was co-located in endothelial spots next to fibroblast regions. YAP1 was predicted as one of the top transcription factors for S3.
  • In the TCGA-BLCA bladder cancer cohort, patients with a high S3 score (FCS3S) had significantly poorer overall survival. This was supported by two other bladder cancer cohorts (GSE188715 and GSE32894).
  • The S3 score also identified patients with poor outcomes in eight other cancer types, including mesothelioma (MESO). No numbers are given in the text.
• The authors' conclusion: The authors concluded that they had mapped the spatial landscape of the MIBC microenvironment and found a specific fibroblast cluster (S3) with prognostic potential.

Topics

Medical terms in this study, explained in our Lexicon: Fibroblast, Prognosis, Angiogenesis, Mesothelioma, Adenocarcinoma, Carcinoma, Squamous Cell Carcinoma.

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