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Induction of Invasive Transitional Cell Bladder Carcinoma in Immune Intact Human MUC1 Transgenic Mice: A Model for Immunotherapy Development
Published on: October 30, 2013
Integrin α5β1-mediated multicellular crosstalk in the tumor microenvironment drives bladder cancer progression and
Ting Liang1, Wuwu Xu2,3, Hu Fang4
1College of Electronics and Information Engineering Shenzhen University Shenzhen China.
Abstract:
Bladder cancer (BCa) progression is driven by complex interactions within the tumor microenvironment, yet the underlying multicellular communication networks remain poorly defined. Here, we integrated bulk, single-cell, and spatial transcriptomic data with multiplexed immunofluorescence to construct a comprehensive cellular atlas across normal urothelium, precancerous lesions, and progressive BCa. We identified a stemness-associated malignant epithelial population (Cluster 1_SDC1), a prognostically unfavorable subset of POSTN+ myofibroblastic cancer-associated fibroblasts (mCAFs), and immunosuppressive monocytic myeloid-derived suppressor cells (M-MDSCs), all enriched in high-grade tumors. Spatial mapping revealed a coordinated signaling cascade wherein POSTN+ mCAFs and M-MDSCs co-localize and engage integrin α5β1 on tip endothelial cells through FN1 and NAMPT, collectively driving angiogenesis. In turn, tip endothelial cells reinforce tumor stemness through downstream COL4A1/2-SDC1 signaling. Therapeutically, targeting integrin α5β1 with RGD peptide suppressed tumor growth and vascularization, while its combination with hydrogel-based delivery and immune checkpoint blockade elicited broad-spectrum antitumor responses. These findings uncover a spatially coordinated immune-stroma-tumor signaling cascade and establish integrin α5β1 as a central therapeutic target, providing a rationale for stroma-directed combination strategies in progressive BCa.
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