TIMP1 Derived from Mesenchymal Stem Cells Promotes Bladder Cancer Progression by Regulating the Formation of VDIMs...

Area of Science:

• Oncology
• Cancer Biology
• Stem Cell Biology

Background:

• The role of mesenchymal stem cells (MSCs) in bladder cancer (BC) progression is not fully understood.
• Identifying specific molecular mechanisms by which MSCs influence BC is crucial for developing targeted therapies.

Purpose of the Study:

• To investigate the pro-tumorigenic function of MSCs in bladder cancer.
• To identify key molecules secreted by MSCs that drive BC progression.
• To elucidate the underlying molecular mechanisms and evaluate therapeutic strategies targeting the MSCs-BC axis.

Main Methods:

• Integration of clinical cohorts, organoid models, and patient-derived xenografts (PDX).
• Multiplex fluorescent immunohistochemistry and enzyme-linked immunosorbent assays to assess MSCs infiltration and TIMP1 levels.
• Single-cell data analysis, mass spectrometry, and mechanistic studies involving signaling pathway analysis (cMet, RAP1).

Main Results:

• Elevated MSCs infiltration and TIMP1 levels in BC tissues and urine correlate with advanced stage, lymphovascular invasion, and poorer survival.
• TIMP1 is the predominant cytokine secreted by MSCs, acting via ADAM10 to stabilize cMet phosphorylation and activate the RAP1 pathway.
• MSC-derived TIMP1 promotes BC proliferation by enhancing intracellular Ca2+ and VDAC1 expression, impacting mitochondrial quality control.
• A TIMP1 inhibitor (FXR agonist 3) suppressed BC proliferation and tumor growth in PDX models by disrupting the cMet-RAP1 pathway without toxicity.

Conclusions:

• MSCs-derived TIMP1 is a key driver of bladder cancer progression through the cMet-RAP1 signaling axis.
• Targeting the MSCs-TIMP1-RAP1 axis represents a promising novel therapeutic strategy for bladder cancer.