Transcriptomic Insights into UTUC: Role of Inflammatory Fibrosis and Potential for Personalized Treatment

Abstract

Background: Upper tract urothelial carcinoma (UTUC) is a rare disease, belonging to the same category of urothelial cancers as bladder cancer (BC). Despite sharing similar non-surgical treatment modalities, UTUC demonstrates a higher propensity for metastasis compared to BC. Additionally, while both cancers exhibit many similar molecular disease emergence mechanisms, sequencing data reveals some differences. Our study aims to understand the transcriptomic distinctions between UTUC and BC, explore the causes behind UTUC's heightened metastatic tendency, construct a model for UTUC metastasis and prognosis, and propose personalized treatment strategies for UTUC. Methods: In our research, we utilized differential gene expression analysis, interaction networks, and Cox regression to explore the enhanced metastatic propensity of UTUC. We formulated and validated a prognostic risk model using a diverse set of techniques, which include cell co-culture, reverse transcription quantitative polymerase chain reaction (rt-qPCR), Western blot, and Transwell experiments. Our methodological approach also involved survival analysis, risk model construction, and drug screening leveraging the databases of CTRPv2, PRISM and CMap. For histological assessments, we employed the Masson staining technique. All statistical evaluations were conducted using R software and GraphPad Prism 9, reinforcing the rigorous and comprehensive nature of our research approach. Results: Screening through inflammatory fibrosis revealed a reduction of extracellular matrix and cell adhesion molecules regulated by proteoglycans in UTUC compared to BC, making UTUC more metastasis-prone. We demonstrated that five molecules, SDC1, LUM, VEGFA, WNT7B, and TIMP3, play critical roles in promoting UTUC metastasis. A risk model based on these five molecules can effectively predict the risk of UTUC metastasis and disease-free survival time. Given UTUC's unique molecular mechanisms distinct from BC, we discovered that UTUC patients could better mitigate the issue of poor prognosis associated with UTUC's easy metastasis by using Tyrosine Kinase Inhibitors (TKIs) alongside the conventional gemcitabine and cisplatin chemotherapy regimen. Conclusions: 1. The poor prognosis of UTUC due to its high metastatic propensity is intimately tied to inflammatory fibrosis induced by ROS accumulation. 2. The biological model constructed using the five molecules SDC1, LUM, VEGFA, WNT7B, and TIMP3 can effectively predict patient prognosis. 3. UTUC patients require specialized treatments in addition to traditional regimens, with TKIs showing significant potential.