Elevated levels of MMP12 sourced from macrophages are associated with poor prognosis in urothelial bladder cancer

Abstract

Abstract Background Urothelial bladder cancer is most frequently diagnosed at the non-muscle-invasive stage (NMIBC). However, recurrences and interventions for intermediate and high-risk NMIBC patients impact quality of life. Biomarkers for patient stratification could help to avoid unnecessary interventions whilst indicating aggressive measures when required. Methods In this study, immuno-oncology focused, multiplexed proximity extension assays were utilised to analyse plasma (n=90) and urine (n=40) samples from 90 newly-diagnosed and treatment-naïve bladder cancer patients. Public single-cell and bulk RNA-sequencing data from patient tumour tissues and murine OH-BBN-induced urothelial carcinomas were also explored. Results Plasma from muscle-invasive, urothelial bladder cancer patients displayed higher levels of MMP7 (p=0.028) and CCL23 (p=0.03) compared to NMIBC patients, whereas urine displayed higher levels of CD27 (p=0.044) and CD40 (p=0.04) in the NMIBC group by two-sided Wilcoxon rank-sum tests. Random forest survival and multivariable regression analyses identified increased MMP12 plasma levels as an independent marker (p<0.001) associated with shorter overall survival (HR=1.8, p<0.001, 95% CI:1.3-2.5); this finding was validated in an independent patient cohort. Single-cell transcriptomics analyses indicated tumour-infiltrating macrophages as a putative source of MMP12. Conclusions The measurable levels of tumour-localised, immune-cell-derived MMP12 in blood suggest MMP12 as an important, tumour-microenvironment-related biomarker that could complement histopathology-based risk stratification and represent a pharmacological target in urothelial bladder cancer.