---
title: "Stromal innervation predicts outcomes in non‑muscle‑invasive bladder cancer and is defined by a di"
id: "biorxiv-16-stromal-innervation-is-prognostic-in-non-muscle-invasive-bladder-cancer-and"
canonical_url: "https://medichelpline.com/clinical-feed/biorxiv-16-stromal-innervation-is-prognostic-in-non-muscle-invasive-bladder-cancer-and"
content_type: "clinical_feed_article"
specialty: "Oncology"
source_name: "bioRxiv (Biomedical Preprints)"
source_url: "https://www.biorxiv.org/content/10.64898/2026.09.21.751588v1?rss=1"
published_at: "2026-09-23T09:50:14.000Z"
evidence_level: "Verified Feed"
license: "CC-BY-NC-4.0 / Informational Use"
---
# Stromal innervation predicts outcomes in non‑muscle‑invasive bladder cancer and is defined by a di
## Provenance & Clinical Metadata
- **Canonical URL:** https://medichelpline.com/clinical-feed/biorxiv-16-stromal-innervation-is-prognostic-in-non-muscle-invasive-bladder-cancer-and
- **Specialty:** [Oncology](https://medichelpline.com/clinical-feed/oncology.md)
- **Primary Source:** bioRxiv (Biomedical Preprints)
- **Source URL:** [Original Journal Publication](https://www.biorxiv.org/content/10.64898/2026.09.21.751588v1?rss=1)
- **Published At:** 2026-09-23T09:50:14.000Z
- **Evidence Rating:** Verified Feed
## Executive GIST (TL;DR)
- Peripheral nerves within the tumor microenvironment (TME) were quantified in 241 treatment‑naive high‑risk non‑muscle‑invasive bladder cancer (NMIBC) regions from 141 patients using multispectral imaging. The study focused on autonomic and sensory nerve populations in the tumor‑adjacent stroma (termed stromal tumor‑associated nerve, STaN). - **STaN abundance** varied markedly between patients and correlated with aggressive clinicopathological features, failure of intravesical Bacillus Calmette‑Guérin (BCG) therapy, and disease progression. - Unsupervised clustering of nerve features identified distinct STaN phenotypic groups with different clinical and spatial associations. - A **noradrenergic** STaN population and a neurochemically heterogeneous STaN population showed the strongest associations with adverse clinical outcomes. - A mixed nerve population with high expression of the synaptic vesicle protein **synaptophysin** underwent pronounced spatial remodeling that associated with BCG failure, even though its abundance alone had limited prognostic value. - Integration with an independent single‑cell atlas nominated **cancer‑associated fibroblasts (CAFs)** and **mast cells** as candidate intermediary cell types mediating neural communication within the TME. - Matched bulk transcriptomic profiling distinguished coordinated programs in STaN‑high tumors (neuronal, extracellular matrix, lipid metabolism, and immune pathways) versus STaN‑low tumors (proliferative and hypoxic stress‑response pathways). - A transcriptomic classifier built from these features discriminated STaN‑high from STaN‑low tumors in an independent test cohort with reported area under the curve (AUC) = 0.87 and stratified clinical outcomes in additional cohorts. - The findings support tumor innervation as a heterogeneous, clinically relevant TME feature in NMIBC, where **innervation abundance, phenotype, and spatial organization** capture distinct aspects of tumor behavior and prognosis. - The work is presented as a preprint (not peer reviewed); code and supplementary resources are available via referenced GitHub repositories. Competing interest: one author is cofounder and CSO of OncoRx Insights; other authors declared no competing interests.
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Cailin S Deiter 1 University of Colorado Anschutz Medical Campus; * [Find this author on Google Scholar](https://www.biorxiv.org/lookup/google-scholar?link_type=googlescholar&gs_type=author&author%5B0%5D=Cailin%2BS%2BDeiter%2B "Open in new tab") * [Find this author on PubMed](https://www.biorxiv.org/lookup/external-ref?access_num=Deiter%20CS&link_type=AUTHORSEARCH "Open in new tab") * [Search for this author on this site](https://www.biorxiv.org/search/author1%3ACailin%2BS%2BDeiter%2B) * [ORCID record for Cailin S Deiter](http://orcid.org/0000-0002-0772-6387 "Open in new tab") Christiaan de Jong 2 Erasmus MC * [Find this author on Google Scholar](https://www.biorxiv.org/lookup/google-scholar?link_type=googlescholar&gs_type=author&author%5B0%5D=Christiaan%2Bde%2BJong%2B "Open in new tab") * [Find this author on PubMed](https://www.biorxiv.org/lookup/external-ref?access_num=de%20Jong%20C&link_type=AUTHORSEARCH "Open in new tab") * [Search for this author on this site](https://www.biorxiv.org/search/author1%3AChristiaan%2Bde%2BJong%2B) * [ORCID record for Christiaan de Jong](http://orcid.org/0000-0001-6853-5982 "Open in new tab") Mitchell Olislagers 2 Erasmus MC * [Find this author on Google Scholar](https://www.biorxiv.org/lookup/google-scholar?link_type=googlescholar&gs_type=author&author%5B0%5D=Mitchell%2BOlislagers%2B "Open in new tab") * [Find this author on PubMed](https://www.biorxiv.org/lookup/external-ref?access_num=Olislagers%20M&link_type=AUTHORSEARCH "Open in new tab") * [Search for this author on this site](https://www.biorxiv.org/search/author1%3AMitchell%2BOlislagers%2B) * [ORCID record for Mitchell Olislagers](http://orcid.org/0000-0002-4002-9006 "Open in new tab") Kimberly R Jordan 1 University of Colorado Anschutz Medical Campus; * [Find this author on Google Scholar](https://www.biorxiv.org/lookup/google-scholar?link_type=googlescholar&gs_type=author&author%5B0%5D=Kimberly%2BR%2BJordan%2B "Open in new tab") * [Find this author on PubMed](https://www.biorxiv.org/lookup/external-ref?access_num=Jordan%20KR&link_type=AUTHORSEARCH "Open in new tab") * [Search for this author on this site](https://www.biorxiv.org/search/author1%3AKimberly%2BR%2BJordan%2B) * [ORCID record for Kimberly R Jordan](http://orcid.org/0000-0001-8380-7157 "Open in new tab") Tahlita C M Zuiverloon 2 Erasmus MC * [Find this author on Google Scholar](https://www.biorxiv.org/lookup/google-scholar?link_type=googlescholar&gs_type=author&author%5B0%5D=Tahlita%2BC%2BM%2BZuiverloon%2B "Open in new tab") * [Find this author on PubMed](https://www.biorxiv.org/lookup/external-ref?access_num=Zuiverloon%20TC&link_type=AUTHORSEARCH "Open in new tab") * [Search for this author on this site](https://www.biorxiv.org/search/author1%3ATahlita%2BC%2BM%2BZuiverloon%2B) James C Costello 1 University of Colorado Anschutz Medical Campus; * [Find this author on Google Scholar](https://www.biorxiv.org/lookup/google-scholar?link_type=googlescholar&gs_type=author&author%5B0%5D=James%2BC%2BCostello%2B "Open in new tab") * [Find this author on PubMed](https://www.biorxiv.org/lookup/external-ref?access_num=Costello%20JC&link_type=AUTHORSEARCH "Open in new tab") * [Search for this author on this site](https://www.biorxiv.org/search/author1%3AJames%2BC%2BCostello%2B) * [ORCID record for James C Costello](http://orcid.org/0000-0003-3158-9682 "Open in new tab") * For correspondence: james.costello@cuanschutz.edu * [Abstract](https://www.biorxiv.org/content/10.64898/2026.09.21.751588v1)[](https://www.biorxiv.org/panels_ajax_tab/biorxiv_tab_art/node:5802681/1) * [Info/History](https://www.biorxiv.org/content/10.64898/2026.09.21.751588v1.article-info)[](https://www.biorxiv.org/panels_ajax_tab/biorxiv_tab_info/node:5802681/1) * [Metrics](https://www.biorxiv.org/content/10.64898/2026.09.21.751588v1.article-metrics)[](https://www.biorxiv.org/panels_ajax_tab/article_tab_metrics/node:5802681/1) * [Supplementary material](https://www.biorxiv.org/content/10.64898/2026.09.21.751588v1.supplementary-material)[](https://www.biorxiv.org/panels_ajax_tab/biorxiv_tab_data/node:5802681/1) * [Data/Code](https://www.biorxiv.org/content/10.64898/2026.09.21.751588v1.external-links)[](https://www.biorxiv.org/panels_ajax_tab/article_tab_data_code/node:5802681/1) * [ Preview PDF](https://www.biorxiv.org/content/10.64898/2026.09.21.751588v1.full.pdf+html)[](https://www.biorxiv.org/panels_ajax_tab/biorxiv_tab_pdf/node:5802681/1) ![Loading](https://www.biorxiv.org/sites/all/modules/contrib/panels_ajax_tab/images/loading.gif) ## Abstract Peripheral nerves are increasingly recognized as active components of the tumor microenvironment (TME). Yet, their role in non-muscle-invasive bladder cancer (NMIBC) and response to Bacillus Calmette-Guerin (BCG) remains poorly defined. Using multispectral imaging, we characterized autonomic and sensory nerve populations within the tumor-adjacent stroma of 241 treatment-naive high-risk NMIBC tumor regions from 141 patients. Stromal tumor-associated nerve (STaN) abundance varied substantially across patients and was associated with aggressive clinicopathological features, BCG failure, and disease progression. Unsupervised clustering resolved distinct STaN phenotypic groups with differential clinical and spatial associations. Noradrenergic and a neurochemically heterogeneous STaN populations showed the strongest associations with adverse outcomes. In contrast, a mixed population of nerves with high expression of the synaptic vesicle protein synaptophysin exhibited prominent spatial remodeling associated with BCG failure, despite limited prognostic value by abundance alone. Integration with an independent single-cell atlas nominated cancer-associated fibroblasts and mast cells as candidate cellular intermediaries of neural communication within the TME. Matched transcriptomic profiling revealed coordinated neuronal, extracellular matrix, lipid metabolism, and immune programs in STaN-high tumors, whereas STaN-low tumors preferentially enriched proliferative and hypoxic stress-response pathways. Leveraging these transcriptional features, we developed a transcriptomic classifier that distinguished STaN-high from STaN-low tumors in an independent test cohort (AUC = 0.87) and stratified clinical outcomes in additional patient cohorts. Together, these findings establish tumor innervation as a heterogeneous and clinically relevant feature of the NMIBC microenvironment, with neural abundance, phenotype, and spatial organization capturing distinct aspects of tumor behavior and clinical outcome. ### Competing Interest Statement J.C.C. is a cofounder and Chief Science Officer of OncoRx Insights. The other authors declare no competing interests. ## Footnotes * * ## Funder Information Declared National Cancer Institute, https://ror.org/040gcmg81, CA268055, CA046934, CA293845 Cancer League of Colorado, https://ror.org/03cy6xx05, AWD-242959 U.S. National Science Foundation, https://ror.org/021nxhr62, 2201538 National Institute of General Medical Sciences, https://ror.org/04q48ey07, GM158468 MRACE, 107477 Copyright The copyright holder for this preprint is the author/funder, who has granted bioRxiv a license to display the preprint in perpetuity. It is made available under a [CC-BY-NC 4.0 International license](http://creativecommons.org/licenses/by-nc/4.0/). bioRxiv and medRxiv thank the following for their generous financial support: > The Chan Zuckerberg Initiative, Cold Spring Harbor Laboratory, the Sergey Brin Family Foundation, California Institute of Technology, Centre National de la Recherche Scientifique, Fred Hutchinson Cancer Center, Imperial College London, Massachusetts Institute of Technology, Stanford University, The University of Edinburgh, University of Washington, and Vrije Universiteit Amsterdam. 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[ Download PDF](https://www.biorxiv.org/content/10.64898/2026.09.21.751588v1.full.pdf) Print/Save Options [Download PDF](https://www.biorxiv.org/content/biorxiv/early/2026/09/23/2026.09.21.751588.full.pdf)Full Text & In-line FiguresXML [More Info](https://www.biorxiv.org/about/FAQ#PrintOptions "More Information on Print/Save Options") [Supplementary Material ](https://www.biorxiv.org/content/10.64898/2026.09.21.751588v1.supplementary-material) [ Data/Code](https://www.biorxiv.org/content/early/2026/09/23/2026.09.21.751588.external-links) [ Email](https://www.biorxiv.org/ "Email this Article") [ Share](https://www.biorxiv.org/) Stromal innervation is prognostic in non-muscle-invasive bladder cancer and predicted by a distinct microenvironmental transcriptomic signature Cailin S Deiter, Christiaan de Jong, Mitchell Olislagers, Kimberly R Jordan, Tahlita C M Zuiverloon, James C Costello bioRxiv 2026.09.21.751588; doi: https://doi.org/10.64898/2026.09.21.751588 This article is a preprint and has not been certified by peer review [[what does this mean?](https://www.biorxiv.org/about/FAQ#unrefereed)]. 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