Author(s)
Derrick C. Wan, MD
Camille Brenac, MD
Maxime Fieux, MD, PhD
Michael T. Longaker, MD, MBA
Michael Januszyk, MD, PhD
Konstantina M Stankovic, MD, PhD
Jennifer C. Alyono, MD
Affiliation(s)
Stanford University
Abstract:
Objective: This meta-analysis aims to define the role of heterogeneous, functionally distinct stromal fibroblast subtypes and their interactions with Schwann cells and immune/inflammatory cell components to better understand how these cells impact VS behavior.
Background: While hearing loss is the most common presenting symptom in patients with vestibular schwannoma (VS), tumor size and growth have poorly correlated with degree of severity. Thus, nerve compression alone does not fully explain the hearing loss associated with VS. Tumor development, aggressiveness, and progression are well-recognized as being closely linked to the stromal microenvironment, with complex interactions described between these components.
Study Design: We conducted a meta-analysis of four publicly available scRNA-seq datasets representing 28 VS human samples and two nerve controls. Data integration was performed using Harmony, followed by dimensionality reduction for visualization. Differential expression and gene set enrichment analysis were conducted to identify inflammatory markers and pathways involved. Cell-cell interactions were further investigated using CellChat, highlighting key signaling interactions.
Results: Five distinct subclusters of tumor-associated fibroblasts were identified with enrichment of inflammatory fibroblasts in tumor samples compared to controls. This group was increased in tumors with greater hearing loss and exhibited elevated NLRP3 inflammasome activity, suggesting these fibroblasts may play a role in tumor-promoting inflammation and tissue damage. Furthermore, this subcluster demonstrated increased intercellular communication with Schwann cells via midkine, a mediator with known role in tumor proliferation, and with immune/inflammatory cells.
Conclusions: These findings suggest a potential role for inflammatory fibroblasts in promoting VS tumor behavior leading to hearing loss and identify a previously under recognized cellular subcluster that could serve as a therapeutic target.
Learning Objective: To understand fibroblast subgroup functional heterogeneity in vestibular schwannoma and how they may interact with other cellular components in driving tumor behavior.
Desired Result: Appreciate fibroblast heterogeneity in tumors and comprehend how specific subsets may impact clinical presentation and be targeted with future therapeutics.
Level of Evidence – Does not Apply
Indicate IRB or IACUC: Not applicable