Abstract 6226: Identifying nested spatial units as a conserved organizing principle of the spatial tumor microenvironment

Abstract

Abstract Heterogeneity of therapeutic response amongst cancer patients has a profound impact on cancer-related mortality. It has been widely hypothesized that diversity in clinical outcomes is driven by variability in tumor biology at scales ranging from inter-patient to inter-cellular. Indeed, the advent of technologies describing the tumor microenvironment (TME) at cellular resolution has demonstrated that TME organization is heterogeneous with respect to intra-tumor spatial location, body tumor location (primary vs metastatic), patient, and tumor type. However, the organizing principles that govern TME heterogeneity remain unclear. Without such organizing principles, it remains an arduous task to link descriptions of tumor biology heterogeneity to clinical outcomes in a mechanistically explainable manner. Through the application of network statistical inference models to spatial transcriptomic data, we have identified that nested spatial units (NSUs) are a core organizing principle of the TME. We find that NSUs are widely conserved across 96 patient biopsies of 14 distinct tumor types and 3 body locations (primary, abdominal metastases, brain metastases). Moreover, NSUs represent a transferrable organizing blueprint that allows for the spatial location of individual spots (5-50 cells) in a tumor biopsy to be predicted by the NSUs of a secondary, unrelated biopsy (Pearson correlation of spot-spot distance: 0.04 - 0.71, median 0.25). By using NSUs as the organizing unit of comparison, we identify variation in gene expression, biological pathways, and multicellular structures occurring across tumors in a distance-dependent manner. In summary, NSUs provide a foundation for the comparative analysis of tumor spatial biology and a path by which spatial biology can be mechanistically linked to patient outcomes. Citation Format: Vivek Behera, Hannah Giba, Benjamin A. Doran, Justin P. Kline, Arjun S. Raman. Identifying nested spatial units as a conserved organizing principle of the spatial tumor microenvironment [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2024; Part 1 (Regular Abstracts); 2024 Apr 5-10; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2024;84(6_Suppl):Abstract nr 6226.