Abstract
The tumor microenvironment is emerging as a key regulator of cancer growth and progression, however the exact mechanisms of interaction with the tumor are poorly understood. Whilst the majority of genomic profiling efforts thus far have focused on the tumor, here we investigate RNA-Seq as a hypothesis-free tool to generate independent tumor and stromal biomarkers, and explore tumor-stroma interactions by exploiting the human-murine compartment specificity of patient-derived xenografts (PDX).Across a pan-cancer cohort of 79 PDX models, we determine that mouse stroma can be separated into distinct clusters, each corresponding to a specific stromal cell type. This implies heterogeneous recruitment of mouse stroma to the xenograft independent of tumor type. We then generate cross-species expression networks to recapitulate a known association between tumor epithelial cells and fibroblast activation, and propose a potentially novel relationship between two hypoxia-associated genes, human MIF and mouse Ddx6. Assessment of disease subtype also reveals MMP12 as a putative stromal marker of triple-negative breast cancer. Finally, we establish that our ability to dissect recruited stroma from trans-differentiated tumor cells is crucial to identifying stem-like poor-prognosis signatures in the tumor compartment.In conclusion, RNA-Seq is a powerful, cost-effective solution to global analysis of human tumor and mouse stroma simultaneously, providing new insights into mouse stromal heterogeneity and compartment-specific disease markers that are otherwise overlooked by alternative technologies. The study represents the first comprehensive analysis of its kind across multiple PDX models, and supports adoption of the approach in pre-clinical drug efficacy studies, and compartment-specific biomarker discovery.
Highlights
The tumor stroma comprises of numerous cell types including endothelial cells, cancer-associated fibroblasts (CAFs), mesenchymal stem cells, and immune cells such as lymphocytes and tumor-associated macrophages
As a proxy for the quantity of original patient stroma in each Patient-derived tumor xenograft (PDX) sample, human expression levels of two CAF markers that are rarely expressed by tumor epithelial cells, fibroblast activation protein alpha (FAP) and chondroitin sulfate proteoglycan 4 (CSPG4), were assessed. 22/79 samples showed evidence of patient stroma retention at a low stringency CAF marker expression threshold (FAP or CSPG4 log2 FPKM > 2.0; Table S3) and flagged as potential confounders in analyses of the human component
PDX models as a source of tumor and stroma specific markers of disease subtype We focused on lung and breast cancer as the two most highly represented diseases in the PDX cohort, in order to assess the potential of our approach to identify clinically relevant, independent human tumor and mouse stroma markers of disease subtype
Summary
The tumor stroma comprises of numerous cell types including endothelial cells, cancer-associated fibroblasts (CAFs), mesenchymal stem cells, and immune cells such as lymphocytes and tumor-associated macrophages It plays a critical role in supporting cancer growth and metastasis [1], and is emerging as rich source of targets for anti-cancer therapy. Patient-derived tumor xenograft (PDX) models are generated when fresh tumor tissue obtained directly from patients is implanted subcutaneously or orthotopically into immune-deficient mice. As such, they maintain the principal histological, clinical and molecular characteristics of the original patients’ tumors while remaining biologically stable when passaged in mice [3,4,5]. Since PDX models more closely resemble and recapitulate tumor growth in humans than standard in vitro cell line or cell line xenograft approaches, they remain key experimental platforms for pre-clinical drug development
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