Browsing by Author "Brown, Samuel"

Now showing 1 - 2 of 2
  • Thumbnail Image
    ItemOpen Access
    Spatiotemporal modeling reveals high-resolution invasion states in glioblastoma
    (2024-10-10) Manoharan, Varsha T.; Abdelkareem, Aly; Gill, Gurveer; Brown, Samuel; Gillmor, Aaron; Hall, Courtney; Seo, Heewon; Narta, Kiran; Grewal, Sean; Dang, Ngoc H.; Ahn, Bo Y.; Osz, Kata; Lun, Xueqing; Mah, Laura; Zemp, Franz; Mahoney, Douglas; Senger, Donna L.; Chan, Jennifer A.; Morrissy, A. S.
    Abstract Background Diffuse invasion of glioblastoma cells through normal brain tissue is a key contributor to tumor aggressiveness, resistance to conventional therapies, and dismal prognosis in patients. A deeper understanding of how components of the tumor microenvironment (TME) contribute to overall tumor organization and to programs of invasion may reveal opportunities for improved therapeutic strategies. Results Towards this goal, we apply a novel computational workflow to a spatiotemporally profiled GBM xenograft cohort, leveraging the ability to distinguish human tumor from mouse TME to overcome previous limitations in the analysis of diffuse invasion. Our analytic approach, based on unsupervised deconvolution, performs reference-free discovery of cell types and cell activities within the complete GBM ecosystem. We present a comprehensive catalogue of 15 tumor cell programs set within the spatiotemporal context of 90 mouse brain and TME cell types, cell activities, and anatomic structures. Distinct tumor programs related to invasion align with routes of perivascular, white matter, and parenchymal invasion. Furthermore, sub-modules of genes serving as program network hubs are highly prognostic in GBM patients. Conclusion The compendium of programs presented here provides a basis for rational targeting of tumor and/or TME components. We anticipate that our approach will facilitate an ecosystem-level understanding of the immediate and long-term consequences of such perturbations, including the identification of compensatory programs that will inform improved combinatorial therapies.
  • Thumbnail Image
    ItemOpen Access
    The impact of clinical irradiation on tumour cells and the microenvironment of undifferentiated pleomorphic sarcoma
    (2023-07) Brown, Samuel; Morrissy, Sorana; Monument, Michael; Jirik, Frank; Schriemer, David
    Introduction: Immunotherapy resistance and tumour heterogeneity in undifferentiated pleomorphic sarcoma (UPS) are driven by an immune-cold tumour microenvironment (TME) with abundant pro-tumour macrophages and low lymphocyte infiltration. While external beam radiation (EBR) can stimulate an immune-hot phenotype in certain contexts, the effects of EBR in UPS remain poorly defined. In Alberta, neoadjuvant protocols can differ between patients. One group undergoes high-dose EBR (50 Gray EBR or low-dose doxorubicin combined with 30 Gray EBR), while another group will not receive neoadjuvant therapy. Pre-treating intends to locally control disease, however, consequences on the TME remain unknown. Here, I quantify the effects of neoadjuvant EBR on both tumour and immune cells using clinical samples. Approach: We profiled transcriptomes from 19 UPS patients, treated with either surgery only, the Edmonton, or the Calgary neoadjuvant protocols. To improve coverage of intra-tumoural TME heterogeneity, we separately sampled multiple regions within each tumour. Immune and tumour cell transcriptomes were collected individually using the NanoString GeoMx digital spatial profiling (DSP) platform. To support these results we further generated global proteomics data from the same samples and integrated these with a large external bulk RNAseq cohort. Results: I systematically evaluated the impact of high-dose radiotherapy on surgical UPS samples with high spatial resolution across histologically-distinct tumour regions. In Aim 1, differential expression analysis identified radiation-associated genes in both tumour and TME cells with significant changes most dramatic in the tumour margin. In Aim 2, I identified gene expression programs and their usage across samples in the 2 treatment groups. Expression programs altered by radiation represented activities related to enhanced antigen presentation and upregulation of cytokine secretion. In Aim 3, data integration revealed that radiation is positively associated with a phenotype that improves patient survival. Conclusion: This study broadens our understanding of how radiation impacts UPS biology. I identify prognostic expression programs that cells alter in response to high-dose radiation and show that the tumour margin is a key region in need of additional research. This work paves the way toward the identification of combination therapies that synergize with radiation to optimize the immune response in UPS.