Gina Bouchard

All Publications

• The colocatome as a spatial -omic reveals shared microenvironment features between tumour-stroma assembloids and human lung cancer. bioRxiv : the preprint server for biology Bouchard, G., Zhang, W., Li, I., Ilerten, I., Bhattacharya, A., Li, Y., Trope, W., Shrager, J. B., Kuo, C., Tian, L., Giaccia, A. J., Plevritis, S. K. 2023

  Abstract

  Computational frameworks to quantify and compare microenvironment spatial features of in-vitro patient-derived models and clinical specimens are needed. Here, we acquired and analysed multiplexed immunofluorescence images of human lung adenocarcinoma (LUAD) alongside tumour-stroma assembloids constructed with organoids and fibroblasts harvested from the leading edge (Tumour-Adjacent Fibroblasts;TAFs) or core (Tumour Core Fibroblasts;TCFs) of human LUAD. We introduce the concept of the "colocatome" as a spatial -omic dimension to catalogue all proximate and distant colocalisations between malignant and fibroblast subpopulations in both the assembloids and clinical specimens. The colocatome expands upon the colocalisation quotient (CLQ) through a nomalisation strategy that involves permutation analysis and thereby allows comparisons of CLQs under different conditions. Using colocatome analysis, we report that both TAFs and TCFs protected cancer cells from targeted oncogene treatment by uniquely reorganising the tumour-stroma cytoarchitecture, rather than by promoting cellular heterogeneity or selection. Moreover, we show that the assembloids' colocatome recapitulates the tumour-stroma cytoarchitecture defining the tumour microenvironment of LUAD clinical samples and thereby can serve as a functional spatial readout to guide translational discoveries.

  View details for DOI 10.1101/2023.09.11.557278

  View details for PubMedID 37745466

  View details for PubMedCentralID PMC10515823

• Role of spatially distinct tumor fibroblast in erlotinib resistance Bouchard, G., Plevritis, S. K. AMER ASSOC CANCER RESEARCH. 2022

  View details for Web of Science ID 000892509500589

• Role of spatially distinct tumor fibroblast in erlotinib resistance. Bouchard, G., Plevritis, S. K. AMER ASSOC CANCER RESEARCH. 2022

  View details for Web of Science ID 000892509502641

• Multi-omics analysis of spatially distinct stromal cells reveals tumor-induced O-glycosylation of the CDK4-pRB axis in fibroblasts at the invasive tumor edge. Cancer research Bouchard, G., Garcia-Marques, F. J., Karacosta, L. G., Zhang, W., Bermudez, A., Riley, N. M., Varma, S., Mehl, L. C., Benson, J. A., Shrager, J. B., Bertozzi, C. R., Pitteri, S. J., Giaccia, A. J., Plevritis, S. K. 2021

  Abstract

  The invasive leading edge represents a potential gateway for tumor metastasis. The role of fibroblasts from the tumor edge in promoting cancer invasion and metastasis has not been comprehensively elucidated. We hypothesize that crosstalk between tumor and stromal cells within the tumor microenvironment (TME) results in activation of key biological pathways depending on their position in the tumor (edge vs core). Here we highlight phenotypic differences between tumor-adjacent-fibroblasts (TAF) from the invasive edge and tumor core fibroblasts (TCF) from the tumor core, established from human lung adenocarcinomas. A multi-omics approach that includes genomics, proteomics, and O-glycoproteomics was used to characterize crosstalk between TAFs and cancer cells. These analyses showed that O-glycosylation, an essential post-translational modification resulting from sugar metabolism, alters key biological pathways including the cyclin-dependent kinase 4 and phosphorylated retinoblastoma protein (CDK4-pRB) axis in the stroma and indirectly modulates pro-invasive features of cancer cells. In summary, the O-glycoproteome represents a new consideration for important biological processes involved in tumor-stroma crosstalk and a potential avenue to improve the anti-cancer efficacy of CDK4 inhibitors.

  View details for DOI 10.1158/0008-5472.CAN-21-1705

  View details for PubMedID 34853070

• A human lung tumor microenvironment interactome identifies clinically relevant cell-type cross-talk. Genome biology Gentles, A. J., Hui, A. B., Feng, W. n., Azizi, A. n., Nair, R. V., Bouchard, G. n., Knowles, D. A., Yu, A. n., Jeong, Y. n., Bejnood, A. n., Forgó, E. n., Varma, S. n., Xu, Y. n., Kuong, A. n., Nair, V. S., West, R. n., van de Rijn, M. n., Hoang, C. D., Diehn, M. n., Plevritis, S. K. 2020; 21 (1): 107

  Abstract

  Tumors comprise a complex microenvironment of interacting malignant and stromal cell types. Much of our understanding of the tumor microenvironment comes from in vitro studies isolating the interactions between malignant cells and a single stromal cell type, often along a single pathway.To develop a deeper understanding of the interactions between cells within human lung tumors, we perform RNA-seq profiling of flow-sorted malignant cells, endothelial cells, immune cells, fibroblasts, and bulk cells from freshly resected human primary non-small-cell lung tumors. We map the cell-specific differential expression of prognostically associated secreted factors and cell surface genes, and computationally reconstruct cross-talk between these cell types to generate a novel resource called the Lung Tumor Microenvironment Interactome (LTMI). Using this resource, we identify and validate a prognostically unfavorable influence of Gremlin-1 production by fibroblasts on proliferation of malignant lung adenocarcinoma cells. We also find a prognostically favorable association between infiltration of mast cells and less aggressive tumor cell behavior.These results illustrate the utility of the LTMI as a resource for generating hypotheses concerning tumor-microenvironment interactions that may have prognostic and therapeutic relevance.

  View details for DOI 10.1186/s13059-020-02019-x

  View details for PubMedID 32381040

• Sparse discriminative latent characteristics for predicting cancer drug sensitivity from genomic features. PLoS computational biology Knowles, D. A., Bouchard, G., Plevritis, S. 2019; 15 (5): e1006743

  Abstract

  Drug screening studies typically involve assaying the sensitivity of a range of cancer cell lines across an array of anti-cancer therapeutics. Alongside these sensitivity measurements high dimensional molecular characterizations of the cell lines are typically available, including gene expression, copy number variation and genomic mutations. We propose a sparse multitask regression model which learns discriminative latent characteristics that predict drug sensitivity and are associated with specific molecular features. We use ideas from Bayesian nonparametrics to automatically infer the appropriate number of these latent characteristics. The resulting analysis couples high predictive performance with interpretability since each latent characteristic involves a typically small set of drugs, cell lines and genomic features. Our model uncovers a number of drug-gene sensitivity associations missed by single gene analyses. We functionally validate one such novel association: that increased expression of the cell-cycle regulator C/EBPdelta decreases sensitivity to the histone deacetylase (HDAC) inhibitor panobinostat.

  View details for DOI 10.1371/journal.pcbi.1006743

  View details for PubMedID 31136571

• GFPT2-expressing cancer-associated fibroblasts mediate metabolic reprogramming in human lung adenocarcinoma. Cancer research Zhang, W., Bouchard, G., Yu, A., Shafiq, M., Jamali, M., Shrager, J. B., Ayers, K., Bakr, S., Gentles, A. J., Diehn, M., Quon, A., West, R. B., Nair, V., van de Rijn, M., Napel, S., Plevritis, S. K. 2018

  Abstract

  Metabolic reprogramming of the tumor microenvironment is recognized as a cancer hallmark. To identify new molecular processes associated with tumor metabolism, we analyzed the transcriptome of bulk and flow-sorted human primary non-small cell lung cancer (NSCLC) together with 18FDG-positron emission tomography scans, which provide a clinical measure of glucose uptake. Tumors with higher glucose uptake were functionally enriched for molecular processes associated with invasion in adenocarcinoma (AD) and cell growth in squamous cell carcinoma (SCC). Next, we identified genes correlated to glucose uptake that were predominately overexpressed in a single cell-type comprising the tumor microenvironment. For SCC, most of these genes were expressed by malignant cells, whereas in AD they were predominately expressed by stromal cells, particularly cancer-associated fibroblasts (CAFs). Among these AD genes correlated to glucose uptake, we focused on Glutamine-Fructose-6-Phosphate Transaminase 2 (GFPT2), which codes for the Glutamine-Fructose-6-Phosphate Aminotransferase 2 (GFAT2), a rate-limiting enzyme of the hexosamine biosynthesis pathway (HBP), which is responsible for glycosylation. GFPT2 was predictive of glucose uptake independent of GLUT1, the primary glucose transporter, and was prognostically significant at both gene and protein level. We confirmed that normal fibroblasts transformed to CAF-like cells, following TGF-beta treatment, upregulated HBP genes, including GFPT2, with less change in genes driving glycolysis, pentose phosphate pathway and TCA cycle. Our work provides new evidence of histology-specific tumor-stromal properties associated with glucose uptake in NSCLC and identifies GFPT2 as a critical regulator of tumor metabolic reprogramming in AD.

  View details for PubMedID 29760045