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Single-cell transcriptome analysis revealed the heterogeneity and microenvironment of gastrointestinal stromal tumors.

ABSTRACT: Gastrointestinal stromal tumor (GIST) is the most common mesenchymal tumor of the human gastrointestinal tract. In this study, we performed single-cell RNA sequencing (RNA-seq) on intra- and peri-tumor tissues from GIST patients with the aim of discovering the heterogeneity of tumor cells in GIST and their interactions with other cells. We found four predominating cell types in GIST tumor tissue, including T cells, macrophages, tumor cells, and NK cells. Tumor cells could be clustered into two groups: one was highly proliferating and associated with high risk of metastasis, the other seemed "resting" and associated with low risk. Their clinical relevance and prognostic values were confirmed by RNA-seq of 65 GIST samples. T cells were the largest cell type in our single-cell data. Two groups of CD8⁺ effector memory (EM) cells were in the highest clonal expansion and performed the highest cytotoxicity but were also the most exhausted among all T cells. A group of macrophages were found polarized to possess both M1 and M2 signatures, and increased along with tumor progression. Cell-to-cell interaction analysis revealed that adipose endothelial cells had high interactions with tumor cells to facilitate their progression. Macrophages were at the center of the tumor microenvironment, recruiting immune cells to the tumor site and having most interactions with both tumor and nontumor cells. In conclusion, we obtained an overview of the GIST microenvironment and revealed the heterogeneity of each cell type and their relevance to risk classifications, which provided a novel theoretical basis for learning and curing GISTs.

SUBMITTER: Mao X

PROVIDER: S-EPMC7935798 | biostudies-literature |

REPOSITORIES: biostudies-literature

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Project description:Breast cancer (BC) is a heterogeneous disease, which is primarily classified according to hormone receptors and HER2 expression. Despite the many advances in BC diagnosis and management, the identification of novel actionable therapeutic targets expressed by cancerous cells has always been a daunting task due to the large heterogeneity of the disease and the presence of non-cancerous cells (i.e., immune cells and stromal cells) within the tumor microenvironment. In the current study, we employed computational algorithms to decipher the cellular composition of estrogen receptor-positive (ER+), HER2+, ER+HER2+, and triple-negative BC (TNBC) subtypes from a total of 49,899 single cells' publicly available transcriptomic data derived from 26 BC patients. Restricting the analysis to EPCAM+Lin- tumor epithelial cells, we identified the enriched gene sets in each BC molecular subtype. Integration of single-cell transcriptomic with CRISPR-Cas9 functional screen data identified 13 potential therapeutic targets for ER+, 44 potential therapeutic targets for HER2+, and 29 potential therapeutic targets for TNBC. Interestingly, several of the identified therapeutic targets outperformed the current standard of care for each BC subtype. Given the aggressive nature and lack of targeted therapies for TNBC, elevated expression of ENO1, FDPS, CCT6A, TUBB2A, and PGK1 predicted worse relapse-free survival (RFS) in basal BC (n = 442), while elevated expression of ENO1, FDPS, CCT6A, and PGK1 was observed in the most aggressive BLIS TNBC subtype. Mechanistically, targeted depletion of ENO1 and FDPS halted TNBC cell proliferation, colony formation, and organoid tumor growth under 3-dimensional conditions and increased cell death, suggesting their potential use as novel therapeutic targets for TNBC. Differential expression and gene set enrichment analysis in TNBC revealed enrichment in the cycle and mitosis functional categories in FDPShigh, while ENO1high was associated with numerous functional categories, including cell cycle, glycolysis, and ATP metabolic processes. Taken together, our data are the first to unravel the unique gene signatures and to identify novel dependencies and therapeutic vulnerabilities for each BC molecular subtype, thus setting the foundation for the future development of more effective targeted therapies for BC.

Project description:Immunotherapy is less effective in patients with epidermal growth factor receptor (EGFR) mutant non-small-cell lung cancer (NSCLC). Lower programmed cell death-ligand 1 (PD-L1) expression and tumor mutation burden (TMB) are reported to be the underlying mechanism. Being another important factor to affect the efficacy of immunotherapy, tumor microenvironment (TME) characteristics of this subgroup of NSCLC are not comprehensively understood up to date. Hence, we initiated this study to describe the specific TME of EGFR-mutant lung adenocarcinoma (LUAD) from cellular compositional and functional perspectives to better understand the immune landscape of this most common subtype of NSCLC. We used single-cell transcriptome sequencing and multiplex immunohistochemistry to investigate the immune microenvironment of EGFR-mutant and EGFR wild-type LUADs and determined the efficacy of immunotherapy. We analyzed single cells from nine treatment-naïve samples and compared them to three post-immunotherapy samples previously reported from single cell perspective using bioinformatics methods. We found that EGFR-mutant malignant epithelial cells had similar characteristics to the epithelial cells in non-responders. EGFR-mutant LUAD lacked CD8+ tissue-resident memory (TRM) cells, which could promote tertiary lymphoid structure generation by secreting CXCL13. In addition, other cell types, including tumor-associated macrophages and cancer-associated fibroblasts, which are capable of recruiting, retaining, and expanding CD8+ TRM cells in the TME, were also deficient in EGFR-mutant LUAD. Furthermore, EGFR-mutant LUAD had significantly less crosstalk between T cells and other cell types via programmed cell death-1 (PD-1) and PD-L1 or other immune checkpoints compared with EGFR wild-type LUAD. Our findings provide a comprehensive understanding of the immune landscape of EGFR-mutant LUAD at the single-cell level. Based on the results, many cellular components might have negative impact on the specific TME of EGFR-mutant LUAD through influencing CD8+ TRM. Lack of CD8+ TRM might be a key factor responsible for the suppressive TME of EGFR-mutant LUAD.

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Single-cell transcriptome analysis revealed the heterogeneity and microenvironment of gastrointestinal stromal tumors.

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