Abstract
BackgroundSolid tumors such as pancreatic ductal adenocarcinoma (PDAC) comprise not just tumor cells but also a microenvironment with which the tumor cells constantly interact. Detailed characterization of the cellular composition of the tumor microenvironment is critical to the understanding of the disease and treatment of the patient. Single-cell transcriptomics has been used to study the cellular composition of different solid tumor types including PDAC. However, almost all of those studies used primary tumor tissues.MethodsIn this study, we employed a single-cell RNA sequencing technology to profile the transcriptomes of individual cells from dissociated primary tumors or metastatic biopsies obtained from patients with PDAC. Unsupervised clustering analysis as well as a new supervised classification algorithm, SuperCT, was used to identify the different cell types within the tumor tissues. The expression signatures of the different cell types were then compared between primary tumors and metastatic biopsies. The expressions of the cell type-specific signature genes were also correlated with patient survival using public datasets.ResultsOur single-cell RNA sequencing analysis revealed distinct cell types in primary and metastatic PDAC tissues including tumor cells, endothelial cells, cancer-associated fibroblasts (CAFs), and immune cells. The cancer cells showed high inter-patient heterogeneity, whereas the stromal cells were more homogenous across patients. Immune infiltration varies significantly from patient to patient with majority of the immune cells being macrophages and exhausted lymphocytes. We found that the tumor cellular composition was an important factor in defining the PDAC subtypes. Furthermore, the expression levels of cell type-specific markers for EMT+ cancer cells, activated CAFs, and endothelial cells significantly associated with patient survival.ConclusionsTaken together, our work identifies significant heterogeneity in cellular compositions of PDAC tumors and between primary tumors and metastatic lesions. Furthermore, the cellular composition was an important factor in defining PDAC subtypes and significantly correlated with patient outcome. These findings provide valuable insights on the PDAC microenvironment and could potentially inform the management of PDAC patients.
Highlights
Solid tumors such as pancreatic ductal adenocarcinoma (PDAC) comprise not just tumor cells and a microenvironment with which the tumor cells constantly interact
The cellular composition was an important factor in defining PDAC subtypes and significantly correlated with patient outcome
2 out of the 3 patients whose tumors had a relatively large number of immune cells (Table 1) show high levels of expression of Immunogenic subtype signature genes (Additional file 1: Fig. S16B). These results indicate that when using expression data from bulk tumor tissues, the composition of different cell types within the tumor might be a determining fact in defining the tumor subtypes
Summary
Solid tumors such as pancreatic ductal adenocarcinoma (PDAC) comprise not just tumor cells and a microenvironment with which the tumor cells constantly interact. Single-cell transcriptomics has been used to study the cellular composition of different solid tumor types including PDAC. The non-cellular components of TME include the extracellular matrix (ECM) and the signaling molecules produced by the cancer cells and stromal cells. Pancreatic ductal adenocarcinoma (PDAC), which accounts for > 90% of all pancreatic cancer cases, is one of the solid tumor types known to have a highly inflammatory and desmoplastic TME. Many drug development programs focus on developing stroma-remodeling agents for PDAC Those agents either target the non-cellular components such as extracellular proteins (e.g., recombinant hyaluronidase that degrades hyaluronan) or aim to modulate the activity of certain stromal cell types such as cancerassociated fibroblasts and immune cells [3,4,5,6]. The accurate initial quantitative measurement of these components and the on-going effects of these stomatargeted agents are critical to their successful development and therapeutic optimization
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