Color key from gray to red indicates relative expression levels from low to high. single-cell RNA-seq (scRNA-seq) to acquire the transcriptomic atlas of 57,530 individual pancreatic cells from primary PDAC tumors and control pancreases, and identified diverse malignant and AMD 070 stromal cell types, including two ductal subtypes with abnormal and malignant gene PECAM1 expression profiles respectively, in PDAC. We found that the heterogenous malignant subtype was composed of several subpopulations with differential proliferative and migratory potentials. Cell trajectory analysis revealed that components of multiple tumor-related pathways and transcription factors (TFs) were differentially expressed along PDAC progression. Furthermore, we found a subset of ductal cells with unique proliferative features were associated with an inactivation state in tumor-infiltrating T cells, providing novel markers for the prediction of antitumor immune response. Together, our findings provide a valuable resource for deciphering the intra-tumoral heterogeneity in PDAC and uncover a connection between tumor intrinsic transcriptional state and T cell activation, suggesting potential biomarkers for anticancer treatment such as targeted therapy and immunotherapy. driver mutation (over 90%) and frequent inactivation of tumor suppressors (over 50%). Other novel recurrent mutations ( 10%) have also been identified from unbiased analyses in PDAC.6 These diverse gene mutations converge on specific pathways and processes, including KRAS, TGF-, Wnt, Notch, ROBO/SLIT signaling, chromatin remodeling and DNA repair pathways. In addition, alteration of epigenetic pathways is an emerging mechanism of PDAC progression. Inactivating mutations of chromatin modifiers have been identified in PDAC patients. These modifiers include histone modification enzymes (24% of PDAC) and SWI/SNF-mediated chromatin AMD 070 remodeling complexes (14% of PDAC).7,8 Unfortunately, none of these findings have been translated into clinical use, mainly due to the very limited knowledge about their potential role during PDAC progression, whereas most patients were already at advanced stages at the time of diagnosis.9 Although initiation- and metastasis-specific mutations begun to be confirmed,10,11 dysregulated signal transduction or variation of gene expression within primary tumor cells are also critical for tumor progression.12 This is further complicated by the signaling cues from the tumor microenvironment and pathways regulating epithelial-to-mesenchymal transition (EMT).13C15 Meanwhile, intra-tumoral heterogeneity exists between cells within PDAC. In particular, the stroma constitutes over 70% of the tumor mass often embedded with normal pancreatic tissue due to the infiltrative nature of PDAC.16 This extensive degree of intra-tumoral heterogeneity makes it rather challenging to identify genetic variants based on bulk mRNA sequencing. Even though some major treatment breakthroughs have been facilitated in a few tumor types, such as melanoma, by the identification of oncogenic drivers using this approach,17 the overall progress in identifying actionable diagnostic markers and therapeutic targets is still largely hindered due to the limitation of bulk profiling technologies in capturing intra-tumoral heterogeneity. Recent advances in single-cell genomics provide powerful tools in exploration of genetic and functional heterogeneity, reconstruction of evolutionary lineages and detection of rare subpopulations.18,19 In addition, scRNA-seq studies in human tumors revealed new insights into tumor heterogeneity and distinct subpopulations, which are pivotal for dissecting tumor-related mechanism in detail.20C27 One recent AMD 070 study on head and neck tumor revealed tumor compositions including the subpopulation with partial epithelial-to-mesenchymal transition (p-EMT), shedding new lamps into prediction of tumor invasion and metastasis. 24 Apart from the malignant cells, tumor mass also contains macrophages, T cells and fibroblasts, etc., forming tumor microenvironment (TME) assisting tumor progression.28C36 For instance, in liver tumor, single-cell sequencing had been applied to depict the panorama of 11 subsets of infiltrating T cells in TME, which is potentially handy in guiding effective immunotherapies.30 One recent scRNA-seq study of four intraductal papillary mucinous neoplasias (IPMNs), and two PDACs revealed.
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