Integrated transcriptional analysis reveals macrophage heterogeneity and tumor-macrophage interactions in the progression of pancreatic ductal adenocarcinoma

Abstract

Background Pancreatic ductal adenocarcinoma (PDAC) is a devastating metastatic disease for which better therapies are urgently needed. It highlights the need for an improved understanding of the biological features underlying the progression of PDACs. Macrophages significantly enhance tumorigenesis and development of pancreatic cancer. However, cellular reprogramming and phenotypic changes of macrophages during PDAC progression remain poorly understood, as well as the molecular mechanism underlying tumor-macrophage interactions. Methods Herein, we performed the computational analysis by combining scRNA-seq and TCGA RNA-seq datasets, through which we identified myeloid lineage and tumor cells as crucial mediators of intercellular communication networks and crosstalk in the tumor microenvironment. Results scRNA-seq analyses highlight the heterogeneity of macrophage with diverse phenotype and functionality. The SCENIC analysis indicated different cell states across the sub-clusters of macrophages through a reconstruction of regulatory networks, and cell trajectory analysis identified the tissue-resident macrophage and inflammatory monocyte as potential sources of tumor-associated macrophages. Furthermore, we uncovered several ligand-receptor pairs lining the tumor cells and macrophages. Among them, we found expression level of HBEGF-CD44, HBEGF-EGFR, LGALS9-CD44, LGALS9-MET, and GRN-EGFR correlated with poor outcome of patients. Conclusion Together, our findings deciphered the macrophage heterogeneity and detected a tumor environmental-specific gene expression program in macrophages of PDAC, which uncover a potential mechanism laying the tumor-promoting role of TAM. The ligand-receptor interactions identified would be potential biomarkers for anti-cancer targeted therapy.

Analysis of single nuclear chromatin accessibility reveals unique myeloid populations in human pancreatic ductal adenocarcinoma

“…Platelet‐derived growth factor receptor beta ( PDGFRB ) is characteristic of PDAC fibroblasts 15 . The myeloid population had opening at the Mannose receptor C‐type 1 ( MRC1 ) gene, characteristic of suppressive macrophages prevalent in PDAC 5,12 . The T‐cell population was characterised by promoter opening at CD69 , an early activation marker for T cells expressed by T cells in PDAC 55 …”

“…This heterogeneity is driven by the interplay between the many factors comprising the PDAC TME, such as tumour cells, stromal cells, immune cells and soluble factors, which can differently impact myeloid populations. For example, CSF1–CSF1R interactions between tumour cells and macrophages, 12 respectively, are important for activation of macrophages. Importantly, colony stimulating factor 1 (CSF1) has been shown to be important for maintaining TRM populations in PDAC, which are pro‐fibrotic and pro‐tumour, 5 and may be responsible for therapeutic resistance to standard of care chemotherapy gemcitabine 43 .…”

“…Single cell RNA sequencing (scRNA‐Seq) has demonstrated heterogeneity between patients in the tumour and stromal components of PDAC 7–12 . Since stroma can comprise much of the tumour volume, 8,13 scRNA‐Seq has been employed to identify the immune cell milieu and ascertain how these cells influence tumour progression, 10 patient prognosis 7,11,12 and chemotherapy response 11 . Given the importance of myeloid cells in PDAC progression, 2,5 scRNA‐Seq studies have also explored the phenotype and function 11,12 as well as source, 12 of macrophages.…”

“…Since stroma can comprise much of the tumour volume, 8,13 scRNA‐Seq has been employed to identify the immune cell milieu and ascertain how these cells influence tumour progression, 10 patient prognosis 7,11,12 and chemotherapy response 11 . Given the importance of myeloid cells in PDAC progression, 2,5 scRNA‐Seq studies have also explored the phenotype and function 11,12 as well as source, 12 of macrophages. Although the transcriptome of cells within the PDAC TME has been heavily studied, 11,14–16 there has been limited progress on the regulome of cells within the TME.…”

“…Recently, single cell sequencing technologies have been harnessed to determine cell function and composition in the TME. Single cell RNA sequencing (scRNA‐Seq) has demonstrated heterogeneity between patients in the tumour and stromal components of PDAC 7–12 . Since stroma can comprise much of the tumour volume, 8,13 scRNA‐Seq has been employed to identify the immune cell milieu and ascertain how these cells influence tumour progression, 10 patient prognosis 7,11,12 and chemotherapy response 11 .…”