Multi-omics analysis reveals the chemoresistance mechanism of proliferating tissue-resident macrophages in PDAC via metabolic adaptation

Zhang, Junlei; Song, Jinyuan; Tang, Shima; Zhao, Yaxing; Wang, Lin; Luo, Yandong; Tang, Jianghui; Ji, Yongtao; Wang, Xun; Li, Taohong; Zhang, Hui; Shao, Wei; Sheng, Jianpeng; Liang, Tingbo; Bai, Xueli

doi:10.1016/j.celrep.2023.112620

Cited by 18 publications

(15 citation statements)

References 72 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…33,34 Furthermore, there was a trend towards worse overall survival in patients with a tissue resident/epithelial-like macrophages gene signature, supporting studies showing TRMs responsible for PDAC progression in murine models 5 and chemotherapy resistance. 43 Similar to previous studies, 5,11 the tissue resident/epithelial-like signature had higher collagen expression. We also uniquely demonstrated TRIM29 expression in the tissue resident/epithelial-like signature, which can drive macrophage immunosuppressive features.…”

Section: Discussionsupporting

confidence: 86%

“…Benign pancreatic ( n = 4) and PDAC ( n = 4) samples were obtained following pancreaticoduodenectomy for eight total patients. Patients had pathology in the pancreatic head, which represents the majority of PDAC cases, 42 and had no neoadjuvant chemotherapy, as neoadjuvant therapy may modulate myeloid cell populations 2,11,43 . Patients were of similar sex and age, and pathology was confirmed by histopathology of the resected specimen listed in Figures S1 and S2.…”

Section: Resultsmentioning

confidence: 99%

“…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 . PDAC tumour cells can also inhibit development of dendritic cells by release of granulocyte colony stimulating factor (G‐CSF), which inhibits IRF8‐mediated development of dendritic cells in the bone marrow 36 .…”

Section: Discussionmentioning

confidence: 99%

“…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 PDAC tumour cells can also inhibit development of dendritic cells by release of granulocyte colony stimulating factor (G-CSF), which inhibits IRF8-mediated development of dendritic cells in the bone marrow. 36 Furthermore, pancreatic stellate cells from the PDAC TME drive infiltrating myeloid cells towards a MDSC state via STAT3 signalling, which can in turn inhibit T-cell function.…”

Section: Discussionmentioning

confidence: 99%

“…Patients had pathology in the pancreatic head, which represents the majority of PDAC cases, 42 and had no neoadjuvant chemotherapy, as neoadjuvant therapy may modulate myeloid cell populations. 2,11,43 Patients were of similar sex and age, and pathology was confirmed by histopathology of the resected specimen listed in Figures S1 and S2. Single nuclei suspensions were made directly from frozen tissues.…”

Section: Single Nuclear Analysis Of Open Chromatin Shows Unique Cell ...mentioning

confidence: 99%

See 4 more Smart Citations

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

Pratt,

Ma,

Dziadowicz

et al. 2024

Clinical & Translational Med

View full text Add to dashboard Cite

BackgroundA better understanding of the pancreatic ductal adenocarcinoma (PDAC) immune microenvironment is critical to developing new treatments and improving outcomes. Myeloid cells are of particular importance for PDAC progression; however, the presence of heterogenous subsets with different ontogeny and impact, along with some fluidity between them, (infiltrating monocytes vs. tissue‐resident macrophages; M1 vs. M2) makes characterisation of myeloid populations challenging. Recent advances in single cell sequencing technology provide tools for characterisation of immune cell infiltrates, and open chromatin provides source and function data for myeloid cells to assist in more comprehensive characterisation. Thus, we explore single nuclear assay for transposase accessible chromatin (ATAC) sequencing (snATAC‐Seq), a method to analyse open gene promoters and transcription factor binding, as an important means for discerning the myeloid composition in human PDAC tumours.MethodsFrozen pancreatic tissues (benign or PDAC) were prepared for snATAC‐Seq using 10× Chromium technology. Signac was used for preliminary analysis, clustering and differentially accessible chromatin region identification. The genes annotated in promoter regions were used for Gene Ontology (GO) enrichment and cell type annotation. Gene signatures were used for survival analysis with The Cancer Genome Atlas (TCGA)‐pancreatic adenocarcinoma (PAAD) dataset.ResultsMyeloid cell transcription factor activities were higher in tumour than benign pancreatic samples, enabling us to further stratify tumour myeloid populations. Subcluster analysis revealed eight distinct myeloid populations. GO enrichment demonstrated unique functions for myeloid populations, including interleukin‐1b signalling (recruited monocytes) and intracellular protein transport (dendritic cells). The identified gene signature for dendritic cells influenced survival (hazard ratio = .63, p = .03) in the TCGA‐PAAD dataset, which was unique to PDAC.ConclusionsThese data suggest snATAC‐Seq as a method for analysis of frozen human pancreatic tissues to distinguish myeloid populations. An improved understanding of myeloid cell heterogeneity and function is important for developing new treatment targets in PDAC.

show abstract

Section: Discussionsupporting

confidence: 86%

Section: Resultsmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

Section: Single Nuclear Analysis Of Open Chromatin Shows Unique Cell ...mentioning

confidence: 99%

See 3 more Smart Citations

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

Pratt,

Ma,

Dziadowicz

et al. 2024

Clinical & Translational Med

View full text Add to dashboard Cite

show abstract

From monocyte‐derived macrophages to resident macrophages—how metabolism leads their way in cancer

Ammarah,

Pereira‐Nunes,

Delfini

et al. 2024

Molecular Oncology

View full text Add to dashboard Cite

Macrophages are innate immune cells that play key roles during both homeostasis and disease. Depending on the microenvironmental cues sensed in different tissues, macrophages are known to acquire specific phenotypes and exhibit unique features that, ultimately, orchestrate tissue homeostasis, defense, and repair. Within the tumor microenvironment, macrophages are referred to as tumor‐associated macrophages (TAMs) and constitute a heterogeneous population. Like their tissue resident counterpart, TAMs are plastic and can switch function and phenotype according to the niche‐derived stimuli sensed. While changes in TAM phenotype are known to be accompanied by adaptive alterations in their cell metabolism, it is reported that metabolic reprogramming of macrophages can dictate their activation state and function. In line with these observations, recent research efforts have been focused on defining the metabolic traits of TAM subsets in different tumor malignancies and understanding their role in cancer progression and metastasis formation. This knowledge will pave the way to novel therapeutic strategies tailored to cancer subtype‐specific metabolic landscapes. This review outlines the metabolic characteristics of distinct TAM subsets and their implications in tumorigenesis across multiple cancer types.

show abstract

Single‐Cell Spatial Transcriptomics Unveils Platelet‐Fueled Cycling Macrophages for Kidney Fibrosis

Liu,

Zheng,

Cui

et al. 2024

Advanced Science

View full text Add to dashboard Cite

With the increasing incidence of kidney diseases, there is an urgent need to develop therapeutic strategies to combat post‐injury fibrosis. Immune cells, including platelets, play a pivotal role in this repair process, primarily through their released cytokines. However, the specific role of platelets in kidney injury and subsequent repair remains underexplored. Here, the detrimental role of platelets in renal recovery following ischemia/reperfusion injury and its contribution to acute kidney injury to chronic kidney disease transition is aimed to investigated. In this study, it is shown that depleting platelets accelerates injury resolution and significantly reduces fibrosis. Employing advanced single‐cell and spatial transcriptomic techniques, macrophages as the primary mediators modulated by platelet signals is identified. A novel subset of macrophages, termed “cycling M2”, which exhibit an M2 phenotype combined with enhanced proliferative activity is uncovered. This subset emerges in the injured kidney during the resolution phase and is modulated by platelet‐derived thrombospondin 1 (THBS1) signaling, acquiring profibrotic characteristics. Conversely, targeted inhibition of THBS1 markedly downregulates the cycling M2 macrophage, thereby mitigating fibrotic progression. Overall, this findings highlight the adverse role of platelet THBS1‐boosted cycling M2 macrophages in renal injury repair and suggest platelet THBS1 as a promising therapeutic target for alleviating inflammation and kidney fibrosis.

show abstract

Multi-omics analysis reveals the chemoresistance mechanism of proliferating tissue-resident macrophages in PDAC via metabolic adaptation

Cited by 18 publications

References 72 publications

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

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

From monocyte‐derived macrophages to resident macrophages—how metabolism leads their way in cancer

Single‐Cell Spatial Transcriptomics Unveils Platelet‐Fueled Cycling Macrophages for Kidney Fibrosis

Contact Info

Product

Resources

About