Single-cell profiling to explore pancreatic cancer heterogeneity, plasticity and response to therapy

Bärthel, Stefanie; Falcomatà, Chiara; Rad, Roland; Theis, Fabian J.; Saur, Dieter

doi:10.1038/s43018-023-00526-x

Cited by 22 publications

(6 citation statements)

References 126 publications

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“…tumour microenvironment (TME) and its adaptive behaviour to therapy. 4 Specifically, PDAC is characterised by a potent immunosuppressive TME, typically excluding cytotoxic T cells from the tumour bed or driving them into functional exhaustion. 5 6 Innate immunity, on the other hand, is abundant in the form of tumour-associated neutrophils (TANs) and tumour-associated macrophages (TAMs), thought to provide a potent immunosuppressive environment.…”

Section: Gi Cancermentioning

confidence: 99%

DYRK1B blockade promotes tumoricidal macrophage activity in pancreatic cancer

Brichkina,

Ems,

Suezov

et al. 2024

Gut

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ObjectiveHighly malignant pancreatic ductal adenocarcinoma (PDAC) is characterised by an abundant immunosuppressive and fibrotic tumour microenvironment (TME). Future therapeutic attempts will therefore demand the targeting of tumours and stromal compartments in order to be effective. Here we investigate whether dual specificity and tyrosine phosphorylation-regulated kinase 1B (DYRK1B) fulfil these criteria and represent a promising anticancer target in PDAC.DesignWe used transplantation and autochthonous mouse models of PDAC with either geneticDyrk1bloss or pharmacological DYRK1B inhibition, respectively. Mechanistic interactions between tumour cells and macrophages were studied in direct or indirect co-culture experiments. Histological analyses used tissue microarrays from patients with PDAC. Additional methodological approaches included bulk mRNA sequencing (transcriptomics) and proteomics (secretomics).ResultsWe found that DYRK1B is mainly expressed by pancreatic epithelial cancer cells and modulates the influx and activity of TME-associated macrophages through effects on the cancer cells themselves as well as through the tumour secretome. Mechanistically, genetic ablation or pharmacological inhibition of DYRK1B strongly attracts tumoricidal macrophages and, in addition, downregulates the phagocytosis checkpoint and ‘don’t eat me’ signal CD24 on cancer cells, resulting in enhanced tumour cell phagocytosis. Consequently, tumour cells lacking DYRK1B hardly expand in transplantation experiments, despite their rapid growth in culture. Furthermore, combining a small-molecule DYRK1B-directed therapy with mammalian target of rapamycin inhibition and conventional chemotherapy stalls the growth of established tumours and results in a significant extension of life span in a highly aggressive autochthonous model of PDAC.ConclusionIn light of DYRK inhibitors currently entering clinical phase testing, our data thus provide a novel and clinically translatable approach targeting both the cancer cell compartment and its microenvironment.

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Section: Gi Cancermentioning

confidence: 99%

DYRK1B blockade promotes tumoricidal macrophage activity in pancreatic cancer

Brichkina,

Ems,

Suezov

et al. 2024

Gut

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“…Increased levels of KRAS oncogenes and signalling drive, for instance, tumour cell differentiation, metastasis and clinical outcomes. 9 KRAS signalling in PDAC cells strongly influences the tumour microenvironment. Researchers are only beginning to unravel the networks of interactions between the diverse range of cells that make up a PDAC.…”

Section: New Treatment Approachesmentioning

confidence: 99%

Pancreatic cancer: the insidious, deadly malignancy

Greener

2023

Prescriber

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“…A number of reports have demonstrated that the key features of PDAC underlying the dismal response to treatment and enabling metastatic spread are the phenotypic heterogeneity and plasticity within the tumour cell compartment 9,10 . In particular, the PDAC cell ability to adopt a stem-like state, which is characterised by high self-renewal capacity and enhanced tumourigenicity, has been associated with the formation of metastasis and the tumour relapse 11,12 .…”

Section: Introductionmentioning

confidence: 99%

High-dimensional mass cytometry reveals stemness state heterogeneity in pancreatic ductal adenocarcinoma

Ervin,

Ahern,

Liu

et al. 2024

Preprint

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Stem-like cancer cells harbour high self-renewal capacity, exhibit enhanced tumourigenicity and have been associated with therapy resistance, metastasis and tumour relapse. Therefore, understanding the molecular features of stem-like cells is critical for targeting them effectively and improving treatment outcomes for cancer patients. Several markers have been used to isolate and study the putative stem-like cells of pancreatic ductal adenocarcinoma (PDAC), but the patterns of marker co-expression and overlap between identified individual subpopulations are yet to be comprehensively studied. Here we developed a mass cytometry antibody panel for simultaneous analysis of 33 stemness-associated markers at single-cell resolution. High-dimensional mass cytometry analysis of PDAC cell lines revealed molecularly heterogeneous stemness states and highlighted the role of genotype in determining the cell line-specific stemness signature. Stemness marker expression lie along a continuum in PDAC cell lines and patient samples indicative of stepwise phenotypic transitions. We also identified a subset of PDAC cells co-expressing high levels of Musashi-2, DCLK1 and CXCR4, and harbouring basal-like and EMT transcriptional programmes associated with highly plastic phenotype. This multiplexed analysis uncovers nuance and complexities of the stemness state in the PDAC.

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Single-cell profiling to explore pancreatic cancer heterogeneity, plasticity and response to therapy

Cited by 22 publications

References 126 publications

DYRK1B blockade promotes tumoricidal macrophage activity in pancreatic cancer

DYRK1B blockade promotes tumoricidal macrophage activity in pancreatic cancer

Pancreatic cancer: the insidious, deadly malignancy

High-dimensional mass cytometry reveals stemness state heterogeneity in pancreatic ductal adenocarcinoma

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