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Activation of adult human pancreatic ductal and ductal progenitor-like cells requires extracellular matrix protein signaling [bulkRNA-seq]

ABSTRACT: Activation of adult human pancreatic ductal and ductal progenitor-like cells requires extracellular matrix protein signaling [bulkRNA-seq]

PROVIDER: PRJNA975945 | ENA |

REPOSITORIES: ENA

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			Action	DRS
	SRR24727128.fastq.gz	Fastqsanger.gz
	SRR24727129.fastq.gz	Fastqsanger.gz
	SRR24727130.fastq.gz	Fastqsanger.gz
	SRR24727131.fastq.gz	Fastqsanger.gz
	SRR24727132.fastq.gz	Fastqsanger.gz

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Activation of adult human pancreatic ductal and ductal progenitor-like cells requires extracellular matrix protein signaling [bulkRNA-seq]

Project description:Ductal progenitor-like cells are a subpopulation of ductal cells in the adult human pancreas that have the potential to contribute to regenerative medicine. However, the microenvironmental cues that regulate their activation are poorly understood. Here, we establish a 3-dimensional suspension culture system containing six defined soluble factors in which primary human ductal and ductal progenitor-like cells can survive but do not proliferate. Expansion and polarization occur when cells are provided with a low concentration (5% v/v) of Matrigel, a sarcoma cell product enriched in many extracellular matrix (ECM) proteins. Screening of ECM proteins identified that collagen IV is capable of partially recapitulating the effects of Matrigel. Inhibition of integrin α1β1, a major collagen IV receptor, negates collagen IV- and Matrigel-stimulated effects. These results demonstrate that collagen IV is a key ECM protein that stimulates the expansion and polarization of human ductal and ductal progenitor-like cells via integrin α1β1 receptor signaling.

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Project description:Intratumor morphological heterogeneity of pancreatic ductal adenocarcinoma (PDAC) predicts clinical outcomes but is only partially understood at the molecular level. To elucidate the gene expression programs underpinning intratumor morphological variation in PDAC, we investigated and deconvoluted at single cell level the molecular profiles of histologically distinct clusters of PDAC cells. We identified three major morphological and functional variants that co-exist in varying proportions in all PDACs, display limited genetic diversity, and are associated with a distinct organization of the extracellular matrix: a glandular variant with classical ductal features; a transitional variant displaying abortive ductal structures and mixed endodermal and myofibroblast-like gene expression; and a poorly differentiated variant lacking ductal features and basement membrane, and showing neuronal lineage priming. Ex vivo and in vitro evidence supports the occurrence of dynamic transitions among these variants in part influenced by extracellular matrix composition and stiffness and associated with local, specifically neural, invasion.

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