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Cancer Associated Fibroblast (CAF) Regulation of PDAC Parenchymal (CPC) and CSC Phenotypes Is Modulated by ECM Composition

Authors :
Stefania Cannone
Maria Raffaella Greco
Tiago M. A. Carvalho
Helene Guizouarn
Olivier Soriani
Daria Di Molfetta
Richard Tomasini
Katrine Zeeberg
Stephan Joel Reshkin
Rosa Angela Cardone
Institut de Biologie Valrose (IBV)
Université Nice Sophia Antipolis (1965 - 2019) (UNS)
COMUE Université Côte d'Azur (2015-2019) (COMUE UCA)-COMUE Université Côte d'Azur (2015-2019) (COMUE UCA)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)-Université Côte d'Azur (UCA)
Centre de Recherche en Cancérologie de Marseille (CRCM)
Aix Marseille Université (AMU)-Institut Paoli-Calmettes
Fédération nationale des Centres de lutte contre le Cancer (FNCLCC)-Fédération nationale des Centres de lutte contre le Cancer (FNCLCC)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)
Department of General and Environmental Physiology
Università degli studi di Bari Aldo Moro = University of Bari Aldo Moro (UNIBA)
Source :
Cancers, Cancers, 2022, 14 (15), ⟨10.3390/cancers14153737⟩, Cancers; Volume 14; Issue 15; Pages: 3737
Publication Year :
2022

Abstract

Simple Summary Here, we demonstrate for the first time that ECM composition cooperates with CAFs to jointly regulate/modulate the highly dynamic interactions between the CPC and CSC cell lines and establish a continuum between tumor initiation and progression in primary PDAC tumors. Altogether, these findings propose a scenario in which the ECM composition and the cellular secretome of the CAFs cooperate to jointly regulate both growth and morphology of the CPC and CSC cell lines and, by modulating the highly dynamic interactions between them, establishes a continuum between tumor initiation and progression in primary PDAC tumors. Background: Pancreatic ductal adenocarcinoma (PDAC) is one of the deadliest of all cancers, having one of the lowest five-year survival rates. One of its hallmarks is a dense desmoplastic stroma consisting in the abnormal accumulation of extracellular matrix (ECM) components, especially Collagen I. This highly fibrotic stroma embeds the bulk cancer (parenchymal) cells (CPCs), cancer stem cells (CSCs) and the main producers of the stromal reaction, the Cancer Associated Fibroblasts (CAFs). Little is known about the role of the acellular ECM in the interplay of the CAFs with the different tumor cell types in determining their phenotypic plasticity and eventual cell fate. Methods: Here, we analyzed the role of ECM collagen I in modulating the effect of CAF-derived signals by incubating PDAC CPCs and CSCs grown on ECM mimicking early (low collagen I levels) and late (high collagen I levels) stage PDAC stroma with conditioned medium from primary cultured CAFs derived from patients with PDAC in a previously described three-dimensional (3D) organotypic model of PDAC. Results: We found that CAFs (1) reduced CPC growth while favoring CSC growth independently of the ECM; (2) increased the invasive capacity of only CPCs on the ECM mimicking the early tumor; and (3) favored vasculogenic mimicry (VM) especially of the CSCs on the ECM mimicking an early tumor. Conclusions: We conclude that the CAFs and acellular stromal components interact to modulate the tumor behaviors of the PDAC CPC and CSC cell types and drive metastatic progression by stimulating the phenotypic characteristics of each tumor cell type that contribute to metastasis.

Details

ISSN :
20726694
Volume :
14
Issue :
15
Database :
OpenAIRE
Journal :
Cancers
Accession number :
edsair.doi.dedup.....da5e4d890d796fd1c1695a972c44b0bf
Full Text :
https://doi.org/10.3390/cancers14153737⟩