Extracellular matrix composition modulates PDAC parenchymal and stem cell plasticity and behavior through the secretome
Authors: Giulia Biondani
Elisa Dalla Pozza
Katrine Zeeberg
Valeria Casavola
Stephan Joel Reshkin
Ilaria Dando
Marta Palmieri
Maria Raffaella Greco
Stefania Forciniti
Maria Mastrodonato
Stefania Cannone
Rosa Angela Cardone
Journal: FEBS Journal (2018)
Discipline: BIOLOGY & BIOCHEMISTRY
Keywords: 3D organotypic cultures; VEFGR-2; cancer stem cells; desmoplastic reaction; pancreatic adenocarcinoma
Affiliations: Department of Neuroscience, Biomedicine and Movement Biochemistry Section University of Verona Italy, Department of Biosciences, Biotechnology and Biopharmaceutics University of Bari Italy, Department of Biology University of Bari Italy

Abstract:  Pancreatic ductal adenocarcinoma (PDAC) is one of the most lethal cancers. Its aggressiveness is driven by an intense fibrotic desmoplastic reaction in which the increasingly collagen I-rich extracellular matrix (ECM) and several cell types, including cancer stem cells (CSCs), create a tumor-supportive environment. However, how ECM composition regulates CSC dynamics and their relationship with the principle parenchymal tumor population to promote early invasive growth is not yet characterized. For this, we utilized a platform of 3D organotypic cultures composed of laminin-rich Matrigel, representative of an early tumor, plus increasing concentrations of collagen I to simulate malignant stroma progression. As ECM collagen I increases, CSCs progress from a rapidly growing, vascular phenotype to a slower growing, avascular phase, while maintaining their endothelial-like gene signatures. This transition is supported autocrinically by the CSCs and paracrinically by the parenchymal cells via their ECM-dependent secretomes. Indeed, when growing on an early tumor ECM, the CSCs are dedicated toward the preparation of a vascular niche by (a) activating their growth program, (b) secreting high levels of proangiogenic factors which stimulate both angiogenesis and vasculogenic mimicry, and (c) overexpressing VEGFR-2, which is activated by VEGF secreted by both the CSC and parenchymal cells. On Matrigel, the more differentiated parenchymal tumor cell population had reduced growth but a high invasive capacity. This concerted high local invasion of parenchymal cells into the CSC-derived vascular network suggests that a symbiotic relationship between the parenchymal cells and the CSCs underlies the initiation and maintenance of early PDAC infiltration and metastasis. 

Retracted: No

PubPeer comments:
 Possible image repeat in Fig. 6. Red boxes identify areas in 6C and 6F; yellow shows specific features. Note image contrast is not identical, and image dimensions are modestly different. *** ![file] , 
 Published: 28 August 2019 In the article by Biondani et al., a duplicated image was detected post-publication. The authors apologize for the inadvertent mixing of images used to generate the original Figure 6, such that the image used to represent u2018CSCs: 100% C of Parental-CCMu2019 was erroneously utilized also in the panel u2018Parental Cells: 100% C of Parental-CCMu2019. The correct image has now been inserted in the panel labelled u2018Parental Cells: 100% C of Parental-CCMu2019 to generate a new Figure 6. This correction has not altered either the interpretation of data or information of the figure and did not affect the conclusions presented in the article. ![file] , 
 It appears there may be at least one other overlap in this paper, with adjusted contrast brightness. The authors may wish to review the other figures and perhaps reevaluate the quantification. *** ![file] , 
 Published: 15 November 2021 In the article by Biondani et al., a second duplicated image was detected after publication. The panel u2018CSCs: 70%M:30%C of Parental-CCMu2019 of Figure 6 was inadvertently utilized also in the panel u2018CSCs: 70%M:30%C of CTRu2019 of Figure 7. A corrected figure 7 has now been provided, in which the correct image is inserted in the panel labelled u2018CSCs: 70%M:30%C of CTRu2019. All of the data and original images have been carefully re-checked, and no further errors remain in the corrected version of the manuscript. Correction of this error has not altered either the interpretation of data or information provided in the figures, and did not affect the conclusions presented in the article. The authors sincerely apologize for their mistake and thank their peers for bringing it to their attention. ![file] ,