Patient-derived scaffolds influence secretion profiles in cancer cells mirroring clinical features and breast cancer subtypes

Cell Communication and Signaling

Sara Rhost¹  Göran Landberg¹  Paul Fitzpatrick¹  Pernilla Gregersson¹  Anna Gustafsson¹  Emma Persson¹  Anders Ståhlberg² 

[1]Department of Laboratory Medicine, Sahlgrenska Center for Cancer Research, Institute of Biomedicine, Sahlgrenska Academy, University of Gothenburg, Medicinaregatan 1G, 41390, Gothenburg, Sweden

[2]Department of Laboratory Medicine, Sahlgrenska Center for Cancer Research, Institute of Biomedicine, Sahlgrenska Academy, University of Gothenburg, Medicinaregatan 1G, 41390, Gothenburg, Sweden

[3]Wallenberg Center for Molecular and Translational Medicine, University of Gothenburg, 41390, Gothenburg, Sweden

[4]Department of Clinical Genetics and Genomics, Sahlgrenska University Hostpital, Region Västra Götaland, 41390, Gothenburg, Sweden

关键词: Breast cancer;    Tumor microenvironment;    Secretion;    Scaffold;    IL-6;    PAI-1;    CCL2;   

DOI  :  10.1186/s12964-021-00746-7

来源: Springer

【 摘 要 】

BackgroundBreast cancer is a common malignancy with varying clinical behaviors and for the more aggressive subtypes, novel and more efficient therapeutic approaches are needed. Qualities of the tumor microenvironment as well as cancer cell secretion have independently been associated with malignant clinical behaviors and a better understanding of the interplay between these two features could potentially reveal novel targetable key events linked to cancer progression.MethodsA newly developed human derived in vivo-like growth system, consisting of decellularized patient-derived scaffolds (PDSs) recellularized with standardized breast cancer cell lines (MCF7 and MDA-MB-231), were used to analyze how 63 individual patient specific microenvironments influenced secretion determined by proximity extension assays including 184 proteins and how these relate to clinical outcome.ResultsThe secretome from cancer cells in PDS cultures varied distinctly from cells grown as standard monolayers and besides a general increase in secretion from PDS cultures, several secreted proteins were only detectable in PDSs. Monolayer cells treated with conditioned media from PDS cultures, further showed increased mammosphere formation demonstrating a cancer stem cell activating function of the PDS culture induced secretion. The detailed secretomic profiles from MCF7s growing on 57 individual PDSs differed markedly but unsupervised clustering generated three separate groups having similar secretion profiles that significantly correlated to different clinical behaviors. The secretomic profile that associated with cancer relapse and high grade breast cancer showed induced secretion of the proteins IL-6, CCL2 and PAI-1, all linked to cancer stem cell activation, metastasis and priming of the pre-metastatic niche. Cancer promoting pathways such as “Suppress tumor immunity” and “Vascular and tissue remodeling” was also linked to this more malignant secretion cluster.ConclusionPDSs repopulated with cancer cells can be used to assess how cancer secretion is effected by specific and varying microenvironments. More malignant secretion patterns induced by specific patient based cancer microenvironments could further be identified pinpointing novel therapeutic opportunities targeting micro environmentally induced cancer progression via secretion of potent cytokines.9knUvc5_SVBB-6ZGgLA6c6Video abstract

【 授权许可】

CC BY