FGF Signalling in the Self-Renewal of Colon Cancer Organoids

• Published in: Scientific reports 2019-11, Vol.9 (1), p.17365-10, Article 17365
• Main Authors: Otte, Jörg, Dizdar, Levent, Behrens, Bianca, Goering, Wolfgang, Knoefel, Wolfram T., Wruck, Wasco, Stoecklein, Nikolas H., Adjaye, James
• Format: Article
• Language: English
• Subjects: 13/100; 13/106; 13/51; 14/63; 38/39; 38/61; 38/77; 45/22; 45/61; 631/1647/767/70; 631/67/1504/1885/1393; 631/67/2329; 631/67/327; 631/67/71; 82/51; Activator protein 1; Aged; Aged, 80 and over; Cancer; Cell differentiation; Cell Differentiation - drug effects; Cell Differentiation - genetics; Cell Proliferation - drug effects; Cell Self Renewal - drug effects; Cell self-renewal; Colon cancer; Colonic Neoplasms - genetics; Colonic Neoplasms - metabolism; Colonic Neoplasms - pathology; Colorectal cancer; Colorectal carcinoma; Embryo cells; Embryos; Female; Fibroblast growth factor 2; Fibroblast Growth Factor 2 - pharmacology; Fibroblast growth factor receptors; Gene expression; Gene Expression Regulation, Neoplastic - drug effects; Humanities and Social Sciences; Humans; Male; MAP kinase; Medicin och hälsovetenskap; Middle Aged; multidisciplinary; Neoplasm Staging; Neoplastic Stem Cells - drug effects; Neoplastic Stem Cells - pathology; Neoplastic Stem Cells - physiology; Organoids; Organoids - drug effects; Organoids - metabolism; Organoids - pathology; Phenotypes; Primary Cell Culture; Protein-tyrosine kinase; Science; Science (multidisciplinary); Signal transduction; Signal Transduction - drug effects; Spheroids, Cellular - drug effects; Spheroids, Cellular - metabolism; Spheroids, Cellular - pathology; Stem cells; Transcription factors; Tumor Cells, Cultured; Tumors
• ISSN: 2045-2322; 2045-2322
• DOI: 10.1038/s41598-019-53907-7

The progression of colorectal cancer (CRC) is supposedly driven by cancer stem cells (CSC) which are able to self-renew and simultaneously fuel bulk tumour mass with highly proliferative and differentiated tumour cells. However, the CSC-phenotype in CRC is unstable and dependent on environmental cues. Fibroblast growth factor 2 (FGF2) is essential and necessary for the maintenance of self-renewal in adult and embryonic stem cells. Investigating its role in self-renewal in advanced CRC patient-derived organoids, we unveiled that FGF-receptor (FGFR) inhibition prevents organoid formation in very early expanding cells but induces cyst formation when applied to pre-established organoids. Comprehensive transcriptome analyses revealed that the induction of the transcription factor activator-protein-1 (AP-1) together with MAPK activation was most prominent after FGFR-inhibition. These effects resemble mechanisms of an acquired resistance against other described tyrosine kinase inhibitors such as EGF-receptor targeted therapies. Furthermore, we detected elevated expression levels of several self-renewal and stemness-associated genes in organoid cultures with active FGF2 signalling. The combined data assume that CSCs are a heterogeneous population while self-renewal is a common feature regulated by distinct but converging pathways. Finally, we highlight FGF2 signalling as one of numerous components of the complex regulation of stemness in cancer.