PT  - JOURNAL ARTICLE
AU  - Heichler, Christina
AU  - Scheibe, Kristina
AU  - Schmied, Anabel
AU  - Geppert, Carol I
AU  - Schmid, Benjamin
AU  - Wirtz, Stefan
AU  - Thoma, Oana-Maria
AU  - Kramer, Viktoria
AU  - Waldner, Maximilian J
AU  - Büttner, Christian
AU  - Farin, Henner F
AU  - Pešić, Marina
AU  - Knieling, Ferdinand
AU  - Merkel, Susanne
AU  - Grüneboom, Anika
AU  - Gunzer, Matthias
AU  - Grützmann, Robert
AU  - Rose-John, Stefan
AU  - Koralov, Sergei B
AU  - Kollias, George
AU  - Vieth, Michael
AU  - Hartmann, Arndt
AU  - Greten, Florian R
AU  - Neurath, Markus F
AU  - Neufert, Clemens
TI  - STAT3 activation through IL-6/IL-11 in cancer-associated fibroblasts promotes colorectal tumour development and correlates with poor prognosis
AID  - 10.1136/gutjnl-2019-319200
DP  - 2020 Jul 01
TA  - Gut
PG  - 1269--1282
VI  - 69
IP  - 7
4099  - http://gut.bmj.com/content/69/7/1269.short
4100  - http://gut.bmj.com/content/69/7/1269.full
SO  - Gut2020 Jul 01; 69
AB  - Objective Cancer-associated fibroblasts (CAFs) influence the tumour microenvironment and tumour growth. However, the role of CAFs in colorectal cancer (CRC) development is incompletely understood.Design We quantified phosphorylation of STAT3 (pSTAT3) expression in CAFs of human colon cancer tissue using a tissue microarray (TMA) of 375 patients, immunofluorescence staining and digital pathology. To investigate the functional role of CAFs in CRC, we took advantage of two murine models of colorectal neoplasia and advanced imaging technologies. In loss-of-function and gain-of-function experiments, using genetically modified mice with collagen type VI (COLVI)-specific signal transducer and activator of transcription 3 (STAT3) targeting, we evaluated STAT3 signalling in fibroblasts during colorectal tumour development. We performed a comparative gene expression profiling by whole genome RNA-sequencing of fibroblast subpopulations (COLVI+ vs COLVI–) on STAT3 activation (IL-6 vs IL-11).Results The analysis of pSTAT3 expression in CAFs of human TMAs revealed a negative correlation of increased stromal pSTAT3 expression with the survival of colon cancer patients. In the loss-of-function and gain-of-function approach, we found a critical role of STAT3 activation in fibroblasts in driving colorectal tumourigenesis in vivo. With different imaging technologies, we detected an expansion of activated fibroblasts in colorectal neoplasias. Comparative gene expression profiling of fibroblast subpopulations on STAT3 activation revealed the regulation of transcriptional patterns associated with angiogenesis. Finally, the blockade of proangiogenic signalling significantly reduced colorectal tumour growth in mice with constitutive STAT3 activation in COLVI+ fibroblasts.Conclusion Altogether our work demonstrates a critical role of STAT3 activation in CAFs in CRC development.