Stromal Hedgehog signalling is downregulated in colon cancer and its restoration restrains tumour growth

Marco Gerling, Nikè V. J. A. Büller, Leonard M. Kirn, Simon Joost, Oliver Frings, Benjamin Englert, Åsa Bergström, Raoul V. Kuiper, Leander Blaas, Mattheus C. B. Wielenga, Sven Almer, Anja A. Kühl, Erik Fredlund, Gijs R. van den Brink and Rune Toftgård ()
Additional contact information
Marco Gerling: Center for Innovative Medicine, Karolinska Institutet, NOVUM
Nikè V. J. A. Büller: Academic Medical Center
Leonard M. Kirn: Center for Innovative Medicine, Karolinska Institutet, NOVUM
Simon Joost: Center for Innovative Medicine, Karolinska Institutet, NOVUM
Oliver Frings: Science for Life Laboratory, Karolinska Institutet
Benjamin Englert: Center for Innovative Medicine, Karolinska Institutet, NOVUM
Åsa Bergström: Center for Innovative Medicine, Karolinska Institutet, NOVUM
Raoul V. Kuiper: Core Facility for Morphologic Phenotype Analysis, Clinical Research Center, Karolinska Institutet
Leander Blaas: Center for Innovative Medicine, Karolinska Institutet, NOVUM
Mattheus C. B. Wielenga: Academic Medical Center
Sven Almer: Solna, Karolinska Institutet
Anja A. Kühl: Infectious Diseases and Rheumatology, Charité, Campus Benjamin Franklin
Erik Fredlund: Science for Life Laboratory, Karolinska Institutet
Gijs R. van den Brink: Academic Medical Center
Rune Toftgård: Center for Innovative Medicine, Karolinska Institutet, NOVUM

Nature Communications, 2016, vol. 7, issue 1, 1-17

Abstract: Abstract A role for Hedgehog (Hh) signalling in the development of colorectal cancer (CRC) has been proposed. In CRC and other solid tumours, Hh ligands are upregulated; however, a specific Hh antagonist provided no benefit in a clinical trial. Here we use Hh reporter mice to show that downstream Hh activity is unexpectedly diminished in a mouse model of colitis-associated colon cancer, and that downstream Hh signalling is restricted to the stroma. Functionally, stroma-specific Hh activation in mice markedly reduces the tumour load and blocks progression of advanced neoplasms, partly via the modulation of BMP signalling and restriction of the colonic stem cell signature. By contrast, attenuated Hh signalling accelerates colonic tumourigenesis. In human CRC, downstream Hh activity is similarly reduced and canonical Hh signalling remains predominantly paracrine. Our results suggest that diminished downstream Hh signalling enhances CRC development, and that stromal Hh activation can act as a colonic tumour suppressor.

Date: 2016
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DOI: 10.1038/ncomms12321

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