The Role of Hedgehog Signaling for the Interplay between Inflammatory, Epithelial, and Stromal Cells in Colitis-associated Carcinogenesis
Final Report Abstract
The Hedgehog (Hh) signaling pathway plays a central role in the homeostasis of the intestine. Signaling is organized in an exclusively paracrine manner: epithelial cells secrete the Hh ligands that activate the GLI transcription factors, the major downstream effectors of the pathway, exclusively in subepithelial fibroblasts and other stroma cells. In turn, Hh‐activated fibroblasts secrete factors that induce differentiation of the overlying epithelium. In colorectal cancer (CRC), previous studies found increased expression of Hh ligands. Moreover, some CRC cell lines show enhanced activity of the GLI proteins. Collectively, these data led to the notion that Hh activation promotes CRC growth. However, a clinical trial with the Hh inhibitor vismodegib did not reveal a positive effect in patients with metastatic CRC. In this project, we show that downstream Hh signaling is unexpectedly diminished in CRC despite increased Hh ligand expression. Furthermore, we provide evidence that the remaining, attenuated Hh activity remains strictly paracrine. By employing Hh‐reporter mice, we identified a chemical CRC mouse model that recapitulates the reduced GLI activity of human CRC. Using this model, we examined the functional role of Hh activity for malignant transformation in the colon in complementary, genetically modified mouse models. We found that epithelial loss of the Hh ligand promotes colonic tumor growth. By contrast, activation of Hh in a novel stroma‐specific Cre‐loxP model leads to a significant reduction in tumor number and size. Moreover, Hh activation in advanced colonic tumors inhibits tumor growth and induces tumor cell apoptosis. Mechanistically, we found complex transcriptional changes resulting from stromal‐specific Hh activation, which restrict the stem cell character of the overlying epithelium. This effect is in part mediated by modulation of the bone morphogenetic protein (BMP) signaling pathway, resulting in differentiation of the overlying epithelial cells. In conclusion, our results present a novel conceptual framework for the role of Hh signaling in CRC and provide first explanations for the failure of vismodegib in clinical trials. Hh‐mediated signals play a central role for the ability of the tumor stroma to modify tumor growth. A deeper understanding of the Hh‐mediated stroma‐tumor interaction therefore holds the potential for novel, stroma‐based therapeutic approaches.
Publications
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Marco Gerling, Ying Zhao, Salvatore Nania, K. Jessica Norberg, Caroline S. Verbeke, Benjamin Englert, Raoul V. Kuiper, Asa Bergström, Moustapha Hassan, Albrecht Neesse, J. Matthias Löhr, Rainer L. Heuchel
(See online at https://doi.org/10.7150/thno.7996) - terleukin 34: a new modulator of human and experimental inflammatory bowel disease. Clinical Science, 2015 Aug 1;129(3):281-90
Stephanie Zwicker, Gisele L. Martinez, Madeleen Bosma, Marco Gerling, Reuben Clark, Mirjam Majster, Jan Söderman, Sven Almer, Elisabeth Almer Boström
(See online at https://doi.org/10.1042/CS20150176) - FNDC4 acts as an anti-inflammatory factor on macrophages and improves colitis in mice. Nature Communications volume 7, Article number: 11314 (2016)
Madeleen Bosma, Marco Gerling, Jenny Pasto, Anastasia Georgiadi, Evan Graham, Olga Shilkova, Yasunori Iwata, Sven Almer, Jan Söderman, Rune Toftgard, Fredrik Wermeling, Elisabeth Almer Boström, Pontus Almer Boström
(See online at https://doi.org/10.1038/ncomms11314) - Stromal Hedgehog signalling is downregulated in colon cancer and its restoration restrains tumour growth. Nature Communications volume 7, Article number: 12321 (2016)
Marco Gerling, Nike V.J.A. Büller, Leonard M. Kirn, Simon Joost, Oliver Frings, Benjamin Englert, Asa Bergström, Raoul V. Kuiper, Leander Blaas, Mattheus C.B. Wielenga, Sven Almer, Anja A. Kühl, Erik Fredlund, Gijs R. van den Brink, Rune Toftgard
(See online at https://doi.org/10.1038/ncomms12321)
