p38MAPK builds a hyaluronan cancer niche to drive lung tumorigenesis
- Anna Brichkina1,7,
- Thomas Bertero2,
- Hui Mun Loh1,
- Nguyet Thi Minh Nguyen1,
- Alexander Emelyanov2,3,4,5,6,
- Sidwell Rigade2,
- Marius Ilie2,3,4,5,6,
- Paul Hofman2,3,4,5,6,
- Cedric Gaggioli2,3,4,5 and
- Dmitry V. Bulavin2,3,4,5,6
- 1Institute of Molecular and Cell Biology, A*STAR (Agency for Science, Technology, and Research), Biopolis, Singapore 138673;
- 2Institute for Research on Cancer and Aging of Nice (IRCAN), Nice 06107, France;
- 3U1081, INSERM (Institut National de la Santé et de la Recherche Médicale), Nice 06107, France;
- 4UMR 7284, CNRS (Centre National de la Recherche Scientifique), Nice 06107, France;
- 5University of Nice-Sophia Antipolis, Nice 06300, France;
- 6Centre Antoine Lacassagne, Nice 06100, France
- Corresponding author: dmitry.bulavin{at}unice.fr
Abstract
Expansion of neoplastic lesions generates the initial signal that instigates the creation of a tumor niche. Nontransformed cell types within the microenvironment continuously coevolve with tumor cells to promote tumorigenesis. Here, we identify p38MAPK as a key component of human lung cancer, and specifically stromal interactomes, which provides an early, protumorigenic signal in the tissue microenvironment. We found that lung cancer growth depends on short-distance cues produced by the cancer niche in a p38-dependent manner. We identified fibroblast-specific hyaluronan synthesis at the center of p38-driven tumorigenesis, which regulates early stromal fibroblast activation, the conversion to carcinoma-associated fibroblasts (CAFs), and cancer cell proliferation. Systemic down-regulation of p38MAPK signaling in a knock-in model with substitution of activating Tyr182 to phenylalanine or conditional ablation of p38 in fibroblasts has a significant tumor-suppressive effect on K-ras lung tumorigenesis. Furthermore, both Kras-driven mouse lung tumors and orthotopically grown primary human lung cancers show a significant sensitivity to both a chemical p38 inhibitor and an over-the-counter inhibitor of hyaluronan synthesis. We propose that p38MAPK–hyaluronan-dependent reprogramming of the tumor microenvironment plays a critical role in driving lung tumorigenesis, while blocking this process could have far-reaching therapeutic implications.
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Footnotes
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Supplemental material is available for this article.
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Article is online at http://www.genesdev.org/cgi/doi/10.1101/gad.290346.116.
- Received September 5, 2016.
- Accepted November 22, 2016.
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