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.
1 Institute of Molecular and Cell Biology, A*STAR (Agency for Science, Technology, and Research), Biopolis, Singapore 138673;
2 Institute for Research on Cancer and Aging of Nice (IRCAN), Nice 06107, France;
3 U1081, INSERM(Institut National de la Santé et de la Recherche Médicale), Nice 06107, France;
4 UMR 7284, CNRS (Centre National de la Recherche Scientifique), Nice 06107,
5 University of Nice-Sophia Antipolis, Nice 06300, France;
6 Centre Antoine Lacassagne, Nice 06100, France
7 Present address: Institute of Molecular Oncology, Center for Tumor and Immunobiology, Philipps University, Marburg, Germany.
Corresponding author: firstname.lastname@example.org
Published online in Genes & Development on 23 December 2016.
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.
p38MAPK in stromal fibroblasts controls KRAS-driven lung cancer. (A) The expanded NSCLC stromal network is color-coded according to functional pathways. Circled areas represent architectural clusters based on the spectral partition-based clustering algorithm. p38MAPK (MAPK14) was ranked in the top 20 genes by the spanning score, reflecting a robust control over the expanded NSCLC stromal network as a whole. The 13 direct targets of MAPK14 span six gene clusters and six functional pathways. (B) Hierarchical ranking of the top 20 genes, color-coded by functional pathway, reveals MAPK14 as a system-level overarching regulator over the expanded NSCLC stromal network. The ranking score is shown in the brackets. (C) Lung tumor lesions in KRAS mice with conditional deletion of p38 in hematopoietic cells (Mx1-Cre) were stained with phospho-specific antibodies for MK2. The analysis is presented as the mean ratio of the pixel number to the tumor area ± SD. (NS) Nonsignificant. n = 7. (D) Percentage of FSP, phospho-p38 (p-p38), and double-FSP/p-p38 cells in the lungs of normal, p38+/+, and p38ki/ki/KRAS tumor-bearing mice. n = 3. A representative FACS analysis is shown in Supplemental Figure S2E. (**) P < 0.01; (***) P < 0.001. (E) Same as in C, but mice had a conditional deletion of p38 in stromal fibroblasts (FSP1-Cre). (***) P < 0.001. n = 10. (F) The number of lung tumor lesions at 10 wk in wild-type p38+/+ (n = 21) and p38fl/fl (n = 17) FSP1-Cre/KRAS mice. A relative tumor area was calculated as the percentage of total lung area. n = 6. (***) P < 0.001