Abstract
Tissue homeostasis is dependent on the controlled localization of specific cell types and the correct composition of the extracellular stroma. While the role of the cancer stroma in tumour progression has been well characterized, the specific contribution of the matrix itself is unknown. Furthermore, the mechanisms enabling normal—not cancer—stroma to provide tumour-suppressive signals and act as an antitumorigenic barrier are poorly understood. Here we show that extracellular matrix (ECM) generated by normal fibroblasts (NFs) is softer than the CAF matrix, and its physical and structural features regulate cancer cell proliferation. We find that normal ECM triggers downregulation and nuclear exit of the histone demethylase JMJD1a resulting in the epigenetic growth restriction of carcinoma cells. Interestingly, JMJD1a positively regulates transcription of many target genes, including YAP/TAZ (WWTR1), and therefore gene expression in a stiffness-dependent manner. Thus, normal stromal restricts cancer cell proliferation through JMJD1a-dependent modulation of gene expression.
Highlights
Tissue homeostasis is dependent on the controlled localization of specific cell types and the correct composition of the extracellular stroma
While the mechanisms whereby cancer stroma and cancer-associated fibroblasts (CAFs) contribute to tumour progression are being actively investigated, much less is known about how the normal stroma exerts tumoursuppressive signals to control tissue homeostasis
We find that the matrix generated by normal fibroblasts (NFs), but not CAF matrix, profoundly inhibits cancer cell proliferation through mechanosensitive downregulation of the histone demethylase enzyme JMJD1a
Summary
To test the ability of the patient-derived stromal ECM to influence the proliferation of cancer cells, we cultured MDA-MB-231 and HeLa cells on CDMs derived from either NFs or CAFs. Interestingly, NF CDM was significantly growth-inhibitory compared with CDM generated by CAFs from the same patient (Fig. 3g), and the same was observed when comparing TIFF and CAF CDM (Supplementary Fig. 3d). To the TIFF CDM, the growth restriction was due to the matrix and not soluble factors as coculture of SCC or MDA-MB-231 cells with NFs or CAFs. JMJD1a levels and localization are regulated by stiffness. MDA-MB-231, HeLa and patient-derived SCC cells proliferated significantly more on stiffer supports (Supplementary Fig. 4a,b), suggesting that the lower stiffness of NF CDM is likely to contribute to its growth-restrictive properties. Unlike YAP/TAZ, JMJD1a localization was not dependent on an intact actin cytoskeleton or Rho-signalling as a kPa
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