The “seed and soil” theory poised the functional importance of the microenvironment (stroma) during the multistep neoplastic development. The malignant progression is determined by a crosstalk between the tumor cells and the surrounding stromal cell. In the heterogeneous stroma, fibroblasts termed Cancer Associated Fibroblasts (CAFs) are key regulators of the tumor microenvironment. Unfortunately, there is currently no effective therapy, causing devastating clinical and public health issues, as the cellular and molecular mechanisms initiating and contributing to tissue fibrosis are only partially addressed. The fibrotic microenvironment is harsh. Indeed, altered pH, hypoxia, increased oxidative stress, and limited access to nutrients are recorded at the site of injury, ultimately culminating into an abnormal ECM hyperthrophy consecutive to an excessive fibronectin fibers synthesis. The ECM fibers deposition largely relies upon cell surface receptors of the integrin family, most particularly upon the archetype fibronectin receptor α5β1 inetrgin. Accordingly, the β1 integrin K794 acetylation may stand as a key molecular and cellular signature of fibroblasts-dependent ECM deposition.