The article "Multiple aspects of matrix stiffness in cancer progression" by Mancini et al. explores the critical role of the extracellular matrix (ECM) in cancer development and progression. The ECM, composed of various proteins and proteoglycans, plays a crucial role in cell differentiation, proliferation, and tissue homeostasis. In cancer, the ECM becomes dysregulated, rigid, and fibrotic, contributing to both pro-tumorigenic and anti-tumorigenic roles. The authors discuss the impact of ECM stiffness on tumor growth, metastasis, and therapeutic resistance, highlighting the involvement of desmoplasia, a dense fibrotic matrix rich in collagen, fibronectin, and proteoglycans. They also examine the role of inflammation, cytokines, and mechanotransduction pathways in tumor progression, suggesting potential targeted therapies. The review emphasizes the complexity of the matrisome, the ensemble of genes encoding ECM proteins, and its dynamic interaction with the oncosome, the ensemble of genes encoding oncogenic drivers. The authors propose a "Matrix Addiction" hypothesis, where matrisome drivers synergize with oncogene addiction to influence tumor hallmarks. The article concludes by discussing the potential of advanced technologies, such as 3D imaging and proteomics, to enhance understanding and development of ECM-targeted therapies.The article "Multiple aspects of matrix stiffness in cancer progression" by Mancini et al. explores the critical role of the extracellular matrix (ECM) in cancer development and progression. The ECM, composed of various proteins and proteoglycans, plays a crucial role in cell differentiation, proliferation, and tissue homeostasis. In cancer, the ECM becomes dysregulated, rigid, and fibrotic, contributing to both pro-tumorigenic and anti-tumorigenic roles. The authors discuss the impact of ECM stiffness on tumor growth, metastasis, and therapeutic resistance, highlighting the involvement of desmoplasia, a dense fibrotic matrix rich in collagen, fibronectin, and proteoglycans. They also examine the role of inflammation, cytokines, and mechanotransduction pathways in tumor progression, suggesting potential targeted therapies. The review emphasizes the complexity of the matrisome, the ensemble of genes encoding ECM proteins, and its dynamic interaction with the oncosome, the ensemble of genes encoding oncogenic drivers. The authors propose a "Matrix Addiction" hypothesis, where matrisome drivers synergize with oncogene addiction to influence tumor hallmarks. The article concludes by discussing the potential of advanced technologies, such as 3D imaging and proteomics, to enhance understanding and development of ECM-targeted therapies.