Collagen architecture and signaling orchestrate cancer development

The tumor microenvironment (TME) controls tumor progression and maintenance. Accordingly, tumor-centric cancer treatment must adjust to being more holistic and TME-centric. Collagens are the most abundant TME proteins, and their dy-namic remodeling profoundly affects both TME architecture and tumor develop-ment. Recent evidence shows that in addition to being structural elements, collagens are an important source of nutrients and decisive growth controlling and immunoregulatory signals. This review focuses on macropinocytosis-dependent collagen support of cancer cell metabolism and the role of collagen fiber remodeling and trimer heterogeneity in control of tumor bioenergetics, growth, progression, and response to therapy. If properly translated, these basic advances may alter the future of cancer treatment.