Figure 2.

Therapy-induced DDR activation triggers the DDSP program and exerts a profound impact to cancer phenotypes. Upon therapeutic genotoxicity that mainly targets cancer cells, which are in active phases of turnaround and proliferation, cells within the TMEN have several responses. At minor damage, such as low doses of irradiation (0.5 Gy), DDR foci disappear within hours after complete DNA damage repair. In contrast, at higher doses (≥5 Gy), most damage foci in stromal cells persist for longer period, and cells enter senescence. Concurrently, majority of cancer cells are sensitized to such severe damage and directly go to apoptosis, while those with DDR-deficiency circumvent apoptosis and survive through treatment. High dosage of DNA damage usually triggers a persistent DDR engaging ATM, CHK2, and NBS1 which activates the cell cycle effectors p53/p16/RB, and leads to continuous and robust secretion of a large spectrum of proteins, dictated by a program coined as DDSP. A few secreted factors function in a cell-autonomous manner, such as IGFBP-7, IL-6, PAI-1, reinforcing senescence through a positive feedback loop that sustains the DDR. Several inflammatory cytokines (for example, CSF-1, MCP-1, CXCL-1, and IL-15), act in a cell non-autonomous way, and potentiate tumor regression by inducing the innate immune response that promotes tumor clearance. However, most components of the secretory phenotype promote cancer progression by enhancing survival, migration, invasiveness, and angiogenesis, accelerating cell repopulation, altering epithelial differentiation and causing epithelial-mesenchymal transition (EMT, e.g. IL-6, IL-8 and recently reported WNT16B and SPINK1). An advanced cancer phenotype, therapy resistance, hereby forms and once activated by such a program, cancer cells are more malignant and refractory to subsequent cycles of therapies. Colored cells: cyan, fibroblasts; green, smooth muscle cells; orange, benign epithelial cells; red, neoplastic epithelial cells; magenta, apoptotic cells; cross-shaped, cells undergoing transient DDR and in acute repair phase; star-shaped, cells that are permanently damaged, become senescent, and exhibit DDSP hallmarks