Interconnections of p53 Status and TGF-β Signaling orchestrate tumor-suppressive and tumor-promoting Effects Irrespective of Tumor Cell Origin.

Background：TGF-beta plays a crucial role in cancer by suppressing early-stage tumors, inhibiting cell growth, and promoting apoptosis in epithelial cells. At advanced stages, TGF-beta plays a major role in metastasis, immune evasion, and blood vessel formation through tumor microenvironment alterations. The determinants that govern this functional switch remain incompletely understood. The tumor suppressor p53 is a key regulator of cellular stress responses and may critically modulate TGF-β–driven phenotypic effects in cancer cells.

Methods：Human cancer cell lines U2OS, A549 (p53wt), H1299 (p53-deleted), and MDA-MB-231 (p53 GOF mutated) were used to systematically evaluate the effects of TGF-β stimulation on tumor cell behavior. Self-renewal capacity was assessed by colony formation assays, while cell collective (2D) and confined (3D) migrations were analyzed using wound-healing and Transwell assays, respectively. The influence of p53 status on TGF-β–induced cellular phenotypes was explored in p53-knock-out U2OS and A549 cell sublines.

Results：TGF-β treatment induced the highest increase in migratory effect in MDA-MB-231 cells, whereas in H1299 and U2OS cells was observed the intermediate and lowest one, respectively, indicating independence of cellular origin and p53 status. Notably, loss of p53 in U2OS and A549 cells further potentiated TGF-β–induced migration and invasion. The impact of TGF-β on self-renewal ability varied among different cell types: cell lines with wild-type p53 (U2OS, A549) and p53GOF (MDA-MB-231) demonstrated lower clonogenic survival compare to p53-KO or p53-deficient (H1299) cell lines.

Conclusion：This study demonstrates that TGF-β consistently promotes cancer cell migration across multiple tumor models, where p53 functions as an important modulator of this effect. Wild-type p53, being a co-factor for SMADs, likely activates cell cycle arrest, while absent p53 allows TGF-β to promote survival of cancer cells. The results may provide mechanistic insight into the context-dependent roles of TGF-β-p53 axis during cancer progression.