Mutant p53 Isoforms as Central Drivers of Malignant Progression and Therapy Resistance

The study of mutant p53 isoforms lies at the forefront of cancer biology, revealing the profound impact of TP53 gene alterations on tumor progression and therapy outcomes. While the wild-type p53 protein is a pivotal tumor suppressor, mutations in TP53 not only abrogate its canonical function but can endow the resulting mutant isoforms with novel, gain-of-function activities. Recent research underscores the role of specific mutant p53 isoforms in promoting cancer cell proliferation, metastasis, immune evasion, metabolic reprogramming, and resistance to treatment. This has shifted p53 from being viewed solely as a “lost” tumor suppressor to a driver of malignancy whose activities are highly context-dependent and intricate. Despite rapidly advancing knowledge, the field grapples with unresolved challenges in dissecting the mechanistic diversity of p53 isoforms, their contributions to cancer heterogeneity, and their interplay with the tumor microenvironment, posing critical questions for both biology and medicine.Advancing this line of inquiry, the primary goal of this Research Topic is to illuminate the mechanistic and translational significance of mutant p53 isoforms in the development, persistence, and treatment resistance of aggressive cancers. This includes investigating how mutant p53 isoforms confer survival advantages to tumor cells, shape the epigenetic and transcriptional landscape, support cancer stemness, and blunt anti-tumor immune responses. Moreover, the topic seeks to clarify the prognostic and predictive value of distinct isoforms, explore their implications for treatment stratification, and evaluate their tractability as direct therapeutic targets or as biomarkers informing precision medicine approaches. Ultimately, the aim is to bridge fundamental molecular insights with clinically actionable strategies, fostering innovation in the management of refractory malignancies.This Research Topic encompasses fundamental, translational, and clinical investigations that focus on the functional, mechanistic, and therapeutic aspects of mutant p53 isoforms in cancer. Submissions should delineate the distinct activities of p53 isoforms, their downstream molecular and cellular consequences, and implications for therapy resistance; however, studies exclusively on wild-type p53 or other non-p53 mutations fall outside this scope. To gather further insights in the relevance and therapeutic harnessing of mutant p53 isoforms, we welcome articles addressing, but not limited to, the following themes:- Mechanisms of mutant p53 isoform-mediated malignant progression and metastasis- Impact of mutant p53 isoforms on tumor metabolism and epigenetic remodeling- Contribution of mutant p53 to cancer stem cell phenotypes and intratumoral heterogeneity- Mutant p53-driven immune evasion and modulation of the tumor microenvironment- Predictive and prognostic value of p53 isoforms in therapeutic response and disease outcomes- Development of therapeutic strategies targeting mutant p53 isoforms or their downstream pathways- Patient-derived models and biomarker-driven approaches to study mutant p53 function- Integration of genomics, in vitro, in vivo, and in silico approaches for discovery and validation Topic editors: Kazuchika Nishitsuji, José Díaz-Chávez, Sourio Chakraborty Source: https://www.frontiersin.org/research-topics/78353/mutant-p53-isoforms-as-central-drivers-of-malignant-progression-and-therapy-resistance