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Thorsten Stiewe: Deciphering the mutant p53-instructed secretome

AIM: The development of an immunosuppressive TME is instrumental for tumor progression and significantly influences the success of immunotherapies. While numerous studies have delineated how oncogenic driver mutations shape distinct TME architectures, there is a lack of similar research on p53, the most frequently mutated tumor suppressor gene. Our own previous work indicates that mutant p53 (mutp53) proteins control protein secretion, exerting pro-metastatic and immune-modulatory functions. With this project we aim to gain insights into the temporal dynamics of TME changes from initiation to metastasis in a lung cancer model, with a specific focus on the mutp53-regulated secretome.

STATE of the ART: p53 mutations are more often missense than nonsense or frameshift mutations and result in the production of a mutant p53 protein. Missense mutations in p53 induce neomorphic properties known as gain-of-function (GOF), which promote tumor survival, generate addiction to mutp53 or its effectors, and enhance tumor progression by stimulating the expression and secretion of pro-metastatic and immune-regulatory molecules. SCLC is an aggressive neuroendocrine subtype of lung cancer, with over 90% of cases with p53 mutations. As the majority of SCLC patients are diagnosed at an advanced stage where surgery is no longer a viable treatment option, mouse models have become indispensable for studying SCLC pathogenesis. However, existing SCLC mouse models have utilized p53-knockout alleles, leaving the immune-modulatory functions of the mutp53-driven tumor secretome unexplored.