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The multifaceted role of mutant p53 in remodeling the tumor transcriptome and secretome
The tumor suppressor gene TP53 is frequently inactivated by missense mutations in human cancers. These genetic alterations give rise to the expression of mutant variants of the encoded p53 protein (mutp53) that have lost their tumor-suppressive functions. Moreover, many mutp53 proteins acquire novel...
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| Format: | Doctoral Thesis |
| Language: | English |
| Published: |
Philipps-Universität Marburg
2023
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| Online Access: | PDF Full Text |
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| Summary: | The tumor suppressor gene TP53 is frequently inactivated by missense mutations in human cancers. These genetic alterations give rise to the expression of mutant variants of the encoded p53 protein (mutp53) that have lost their tumor-suppressive functions. Moreover, many mutp53 proteins acquire novel neomorphic properties that can significantly modulate cancer cell behavior, promoting aggressiveness, metastasis, and therapy resistance. Mutp53 primarily promotes tumor growth by interacting with various cellular proteins, especially transcription factors, leading to significant changes in transcriptional regulation. Remarkably, these pro-tumorigenic molecular alterations are not limited to intracellular processes but may also extend to the extracellular environment through mutp53-mediated changes in the composition of the tumor cell secretome. Consequently, this can profoundly influence the tumor microenvironment, creating a supportive milieu that favors tumor progression. The exceptionally high prevalence of TP53 mutations in human tumors and the diverse pro-tumorigenic activities of mutp53 render it an attractive target for cancer therapy. However, despite extensive research, no drug designed to specifically target tumors with TP53 mutations has been approved for clinical use, underscoring the ongoing need for further research into the underlying mechanisms.
In this study, various cancer models were established and characterized to enhance our understanding of mutp53's role in shaping the tumor microenvironment. Different human and murine cancer cell lines that harbor TP53 mutations were successfully deleted of mutp53 using the CRISPR/Cas9 technology. In addition, a conditional mutp53 knockout cell line was generated, enabling the acute deletion of mutp53. This approach facilitated the study of mutp53's oncogenic functions in a cell line highly dependent on mutp53. Furthermore, primary cell cultures were derived from paired cohorts of mice with mutp53-driven and mutp53-deficient small cell and non-small cell lung cancer tumors, induced by a combination of germline and somatic, CRISPR/Cas9-mediated, in vivo gene editing. Phenotypic analyses of small cell lung cancer derived cell cultures unveiled that mutp53 plays a role in enforcing the neuroendocrine phenotype, holding significant therapeutic implications. Moreover, transcriptomic profiling of all the generated mutp53-deleted tumor cell cultures, along with their parental mutp53-expressing counterparts, revealed several secreted factors and signaling pathways differentially regulated by mutp53. Notably, mutp53 consistently suppressed proinflammatory signaling pathways across various cancer models. Intriguingly, targeted proteomic analysis of the tumor cell secretome indicated that mutp53 stimulates global protein secretion and induces the context-specific secretion of several key components of the NF-κB signaling pathway, with NF-κB coactivator MTDH being most prominent.
In summary, the generation and combined transcriptomic and proteomic analysis of isogenic cell-based cancer models have provided insights into mutp53-regulated factors and signaling pathways that participate in the reciprocal communication between cancer cells and their surroundings. This work highlights the multifaceted potential of mutp53 in remodeling the tumor microenvironment. |
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| DOI: | 10.17192/z2024.0001 |