Cancer Cells Shuttle Extracellular Vesicles Containing Oncogenic Mutant p53 Proteins to the Tumor Microenvironment

Bhatta, Bibek; Luz, Ishai; Krueger, Christian G.; Teo, Fanny Xueting; Lane, David P.; Sabapathy, Kanaga; Cooks, Tomer

doi:10.3390/cancers13122985

Cited by 15 publications

(10 citation statements)

References 47 publications

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“…For instance, p53 (WT or mutant) regulates exosomal secretion by participating in exosome biogenesis, promoting exosome secretion, and altering exosome content to modify cell secretome and remodel TME [ 38 – 41 ]. Moreover, mutant p53 is secreted into the TME by several tumor cells, including cancer-associated fibroblasts [ 42 , 43 ]. A previous study demonstrated the biological role of EV-mediated p53 WT secretion [ 22 ].…”

Section: Discussionmentioning

confidence: 99%

Regulated secretion of mutant p53 negatively affects T lymphocytes in the tumor microenvironment

Dong,

Li,

Deng

et al. 2023

Oncogene

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Several studies have demonstrated the role of the oncogenic mutant p53 in promoting tumor progression; however, there is limited information on the effects of secreted oncogenic mutant p53 on the tumor microenvironment and tumor immune escape. In this study, we found that secretion of mutant p53, determined by exosome content, is dependent on its N-terminal dileucine motif via its binding to β-adaptin, and inhibited by the CHK2-mediated-Ser 20 phosphorylation. Moreover, we observed that the mutant p53 caused downregulation and dysfunction of CD4+ T lymphocytes in vivo and downregulated the levels and activities of rate-limiting glycolytic enzymes in vitro. Furthermore, inhibition of mutant p53 secretion by knocking down AP1B1 or mutation of dileucine motif could reverse the quantity and function of CD4+ T lymphocytes and restrain the tumor growth. Our study demonstrates that the tumor-derived exosome-mediated secretion of oncogenic mutant p53 inhibits glycolysis to alter the immune microenvironment via functional suppression of CD4+ T cells, which may be the underlying mechanism for tumor immune escape. Therefore, targeting TDE-mediated p53 secretion may serve as a potential therapeutic target for cancer treatment.

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Section: Discussionmentioning

confidence: 99%

Regulated secretion of mutant p53 negatively affects T lymphocytes in the tumor microenvironment

Dong,

Li,

Deng

et al. 2023

Oncogene

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“…A previous study revealed that mutant p53 can be transported between cells through EVs to alter the tumor microenvironment, which could trigger immunosuppression ( 71 ). A previous study has shown that mutant p53 proteins are expressed in pancreatic, lung, and colon cancer cell lines; these proteins can be selectively packaged into EVs and then affect the reprogramming of the tumor microenvironment ( 72 ). It has been shown that exosomal miR-1246 can transfer the mutant p53 protein product from cancer cells to neighboring cancer cells and macrophages, leading to alterations in the tumor microenvironment ( 73 ).…”

Section: Mutant P53 Gof Activities and Mechanisms In Hnsccmentioning

confidence: 99%

Mutant p53 in head and neck squamous cell carcinoma: Molecular mechanism of gain‑of‑function and targeting therapy (Review)

Sun

Song

et al. 2023

Oncol Rep

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Head and neck squamous cell carcinoma (HNSCC) is one of the most widespread malignancies worldwide. p53, as a transcription factor, can play its role in tumor suppression by activating the expression of numerous target genes. However, p53 is one of the most commonly mutated genes, which frequently harbors missense mutations. These missense mutations are nucleotide substitutions that result in the substitution of an amino acid in the DNA binding domain. Most p53 mutations in HNSCC are missense mutations and the mutation rate of p53 reaches 65–85%. p53 mutation not only inhibits the tumor suppressive function of p53 but also provides novel functions to facilitate tumor recurrence, called gain-of-function (GOF). The present study focused on the prevalence and clinical relevance of p53 mutations in HNSCC, and further described how mutant p53 accumulates. Moreover, mutant p53 in HNSCC can interact with proteins, RNA, and exosomes to exert effects on proliferation, migration, invasion, immunosuppression, and metabolism. Finally, several treatment strategies have been proposed to abolish the tumor-promoting function of mutant p53; these strategies include reactivation of mutant p53 into wild-type p53, induction of mutant p53 degradation, enhancement of the synthetic lethality of mutant p53, and treatment with immunotherapy. Due to the high frequency of p53 mutations in HNSCC, a further understanding of the mechanism of mutant p53 may provide potential applications for targeted therapy in patients with HNSCC.

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“…To investigate the radio-sensitivity of cancer cells based on their p53 status, we used two separate cellular models: PANC-1 cells (pancreatic ductal adenocarcinoma, PDAC) as well as HCT116 cells (colorectal cancer, CRC). For the PANC-1, harboring the gain-of-function p53 mutant in the 273 position (arginine to histidine, R273H), we used negative control cells where the mutant p53 was knocked out (KO) using crisper as described in (43). For the HCT116, harboring the gain-of-function p53 mutant in the 248 position (arginine to tryptophan, R248W), we used the isogenic set of WT (p53 +/+) to compare with the mutant cells as described in (44).…”

Section: Mutant P53 Cancer Cells Confer Radio-sensitivity When Expose...mentioning

confidence: 99%

Reactivation of p53 as a radiosensitization strategy for mutant p53 cancers treated with high-LET radiotherapy

Cooks,

Michaeli,

Luz

et al. 2023

Preprint

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Radiation therapy (RT) remains a common treatment for cancer patients worldwide, despite the development of targeted biological compounds and immunotherapeutic drugs. The challenge in RT lies in delivering a lethal dose to the cancerous site while sparing the surrounding healthy tissues. Low linear energy transfer (low-LET) and high linear energy transfer (high-LET) radiations have distinct effects on cells. High-LET radiation, such as alpha particles, induces clustered DNA double-strand breaks (DSBs), potentially inducing cell death more effectively. However, due to limited range, alpha-particle therapies have been restricted. In human cancer, mutations in TP53 (encoding for the p53 tumor suppressor) are the most common genetic alteration. It was previously reported that cells carrying wild-type p53 exhibit accelerated senescence and significant rates of apoptosis in response to RT, whereas cells harboring mutant p53 (mutp53) do not. This study investigated the combination of the high-LET RT based on 224Ra sources and APR-246 (a p53 reactivating compound) to treat tumors with mutant p53. Cellular models of colorectal cancer (CRC) or pancreatic ductal adenocarcinoma (PDAC) harboring mutant p53, were exposed to alpha particles, and tumor xenografts with mutant p53 were treated using Radium-224 (224Ra) source and APR-246. Effects on cell survival, tumor growth, and apoptosis were assessed. The spread of alpha emitters in tumors was also evaluated as well as the spatial distribution of apoptosis within the treated tumors. We show that mutant p53 cancer cells exhibit radio-sensitivity to alpha particles in vitro and to high-LET RT in vivo. APR-246 treatment enhanced sensitivity to high-LET radiation, leading to reduced tumor growth and increased rates of tumor eradication. Combining high-LET RT with p53 restoration via APR-246 triggered apoptosis, resulting in improved therapeutic outcomes. Further preclinical and clinical studies are needed to provide a promising approach for improving treatment outcomes in patients with mutant p53 tumors.

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Cancer Cells Shuttle Extracellular Vesicles Containing Oncogenic Mutant p53 Proteins to the Tumor Microenvironment

Cited by 15 publications

References 47 publications

Regulated secretion of mutant p53 negatively affects T lymphocytes in the tumor microenvironment

Regulated secretion of mutant p53 negatively affects T lymphocytes in the tumor microenvironment

Mutant p53 in head and neck squamous cell carcinoma: Molecular mechanism of gain‑of‑function and targeting therapy (Review)

Reactivation of p53 as a radiosensitization strategy for mutant p53 cancers treated with high-LET radiotherapy

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