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

Dong, Xiang; Li, Chunlu; Deng, Chengsi; Liu, Jingwei; Li, Danni; Zhou, Tingting; Yang, Xindi; Liu, Yunchan; Guo, Qiqiang; Feng, Yanling; Yu, Yang; Wang, Zhuo; Guo, Wendong; Zhang, Siyi; Cui, Hongyan; Jiang, Cui; Wang, Xiwen; Song, Xiaoyu; Sun, Xun; Cao, Liu

doi:10.1038/s41388-023-02886-1

Cited by 5 publications

(1 citation statement)

References 56 publications

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“…The secretion of mutp53 via exosomes impacts the immune microenvironment, notably by suppressing CD4+ T lymphocytes and altering glycolysis. Targeting this exosome-mediated secretion might offer a therapeutic approach for cancer treatment [ 33 ]. In another study, Cooks et al showed that mutp53 cancer cells shed miR-1246-enriched exosomes, reprogramming macrophages into a tumor-supportive state.…”

Section: Novel Mechanisms Of Mutant P53 Gain Of Function (Gof)mentioning

confidence: 99%

Recent Advances on Mutant p53: Unveiling Novel Oncogenic Roles, Degradation Pathways, and Therapeutic Interventions

Cordani,

Garufi,

Benedetti

et al. 2024

Biomolecules

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The p53 protein is the master regulator of cellular integrity, primarily due to its tumor-suppressing functions. Approximately half of all human cancers carry mutations in the TP53 gene, which not only abrogate the tumor-suppressive functions but also confer p53 mutant proteins with oncogenic potential. The latter is achieved through so-called gain-of-function (GOF) mutations that promote cancer progression, metastasis, and therapy resistance by deregulating transcriptional networks, signaling pathways, metabolism, immune surveillance, and cellular compositions of the microenvironment. Despite recent progress in understanding the complexity of mutp53 in neoplastic development, the exact mechanisms of how mutp53 contributes to cancer development and how they escape proteasomal and lysosomal degradation remain only partially understood. In this review, we address recent findings in the field of oncogenic functions of mutp53 specifically regarding, but not limited to, its implications in metabolic pathways, the secretome of cancer cells, the cancer microenvironment, and the regulating scenarios of the aberrant proteasomal degradation. By analyzing proteasomal and lysosomal protein degradation, as well as its connection with autophagy, we propose new therapeutical approaches that aim to destabilize mutp53 proteins and deactivate its oncogenic functions, thereby providing a fundamental basis for further investigation and rational treatment approaches for TP53-mutated cancers.

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Section: Novel Mechanisms Of Mutant P53 Gain Of Function (Gof)mentioning

confidence: 99%

Recent Advances on Mutant p53: Unveiling Novel Oncogenic Roles, Degradation Pathways, and Therapeutic Interventions

Cordani,

Garufi,

Benedetti

et al. 2024

Biomolecules

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Integrated multiomics analysis identified comprehensive crosstalk between diverse programmed cell death patterns and novel molecular subtypes in Hepatocellular Carcinoma

Chen,

Hu,

et al. 2024

Sci Rep

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Hepatocellular carcinoma (HCC) is a highly aggressive malignancy with increasing global prevalence and is one of the leading causes of cancer-related mortality in the human population. Developing robust clinical prediction models and prognostic stratification strategies is crucial for developing individualized treatment plans. A range of novel forms of programmed cell death (PCD) plays a role in the pathological progression and advancement of HCC, and in-depth study of PCD is expected to further improve the prognosis of HCC patients. Sixteen patterns (apoptosis, autophagy, anoikis, lysosome-dependent cell death, immunogenic cell death, necroptosis, ferroptosis, netosis, pyroptosis, disulfidptosis, entotic cell death, cuproptosis, parthanatos, netotic cell death, alkaliptosis, and oxeiptosis) related to PCD were collected from the literatures and used for subsequent analysis. Supervised (Elastic net, Random Forest, XgBoost, and Boruta) and unsupervised (Nonnegative Matrix Factorization, NMF) clustering algorithms were applied to develop and validate a novel classifier for the individualized management of HCC patients at the transcriptomic, proteomic and single-cell levels. Multiple machine learning algorithms developed a programmed cell death index (PCDI) comprising five robust signatures (FTL, G6PD, SLC2A1, HTRA2, and DLAT) in four independent HCC cohorts, and a higher PCDI was predictive of higher pathological grades and worse prognoses. Furthermore, a higher PCDI was found to be correlated with the presence of a repressive tumor immune microenvironment (TME), as determined through an integrated examination of bulk and single-cell transcriptome data. In addition, patients with TP53 mutation had higher PCDI in comparison with TP53 WT patients. Three HCC subtypes were identified through unsupervised clustering (NMF), exhibiting distinct prognoses and significant biological processes, among the three subtypes, PCDcluster 3 was of particular interest as it contained a large proportion of patients with high risk and low metabolic activity. Construction and evaluation of the Nomogram model was drawn based on the multivariate logistic regression analysis, and highlighted the robustness of the Nomogram model in other independent HCC cohorts. Finally, to explore the prognostic value, we also validated the frequent upregulation of DLAT in a real-world cohort of human HCC specimens by qPCR, western blot, and immunohistochemical staining (IHC). Together, our work herein comprehensively emphasized PCD-related patterns and key regulators, such as DLAT, contributed to the evolution and prognosis of tumor foci in HCC patients, and strengthened our understanding of PCD characteristics and promoted more effective risk stratification strategies.

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Extracellular vesicles in cancer: golden goose or Trojan horse

Han,

Hao,

Chao

et al. 2024

Journal of Molecular Cell Biology

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Intercellular communication can be mediated by direct cell-to-cell contact and indirect interactions through secretion of soluble chemokines, cytokines, and growth factors. Extracellular vesicles (EVs) have emerged as important mediators of cell-to-cell and cell-to-environment communications. EVs from tumor cells, immune cells, and stromal cells can remodel the tumor microenvironment and promote cancer cell survival, proliferation, metastasis, immune evasion, and therapeutic resistance. Most importantly, EVs as natural nanoparticles can be manipulated to serve as a potent delivery system for targeted cancer therapy. EVs can be engineered or modified to improve their ability to target tumors and deliver therapeutic substances, such as chemotherapeutic drugs, nucleic acids, and proteins, for the treatment of cancer. This review provides an overview of the biogenesis and recycling of EVs, discusses their roles in cancer development, and highlights their potential as a delivery system for targeted cancer therapy.

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

Cited by 5 publications

References 56 publications

Recent Advances on Mutant p53: Unveiling Novel Oncogenic Roles, Degradation Pathways, and Therapeutic Interventions

Recent Advances on Mutant p53: Unveiling Novel Oncogenic Roles, Degradation Pathways, and Therapeutic Interventions

Integrated multiomics analysis identified comprehensive crosstalk between diverse programmed cell death patterns and novel molecular subtypes in Hepatocellular Carcinoma

Extracellular vesicles in cancer: golden goose or Trojan horse

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