RETRACTED ARTICLE: Tumor necrosis factor overcomes immune evasion in p53-mutant medulloblastoma

Garancher, Alexandra; Suzuki, Hiromichi; Haricharan, Svasti; Chau, Lianne Q.; Masihi, Meher Beigi; Rusert, Jessica M.; Norris, Paula S.; Carrette, Florent; Romero, Megan M.; Morrissy, Sorana; Skowron, Patryk; Cavalli, Florence M.G.; Farooq, Hamza; Ramaswamy, Vijay; Jones, Steven J.M.; Moore, Richard A.; Mungall, Andrew J.; Ma, Yussanne; Thiessen, Nina; Li, Yisu; Morcavallo, Alaide; Qi, Lin; Kogiso, Mari; Du, Yuchen; Baxter, Patrícia; Henderson, Jacob J.; Crawford, John R.; Levy, Michael L.; Olson, James M.; Cho, Yoon Jae; Deshpande, Aniruddha J.; Li, Xiao Nan; Chesler, Louis; Marra, Marco A.; Wajant, Harald; Becher, Oren J.; Bradley, Linda M.; Ware, Carl F.; Taylor, Michael D.; Wechsler‐Reya, Robert J.

doi:10.1038/s41593-020-0628-4

Cited by 40 publications

(27 citation statements)

References 53 publications

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“…Taking into account that mutp53 cells show low levels of MHC-I, this could represent an important barrier for T cell recognition. Recently, it has been proposed that low doses of TNF (Tumor Necrosis Factor) can rescue the expression of MHC, making mutp53 cancer cells more sensitive to immunological therapy (Garancher et al, 2020 ).…”

Section: Impact Of Mutp53 Gain-of-functionmentioning

confidence: 99%

Mutant p53 Gain-of-Function: Role in Cancer Development, Progression, and Therapeutic Approaches

Alvarado-Ortiz

Cruz-López

Becerril-Rico

et al. 2021

Front. Cell Dev. Biol.

104

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Frequent p53 mutations (mutp53) not only abolish tumor suppressor capacities but confer various gain-of-function (GOF) activities that impacts molecules and pathways now regarded as central for tumor development and progression. Although the complete impact of GOF is still far from being fully understood, the effects on proliferation, migration, metabolic reprogramming, and immune evasion, among others, certainly constitute major driving forces for human tumors harboring them. In this review we discuss major molecular mechanisms driven by mutp53 GOF. We present novel mechanistic insights on their effects over key functional molecules and processes involved in cancer. We analyze new mechanistic insights impacting processes such as immune system evasion, metabolic reprogramming, and stemness. In particular, the increased lipogenic activity through the mevalonate pathway (MVA) and the alteration of metabolic homeostasis due to interactions between mutp53 and AMP-activated protein kinase (AMPK) and Sterol regulatory element-binding protein 1 (SREBP1) that impact anabolic pathways and favor metabolic reprograming. We address, in detail, the impact of mutp53 over metabolic reprogramming and the Warburg effect observed in cancer cells as a consequence, not only of loss-of-function of p53, but rather as an effect of GOF that is crucial for the imbalance between glycolysis and oxidative phosphorylation. Additionally, transcriptional activation of new targets, resulting from interaction of mutp53 with NF-kB, HIF-1α, or SREBP1, are presented and discussed. Finally, we discuss perspectives for targeting molecules and pathways involved in chemo-resistance of tumor cells resulting from mutp53 GOF. We discuss and stress the fact that the status of p53 currently constitutes one of the most relevant criteria to understand the role of autophagy as a survival mechanism in cancer, and propose new therapeutic approaches that could promote the reduction of GOF effects exercised by mutp53 in cancer.

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Section: Impact Of Mutp53 Gain-of-functionmentioning

confidence: 99%

Mutant p53 Gain-of-Function: Role in Cancer Development, Progression, and Therapeutic Approaches

Alvarado-Ortiz

Cruz-López

Becerril-Rico

et al. 2021

Front. Cell Dev. Biol.

104

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show abstract

“…The mechanistic study showed that this is due to the loss of expression of TAP1 and ERAP1, but tumor necrosis factor factor-alpha (TNF-α) agonists can rescue the expression of these proteins. Moreover, in vivo studies also supported the notion that the p53 null state plays a pivotal role in immune evasion, and TNF can reverse this phenotype [49].…”

Section: Cross-talk Between P53 and Mhci Pathwaymentioning

confidence: 67%

Dietary Flavonoids in p53—Mediated Immune Dysfunctions Linking to Cancer Prevention

et al. 2020

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The p53 protein plays a central role in mediating immune functioning and determines the fate of the cells. Its role as a tumor suppressor, and in transcriptional regulation and cytokine activity under stress conditions, is well defined. The wild type (WT) p53 functions as a guardian for the genome, while the mutant p53 has oncogenic roles. One of the ways that p53 combats carcinogenesis is by reducing inflammation. WT p53 functions as an anti-inflammatory molecule via cross-talk activity with multiple immunological pathways, such as the major histocompatibility complex I (MHCI) associated pathway, toll-like receptors (TLRs), and immune checkpoints. Due to the multifarious roles of p53 in cancer, it is a potent target for cancer immunotherapy. Plant flavonoids have been gaining recognition over the last two decades to use as a potential therapeutic regimen in ameliorating diseases. Recent studies have shown the ability of flavonoids to suppress chronic inflammation, specifically by modulating p53 responses. Further, the anti-oxidant Keap1/Nrf2/ARE pathway could play a crucial role in mitigating oxidative stress, leading to a reduction of chronic inflammation linked to the prevention of cancer. This review aims to discuss the pharmacological properties of plant flavonoids in response to various oxidative stresses and immune dysfunctions and analyzes the cross-talk between flavonoid-rich dietary intake for potential disease prevention.

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“…MYC is known to suppress checkpoint proteins PD-1 and CD47 ( 43 ) and MYC inhibition is found to re-express these proteins making these immunotherapies effective again ( 44 ). Recent animal studies further suggest that p53 depletion is suppressing major histocompatibility complex (MHC) class 1 presentation, which mediates T cell immune escape in MYC-driven medulloblastoma ( 45 ).…”

Section: Current Treatment Of Brain Tumorsmentioning

confidence: 99%

Targeting MYCN in Molecularly Defined Malignant Brain Tumors

et al. 2021

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Misregulation of MYC genes, causing MYC overexpression or protein stabilization, is frequently found in malignant brain tumors highlighting their important roles as oncogenes. Brain tumors in children are the most lethal of all pediatric malignancies and the most common malignant primary adult brain tumor, glioblastoma, is still practically incurable. MYCN is one of three MYC family members and is crucial for normal brain development. It is associated with poor prognosis in many malignant pediatric brain tumor types and is focally amplified in specific adult brain tumors. Targeting MYCN has proved to be challenging due to its undruggable nature as a transcription factor and for its importance in regulating developmental programs also in healthy cells. In this review, we will discuss efforts made to circumvent the difficulty of targeting MYCN specifically by using direct or indirect measures to treat MYCN-driven brain tumors. We will further consider the mechanism of action of these measures and suggest which molecularly defined brain tumor patients that might benefit from MYCN-directed precision therapies.

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RETRACTED ARTICLE: Tumor necrosis factor overcomes immune evasion in p53-mutant medulloblastoma

Cited by 40 publications

References 53 publications

Mutant p53 Gain-of-Function: Role in Cancer Development, Progression, and Therapeutic Approaches

Mutant p53 Gain-of-Function: Role in Cancer Development, Progression, and Therapeutic Approaches

Dietary Flavonoids in p53—Mediated Immune Dysfunctions Linking to Cancer Prevention

Targeting MYCN in Molecularly Defined Malignant Brain Tumors

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