Opposing Roles of Wild-type and Mutant p53 in the Process of Epithelial to Mesenchymal Transition

Semenov, Oleg V.; Daks, Alexandra; Fedorova, Olga; Shuvalov, Oleg; Barlev, Nickolai A.

doi:10.3389/fmolb.2022.928399

Cited by 21 publications

(16 citation statements)

References 94 publications

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“…Interestingly, we found that the K tumor organoids are almost depleted of the Hmga2-high Group 4, raising the possibility that Kras G12D mutation alone cannot drive AT2 cells to acquire the Hmga2-high Group 4 state, at least at the 7 day timepoint. This is consistent with previous findings that P53 loss can promote EMT-program activation 37,38 . These results may suggest that tumors with different oncogenic genotypes may differ in cell states composition, providing further proof of concept for using the organoids system to dissect phenotypic variations in tumorigenesis.…”

Section: Spc-high Cells and Hmga2-high Cells Represent Distinct Path ...supporting

confidence: 94%

Organoid modeling reveals the tumorigenic potential of the alveolar progenitor cell state

Kim

Dang

et al. 2023

Preprint

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Alveolar type 2 (AT2) cells, the epithelial progenitor cells of the distal lung, are known to be the prominent cell of origin for lung adenocarcinoma. The regulatory programs that control chromatin and gene expression in AT2 cells during the early stages of tumor initiation are not well understood. Here, we dissected the response of AT2 cells to Kras activation and p53 loss (KP) using combined single cell RNA and ATAC sequencing in an established tumor organoid system. Multi-omic analysis showed that KP tumor organoid cells exhibit two major cellular states: one more closely resembling AT2 cells (SPC-high) and another with loss of AT2 identity (hereafter, Hmga2-high). These cell states are characterized by unique transcription factor (TF) networks, with SPC-high states associated with TFs known to regulate AT2 cell fate during development and homeostasis, and distinct TFs associated with the Hmga2-high state. CD44 was identified as a marker of the Hmga2-high state, and was used to separate organoid cultures for functional comparison of these two cell states. Organoid assays and orthotopic transplantation studies indicated that SPC-high cells have higher tumorigenic capacity in the lung microenvironment compared to Hmga2-high cells. These findings highlight the utility of understanding chromatin regulation in the early oncogenic versions of epithelial cells, which may reveal more effective means to intervene the progression of Kras-driven lung cancer.

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Section: Spc-high Cells and Hmga2-high Cells Represent Distinct Path ...supporting

confidence: 94%

Organoid modeling reveals the tumorigenic potential of the alveolar progenitor cell state

Kim

Dang

et al. 2023

Preprint

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“…69 Since EMT-TFs can likewise inhibit p53 and other tumor-suppressive programs, it appears that a sophisticated mutual inhibition of EMT and p53 is governing EMT commitment and tumor suppression versus malignancy. 70,71 Intriguingly, in our study, there was no apparent dependence of the ZEB1 hi phenotype on p53 status across the various cell lines we used, i.e., MCF10A (p53 wild-type [WT]), HCT116 (p53WT), A549 (p53WT), J82 (p53 mutant [mut]), Panc1 (p53 mut), and MDA-MB-231 (p53 mut). We thus conclude that p53 status seems not to dramatically affect the role of ZEB1 promoting S-phase entry triggering sub-lethal DNA replication stress.…”

Section: Discussionmentioning

confidence: 57%

The EMT transcription factor ZEB1 governs a fitness-promoting but vulnerable DNA replication stress response

et al. 2022

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“…Among all these genes only MMP9 resulted in signi cant survival increase depending on p53. Given that p53 may regulate not only gene expression but also protein stability of EMT transcription factors like SNAIL and TWIST1 in HCC and in diverse tumor cells 47,53,54 , and considering that protein escindition of E-cadherin by metalloproteinases like MMP9 is also a way of EMT regulation in different cancers 55,56,57 , the complete picture is missing in transcriptomic analyses. Proteomic analyses from patients organized in databases are still scarce, but further studies would be necessary in HCC to nd actual EMT determinants of the disease progression.…”

Section: Discussionmentioning

confidence: 99%

Alpha lipoic acid diminishes migration and invasion in hepatocellular carcinoma cells through an AMPK-p53 axis

Hidalgo,

Ferretti,

Etichetti

et al. 2023

Preprint

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Hepatocellular carcinoma (HCC) associated with viral or metabolic liver diseases is a growing cancer that lacks effective therapy. AMPK is downregulated in the early stages of HCC and its activation diminishes tumor progression in culture and in vivo. Alpha lipoic acid (ALA), an indirect AMPK activator that inhibits hepatic steatosis in rodents, shows antitumor effects in different cancers. We aimed to study the putative antitumor action of ALA in HCC cells through AMPK signaling. ALA led to significant inhibition of cell migration and invasion in HCC cells with wild-type TP53. We showed that these effects depended on AMPK, and ALA also increased the levels and nuclear compartmentalization of the AMPK target p53. The anti-invasive effect of ALA was abrogated in stable-silenced versus isogenic-TP53 cells. Furthermore, ALA inhibited epithelial-mesenchymal transition in control wild-type TP53, but no significant changes of EMT markers were observed in silenced TP53 cells. In addition, we spotted that in patients from the HCC-TCGA dataset some EMT genes showed different expression patterns or survival profiles depending on TP53 status. ALA emerges as a potent activator of AMPK-p53 axis in HCC cells, and it decreases migration/invasion by reducing EMT which could mitigate the disease in wild-type TP53 patients.

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Opposing Roles of Wild-type and Mutant p53 in the Process of Epithelial to Mesenchymal Transition

Cited by 21 publications

References 94 publications

Organoid modeling reveals the tumorigenic potential of the alveolar progenitor cell state

Organoid modeling reveals the tumorigenic potential of the alveolar progenitor cell state

The EMT transcription factor ZEB1 governs a fitness-promoting but vulnerable DNA replication stress response

Alpha lipoic acid diminishes migration and invasion in hepatocellular carcinoma cells through an AMPK-p53 axis

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