Outcompeting p53-Mutant Cells in the Normal Esophagus by Redox Manipulation

Fernández‐Antorán, David; Piedrafita, Gabriel; Murai, Kiyohito; Ong, Swee Hoe; Herms, Albert; Frezza, Christian; Jones, Philip H.

doi:10.1016/j.stem.2019.06.011

Cited by 97 publications

(82 citation statements)

References 41 publications

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“…The ability to transiently increase the likelihood of progenitors generating proliferating progeny provides a rapid and robust response to injury. The down side of this adjustable progenitor fate is that it may be subverted by mutations acquired during tissue aging, leading to mutant clonal expansions that may undergo malignant transformation 22,[41][42][43] .…”

Section: Discussionmentioning

confidence: 99%

A single-progenitor model as the unifying paradigm of epidermal and esophageal epithelial maintenance in mice

et al. 2020

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In adult skin epidermis and the epithelium lining the esophagus cells are constantly shed from the tissue surface and replaced by cell division. Tracking genetically labelled cells in transgenic mice has given insight into cell behavior, but conflicting models appear consistent with the results. Here, we use an additional transgenic assay to follow cell division in mouse esophagus and the epidermis at multiple body sites. We find that proliferating cells divide at a similar rate, and place bounds on the distribution cell cycle times. By including these results in a common analytic approach, we show that data from eight lineage tracing experiments is consistent with tissue maintenance by a single population of proliferating cells. The outcome of a given cell division is unpredictable but, on average, the likelihood of producing proliferating and differentiating cells is equal, ensuring cellular homeostasis. These findings are key to understanding squamous epithelial homeostasis and carcinogenesis.

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Section: Discussionmentioning

confidence: 99%

A single-progenitor model as the unifying paradigm of epidermal and esophageal epithelial maintenance in mice

et al. 2020

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“…In the case of p53, this function may act to help to eliminate damaged cells from the epidermal stem cell pool without inducing apoptosis, which could comprise the barrier function of squamous epithelial surfaces. Consistent with this idea, recent work has shown that low-dose radiation induces the differentiation of esophageal squamous cells at the expense of self-renewal in vivo (Fernandez-Antoran et al, 2019). TP53 and Notch genes are frequently comutated in squamous carcinomas of the skin (as in our model system) and other sites; although co-mutation of tumor suppressor genes in a particular cancer is typically taken as evidence of complementary anti-oncogenic activities, our work suggests that in the cases of squamous carcinoma it may reflect, at least in part, redundant Notch and p53 functions.…”

Section: Discussionmentioning

confidence: 66%

IER5, a DNA-damage response gene, is required for Notch-mediated induction of squamous cell differentiation

Lemieux

Thomas

et al. 2020

Preprint

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Notch signaling regulates normal squamous cell proliferation and differentiation and is frequently disrupted in squamous cell carcinomas, in which Notch is a key tumor suppressive pathway. To identify the direct targets of Notch that produce these phenotypes, we introduced a conditional Notch transgene into squamous cell carcinoma cell lines, which respond to Notch activation in 2D culture and in organoid cultures by undergoing differentiation. RNA-seq and ChIP-seq analyses show that in squamous cells Notch activates a context-specific program of gene expression that depends on lineage-specific regulatory elements, most of which lie in longrange enhancers. Among the direct Notch target genes are multiple DNA damage response genes, including IER5, which is regulated by Notch through several enhancer elements. We show that IER5 is required for Notch-induced differentiation in squamous carcinoma cells and in TERT-immortalized keratinocytes. Its function is epistatic to PPP2R2A, which encodes the B55a subunit of PP2A, and IER5 interacts with B55a in cells and in purified systems. These results show that Notch and DNA-damage response pathways converge in squamous cells and that some components of these pathways promote differentiation, which may serve to eliminate DNA-damaged cells from the proliferative pool in squamous epithelia. Crosstalk involving Notch and PP2A may enable Notch signaling to be tuned and integrated with other pathways that regulate squamous differentiation. Our work also suggests that squamous cell carcinomas remain responsive to Notch signaling, providing a rationale for reactivation of Notch as a therapeutic strategy in these cancers. ImpactOur findings highlight context-specific crosstalk between Notch, DNA damage response genes, and PP2A, and provide a roadmap for understanding how Notch induces the differentiation of squamous cells.

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“…Another possible mechanism by which oncogenic mutants can exist in normal tissue but not cause cancer is illustrated by a study that showed that normal human esophagus contains TP53-mutant progenitors. Yet, TP53-mutant cells can be displaced from normal tissues through the improvement of the competitive fitness of wild-type progenitors by antioxidants [150].…”

Section: Sporadic Benign Conditions Associated With Alterations In "Dmentioning

confidence: 99%

The paradox of cancer genes in non-malignant conditions: implications for precision medicine

et al. 2020

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Next-generation sequencing has enabled patient selection for targeted drugs, some of which have shown remarkable efficacy in cancers that have the cognate molecular signatures. Intriguingly, rapidly emerging data indicate that altered genes representing oncogenic drivers can also be found in sporadic non-malignant conditions, some of which have negligible and/or low potential for transformation to cancer. For instance, activating KRAS mutations are discerned in endometriosis and in brain arteriovenous malformations, inactivating TP53 tumor suppressor mutations in rheumatoid arthritis synovium, and AKT, MAPK, and AMPK pathway gene alterations in the brains of Alzheimer's disease patients. Furthermore, these types of alterations may also characterize hereditary conditions that result in diverse disabilities and that are associated with a range of lifetime susceptibility to the development of cancer, varying from near universal to no elevated risk. Very recently, the repurposing of targeted cancer drugs for non-malignant conditions that are associated with these genomic alterations has yielded therapeutic successes. For instance, the phenotypic manifestations of CLOVES syndrome, which is characterized by tissue overgrowth and complex vascular anomalies that result from the activation of PIK3CA mutations, can be ameliorated by the PIK3CA inhibitor alpelisib, which was developed and approved for breast cancer. In this review, we discuss the profound implications of finding molecular alterations in non-malignant conditions that are indistinguishable from those driving cancers, with respect to our understanding of the genomic basis of medicine, the potential confounding effects in early cancer detection that relies on sensitive blood tests for oncogenic mutations, and the possibility of reverse repurposing drugs that are used in oncology in order to ameliorate nonmalignant illnesses and/or to prevent the emergence of cancer.

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Outcompeting p53-Mutant Cells in the Normal Esophagus by Redox Manipulation

Cited by 97 publications

References 41 publications

A single-progenitor model as the unifying paradigm of epidermal and esophageal epithelial maintenance in mice

A single-progenitor model as the unifying paradigm of epidermal and esophageal epithelial maintenance in mice

IER5, a DNA-damage response gene, is required for Notch-mediated induction of squamous cell differentiation

The paradox of cancer genes in non-malignant conditions: implications for precision medicine

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