Peritumoral activation of the Hippo pathway effectors YAP and TAZ suppresses liver cancer in mice

Science, Год журнала: 2019, Номер 366(6468), С. 1029 - 1034

Опубликована: Ноя. 22, 2019

The Hippo signaling pathway and its two downstream effectors, the YAP TAZ transcriptional coactivators, are drivers of tumor growth in experimental models. Studying mouse models, we show that can also exert a tumor-suppressive function. We found normal hepatocytes surrounding liver tumors displayed activation deletion Yap Taz these peritumoral accelerated growth. Conversely, hyperactivation triggered regression primary melanoma-derived metastases. Furthermore, whereas cells growing wild-type livers required for their survival, those surrounded by Yap- Taz-deficient were not dependent on TAZ. Tumor cell survival thus depends relative activity tissue, suggesting act through mechanism competition to eliminate cells.

Язык: Английский

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Solid stress, competition for space and cancer: The opposing roles of mechanical cell competition in tumour initiation and growth

Seminars in Cancer Biology, Год журнала: 2019, Номер 63, С. 69 - 80

Опубликована: Май 9, 2019

The regulation of cell growth, proliferation and death is at the basis homeostasis tissues. While they can be regulated by intrinsic genetic factors, their response to external signals emanating from local environment also essential for tissue homeostasis. Tumour initiation progression based on misregulation mostly through accumulation mutations. Yet, there an increasing body evidences showing that tumour microenvironment has a strong impact cancer progression. This includes mechanical constrains compressive forces generated resistance surrounding tissue/matrix expansion. Recently, stress been proposed promote competitive interactions between cells process called competition. Cell population with high proliferative rate compact eliminate neighbouring which are more sensitive compaction. this emerging concept recently validated in vivo, relevance during never discussed extensively. In review, I will first describe phenomenology competition focusing main parameters pathways regulating elimination. then discuss expansion while emphasizing its potential opposing contributions tumourogenesis.

Язык: Английский

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Tumour–host interactions through the lens of Drosophila

Nature reviews. Cancer, Год журнала: 2021, Номер 21(11), С. 687 - 700

Опубликована: Авг. 13, 2021

Язык: Английский

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Cell Competition Is Driven by Autophagy

Developmental Cell, Год журнала: 2019, Номер 51(1), С. 99 - 112.e4

Опубликована: Сен. 19, 2019

Язык: Английский

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Hyperinsulinemia Drives Epithelial Tumorigenesis by Abrogating Cell Competition

Developmental Cell, Год журнала: 2020, Номер 53(4), С. 379 - 389.e5

Опубликована: Май 1, 2020

Язык: Английский

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Myc as a Regulator of Ribosome Biogenesis and Cell Competition: A Link to Cancer

International Journal of Molecular Sciences, Год журнала: 2020, Номер 21(11), С. 4037 - 4037

Опубликована: Июнь 5, 2020

The biogenesis of ribosomes is a finely regulated multistep process linked to cell proliferation and growth—processes which require high rate protein synthesis. One the master regulators ribosome Myc, well-known proto-oncogene that has an important role in ribosomal function regulation relationship between Myc was first highlighted Drosophila, where Myc’s controlling Pol-I, II III evidenced by both microarrays data, ability control growth (mass), cellular animal size. Moreover, can induce competition, physiological mechanism through cells with greater fitness grow better thereby prevail over less competitive cells, are actively eliminated apoptosis. Myc-induced competition shown regulate vertebrate development tumor promotion; however, how these functions biogenesis, synthesis not clear yet. In this review, we will discuss major pathways link also light its mechanisms may reflect favoring promotion.

Язык: Английский

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The hippo pathway: A master regulator of liver metabolism, regeneration, and disease

The FASEB Journal, Год журнала: 2021, Номер 35(5)

Опубликована: Апрель 8, 2021

The liver is the only visceral organ in body with a tremendous capacity to regenerate response insults that induce inflammation, cell death, and injury. Liver regeneration complicated process involving well-orchestrated activation of non-parenchymal cells injured area proliferation undamaged hepatocytes. Furthermore, has Hepatostat, defined as adjustment its volume required for homeostasis. Understanding mechanisms control different steps critical informing therapies repair, help patients disease. Hippo signaling pathway well known playing an essential role regulation size, regeneration, stem self-renewal, cancer. Thus, regulates dynamic fates liver, absence downstream effectors YAP TAZ, severely impaired, proliferative expansion blocked. We will mainly review upstream activating following partial hepatectomy mouse model patients, roles during metabolism, also discuss how targeting cascade might improve suppress tumorigenesis.

Язык: Английский

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Epithelial monitoring through ligand-receptor segregation ensures malignant cell elimination

Science, Год журнала: 2022, Номер 376(6590), С. 297 - 301

Опубликована: Апрель 14, 2022

Animals have evolved mechanisms, such as cell competition, to remove dangerous or nonfunctional cells from a tissue. Tumor necrosis factor signaling can eliminate clonal malignancies Drosophila imaginal epithelia, but why this pathway is activated in tumor not normal tissue unknown. We show that the ligand drives elimination present basolateral circulation remains latent because it spatially segregated its apically localized receptor. Polarity defects associated with malignant transformation cause receptor mislocalization, allowing binding and subsequent apoptotic signaling. This process occurs irrespective of neighboring cells' genotype thus distinct competition. Related phenomena at epithelial wound sites are required for efficient repair. mechanism polarized compartmentalization generally monitor integrity promote homeostasis.

Язык: Английский

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Cell competition: emerging signaling and unsolved questions

FEBS Letters, Год журнала: 2024, Номер 598(4), С. 379 - 389

Опубликована: Фев. 1, 2024

Multicellular communities have an intrinsic mechanism that optimizes their structure and function via cell–cell communication. One of the driving forces for such self‐organization multicellular system is cell competition, elimination viable unfit or deleterious cells interaction. Studies in Drosophila mammals identified multiple mechanisms competition caused by different types mutations cellular changes. Intriguingly, recent studies found “losers” commonly show reduced protein synthesis. In , reduction synthesis levels loser phosphorylation translation initiation factor eIF2α a bZip transcription Xrp1. Given variety stresses converge on thus global inhibition synthesis, may be machinery fitness removing stressed cells. this review, we summarize discuss emerging signaling critical unsolved questions, as well role competition.

Язык: Английский

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Roles of C/EBP class bZip proteins in the growth and cell competition of Rp (‘Minute’) mutants in Drosophila

eLife, Год журнала: 2019, Номер 9

Опубликована: Дек. 24, 2019

Reduced copy number of ribosomal protein (Rp) genes adversely affects both flies and mammals. Xrp1 encodes a reportedly Drosophila-specific AT-hook, bZIP responsible for many the effects including elimination Rp mutant cells by competition with wild type cells. Irbp18, an evolutionarily conserved gene, heterodimerizes another bZip protein, dATF4. We show that Irbp18 is required Xrp1, whereas dATF4 does not share same phenotype, indicating Xrp1/Irbp18 complex active in cells, independently other complexes Irbp18. transcripts proteins are upregulated auto-regulatory expression depends on DNA binding domains necessary cell competition. beyond Drosophila, although under positive selection rapid evolution, at least one human can similarly affect Drosophila development.

Язык: Английский

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