On the origin of metastases: Induction of pro-metastatic states after impending cell death via ER stress, reprogramming, and a cytokine storm

Conod, Arwen; Silvano, Marianna; Altaba, Ariel Ruiz i

doi:10.1016/j.celrep.2022.110490

Cited by 23 publications

(13 citation statements)

References 163 publications

(216 reference statements)

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“…Here, we develop tools to directly activate and measure caspase-3 dynamics in living cells and use them to address two questions: whether cells can survive direct caspase activation and how well effector caspase dynamics predicts cell survival vs. death. Our results show that cells can recover from direct caspase activation and add to the evidence that the apoptotic cascade is not strictly irreversible ( 25 – 27 , 30 , 31 , 36 – 38 ).…”

Section: Discussionsupporting

confidence: 79%

“…These persister cells display signs of epithelial to mesenchymal transition (EMT) and are more metastatic in mouse cancer models. Similarly, cells that recover from the brink of death after caspase activation, i.e., anastatic cells, also up-regulate EMT-associated genes, increase their motility ( 26 ), and show increased metastasis in mouse cancer models ( 36 ).…”

Section: Discussionmentioning

confidence: 99%

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Cell survival following direct executioner-caspase activation

Nano

Mondo

Harwood

et al. 2023

Proc. Natl. Acad. Sci. U.S.A.

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Executioner-caspase activation has been considered a point-of-no-return in apoptosis. However, numerous studies report survival from caspase activation after treatment with drugs or radiation. An open question is whether cells can recover from direct caspase activation without pro-survival stress responses induced by drugs. To address this question, we engineered a HeLa cell line to express caspase-3 inducibly and combined it with a quantitative caspase activity reporter. While high caspase activity levels killed all cells and very low levels allowed all cells to live, doses of caspase activity sufficient to kill 15 to 30% of cells nevertheless allowed 70 to 85% to survive. At these doses, neither the rate, nor the peak level, nor the total amount of caspase activity could accurately predict cell death versus survival. Thus, cells can survive direct executioner-caspase activation, and variations in cellular state modify the outcome of potentially lethal caspase activity. Such heterogeneities may underlie incomplete tumor cell killing in response to apoptosis-inducing cancer treatments.

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Section: Discussionsupporting

confidence: 79%

Section: Discussionmentioning

confidence: 99%

Cell survival following direct executioner-caspase activation

Nano

Mondo

Harwood

et al. 2023

Proc. Natl. Acad. Sci. U.S.A.

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“…Most death of the cancer patients are resulted by the tumor metastasis, in which tumor cells with versatile self‐reprogramming abilities, must convert from an epithelial to a mesenchymal state and gain stemness properties to defend against attacks from hostile immunity and apoptotic signals 1 ; these transformed cells can ultimately survive and contribute to local cancer metastasis 2 . Thus, it is well recognized that the acquisition of cancer stem cell (CSC)‐like properties, or called stemness, of metastatic cancer cells are considered to be fundamental in the multistep process of cancer metastasis.…”

Section: Introductionmentioning

confidence: 99%

EHD1 promotes the cancer stem cell (CSC)‐like traits of glioma cells via interacting with CD44 and suppressing CD44 degradation

Lu¹,

Wang²,

Shi³

2022

Environmental Toxicology

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Plenty of evidence has shown that endocytosis plays a key role in cancer progression; however, its effects in the progression of cancer stem cells (CSCs) are still fragmentary. In the present study, we firstly identified that mammalian Eps15 homology domain protein 1 (EHD1), an endocytic and metastasis‐associated gene, was upregulated in the 3D non‐adherent spheres derived from glioma cells compared to that in the corresponding parental cells. Further functional experiments revealed that EHD1 knockdown reduced the CSC‐like traits of glioma cells, which were evident by the decrease of sphere‐formation ability, ALDH1 activity, and CSC markers' expression. Additionally, EHD1 knockdown attenuated the tumor‐initiating ability of glioma cells in vivo. Furthermore, it was shown that EHD1 bound to CD44, enhanced CD44 stability, and prevented its total ubiquitination. Indeed, overexpression of CD44 rescued the inhibitory effects of EHD1 knockdown on the CSC‐like traits of glioma cells. Finally, through the online dataset analysis, we found that EHD1 indeed exhibited a higher level in glioma tissues relative to that in normal tissues, and a positive correlation with CSC markers' expression in glioma tissues. Notably, EHD1 expression was negatively correlated with the overall survival and relapse‐free survival of glioma patients. Thus, this work indicates that EHD1 might be a potent target for glioma progression, especially through breaking the EHD1–CD44 interaction.

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“…Follower cell contributions have primarily been studied in collective sheet migration in vitro , rather than in small clusters. But clusters are emerging as major contributors to metastasis (Aceto et al, 2014; Au et al, 2016; Cheung and Ewald, 2016; Cheung et al, 2016; Conod et al, 2022), so it is of interest to understand the mechanisms by which clusters maintain cohesion as they move.…”

Section: Discussionmentioning

confidence: 99%

“…clusters are emerging as major contributors to metastasis (Aceto et al, 2014;Au et al, 2016;Cheung and Ewald, 2016;Conod et al, 2022), so it is of interest to understand the mechanisms by which clusters maintain cohesion as they move.…”

Section: Follower Cell Crawling Depends On Rac and Promotes Cluster C...mentioning

confidence: 99%

A Scribble/Cdep/Rac pathway regulates follower cell crawling and cluster cohesion during collective border cell migration

Campanale¹,

Mondo²,

Montell³

2022

Preprint

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Apicobasal polarity is a defining characteristic of epithelial cells and its disruption is a cancer hallmark. Distinct apical and basolateral protein modules antagonize each other to establish separate membrane domains. These modules interact with dozens of potential effector proteins. Here we describe polarity protein localization and function within a migrating epithelial cell cluster and identify a functionally significant effector protein. In Drosophila egg chambers, border cells delaminate from the follicular epithelium and migrate collectively. We report that the basolateral protein Scribble is required for border cell cluster cohesion and migration. The basolateral module localizes the Rac guanine nucleotide exchange factor Cdep to membranes, and Cdep knockdown phenocopies Scribble cluster cohesion defects. Remarkably, membrane targeting of Cdep is sufficient to partially suppress multiple Scribble phenotypes. We describe specialized basolateral protrusions that promote cluster cohesion. Scribble restricts these protrusions from encroaching onto the apical domain. Thus, a major function of the basolateral module is to localize Cdep, promoting specialized protrusions, cluster cohesion, and collective migration.

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On the origin of metastases: Induction of pro-metastatic states after impending cell death via ER stress, reprogramming, and a cytokine storm

Cited by 23 publications

References 163 publications

Cell survival following direct executioner-caspase activation

Cell survival following direct executioner-caspase activation

EHD1 promotes the cancer stem cell (CSC)‐like traits of glioma cells via interacting with CD44 and suppressing CD44 degradation

A Scribble/Cdep/Rac pathway regulates follower cell crawling and cluster cohesion during collective border cell migration

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