Cellular Pliancy and the Multistep Process of Tumorigenesis

Puisieux, Alain; Pommier, Roxane M.; Morel, Anne-Pierre; Lavial, Fabrice

doi:10.1016/j.ccell.2018.01.007

Cited by 83 publications

(84 citation statements)

References 90 publications

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“…Intermediate states of EMT have also been associated increased tumor-cell plasticity, or stemness, i.e. the capacity of a tumor cell to differentiate into multiple lineages, a capacity which may favor survival of the line because of the greater chance that certain progeny metastasize and form secondary tumors (Brabletz, 2012;Puisieux et al, 2018). Therefore the low-contractile-force phenotype of E/M cells may also be correlated with stemness.…”

Section: The Initiation Of Emt and Establishment Of The Intermediate mentioning

confidence: 99%

Biophysical properties of intermediate states of EMT outperform both epithelial and mesenchymal states

Margaron

Nagai

Guyon

et al. 2019

Preprint

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Potential metastatic cells can dissociate from a primary breast tumor by undergoing an epithelial-to-mesenchymal transmission (EMT). Recent work has revealed that cells in intermediate states of EMT acquire an augmented capacity for tumor-cell dissemination. These states have been characterized by molecular markers, but the structural features and the cellular mechanisms that underlie the acquisition of their invasive properties are still unknown. Using human mammary epithelial cells, we generated cells in intermediate states of EMT through the induction of a single EMT-inducing transcription factor, ZEB1, and cells in a mesenchymal state by stimulation with TGFβ. In stereotypic and spatially-defined culture conditions, the architecture, internal organization and mechanical properties of cells in the epithelial, intermediate and mesenchymal state were measured and compared. We found that the lack of intercellular cohesiveness in epithelial and mesenchymal cells can be detected early by microtubule destabilization and the repositioning of the centrosome from the cell-cell junction to the cell center. Consistent with their high migration velocities, cells in intermediate states produced low contractile forces compared with epithelial and mesenchymal cells. The high contractile forces in mesenchymal cells powered a retrograde flow pushing the nucleus away from cell adhesion to the extracellular matrix. Therefore, cells in intermediate state had structural and mechanical properties that were distinct but not necessarily intermediate between epithelial and mesenchymal cells. Based on these observations, we found that a panel of triple-negative breast cancer lines had intermediate rather than mesenchymal characteristics suggesting that the structural and mechanical properties of the intermediate state are important for understanding tumor-cell dissemination.

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Section: The Initiation Of Emt and Establishment Of The Intermediate mentioning

confidence: 99%

Biophysical properties of intermediate states of EMT outperform both epithelial and mesenchymal states

Margaron

Nagai

Guyon

et al. 2019

Preprint

Self Cite

View full text Add to dashboard Cite

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“…Our exploratory model aimed at simplicity and still suffers from several limitations. First of all, our model is solely based on genetics and ignores how a cell's context and phenotypic state can dictate its response to specific genetic insults (Sieber, Tomlinson, & Tomlinson, 2005), which can impact tumorigenesis (Morel et al, 2017;Puisieux, Pommier, Morel, & Lavial, 2018) or lead to non-genetic selection (Shaffer et al, 2017). It also ignores the contribution of epigenetic alterations as potential drivers; the inclusion of which will require a more general understanding on the recurrent epigenetic alterations functionally linked to tumour formation (Timp & Feinberg, 2013 (Ortmann et al, 2015).…”

Section: Discussionmentioning

confidence: 99%

Quantifying local malignant adaptation in tissue‐specific evolutionary trajectories by harnessing cancer’s repeatability at the genetic level

Tokutomi

Moyret‐Lalle

Puisieux

et al. 2019

Evolutionary Applications

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Cancer is a potentially lethal disease, in which patients with nearly identical genetic backgrounds can develop a similar pathology through distinct combinations of genetic alterations. We aimed to reconstruct the evolutionary process underlying tumour initiation, using the combination of convergence and discrepancies observed across 2,742 cancer genomes from nine tumour types. We developed a framework using the repeatability of cancer development to score the local malignant adaptation (LMA) of genetic clones, as their potential to malignantly progress and invade their environment of origin. Using this framework, we found that premalignant skin and colorectal lesions appeared specifically adapted to their local environment, yet insufficiently for full cancerous transformation. We found that metastatic clones were more adapted to the site of origin than to the invaded tissue, suggesting that genetics may be more important for local progression than for the invasion of distant organs. In addition, we used network analyses to investigate evolutionary properties at the system‐level, highlighting that different dynamics of malignant progression can be modelled by such a framework in tumour‐type‐specific fashion. We find that occurrence‐based methods can be used to specifically recapitulate the process of cancer initiation and progression, as well as to evaluate the adaptation of genetic clones to given environments. The repeatability observed in the evolution of most tumour types could therefore be harnessed to better predict the trajectories likely to be taken by tumours and preneoplastic lesions in the future.

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“…Our exploratory model aimed at simplicity and still suffers from several limitations. First of all, our model is solely based on genetics and ignores the potential influence of a cell's phenotypic state on its response to specific genetic insults, which can impact tumorigenesis (Morel et al, 2017;Puisieux, Pommier, Morel, & Lavial, 2018) or lead to non-genetic selection (Shaffer et al, 2017). It also ignores the contribution of epigenetic alterations as potential drivers, the inclusion of which will require a more general understanding on the recurrent epigenetic alterations functionally linked to tumour formation (Timp & Feinberg, 2013).…”

Section: Discussionmentioning

confidence: 99%

Quantifying local malignant adaptation in tissue-specific evolutionary trajectories by harnessing cancer’s repeatability at the genetic level

Tokutomi

Moyret‐Lalle

Puisieux

et al. 2018

Preprint

View full text Add to dashboard Cite

Cancer is a potentially lethal disease, in which patients with nearly identical genetic backgrounds can develop a similar pathology through distinct combinations of genetic alterations. We aimed to reconstruct the evolutionary process underlying tumour initiation, using the combination of convergence and discrepancies observed across 2,742 cancer genomes from 9 tumour types. We developed a framework using the repeatability of cancer development to score the fitness of genetic clones, as their potential to malignantly progress and invade their environment of origin. Using this framework, we found that pre-malignant skin and colorectal lesions appeared specifically adapted to their local environment, yet insufficiently for full cancerous transformation. We found that metastatic clones were more adapted to the site of origin than to the invaded tissue, suggesting that genetics may be more important for local progression than for the invasion of distant organs. In addition, we used network analyses to investigate evolutionary properties at the system-level, highlighting that different dynamics of fitness progression can be modelled by such a framework in tumourtype-specific fashion. We find that occurrence-based methods can be used to specifically recapitulate the process of cancer initiation and progression, as well as to evaluate the adaptation of genetic clones to given environments. The repeatability observed in the evolution of most tumour types could therefore be harnessed to better predict the trajectories likely to be taken by tumours and pre-neoplastic lesions in the future.

show abstract

Cellular Pliancy and the Multistep Process of Tumorigenesis

Cited by 83 publications

References 90 publications

Biophysical properties of intermediate states of EMT outperform both epithelial and mesenchymal states

Biophysical properties of intermediate states of EMT outperform both epithelial and mesenchymal states

Quantifying local malignant adaptation in tissue‐specific evolutionary trajectories by harnessing cancer’s repeatability at the genetic level

Quantifying local malignant adaptation in tissue-specific evolutionary trajectories by harnessing cancer’s repeatability at the genetic level

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