Circumventing senescence is associated with stem cell properties and metformin sensitivity

Xavier Deschênes-Simard, Maxime Parisotto, Marie Camille Rowell, Benjamin Le Calvé, Sebastian Igelmann, Karine Moineau-Vallée, Emmanuelle Saint-Germain, Paloma Kalegari, Véronique Bourdeau, Filippos Kottakis, Nabeel Bardeesy, Gerardo Ferbeyre

Research output: Contribution to journalArticle

Abstract

Most cancers arise in old individuals, which also accumulate senescent cells. Cellular senescence can be experimentally induced by expression of oncogenes or telomere shortening during serial passage in culture. In vivo, precursor lesions of several cancer types accumulate senescent cells, which are thought to represent a barrier to malignant progression and a response to the aberrant activation of growth signaling pathways by oncogenes (oncogene toxicity). Here, we sought to define gene expression changes associated with cells that bypass senescence induced by oncogenic RAS. In the context of pancreatic ductal adenocarcinoma (PDAC), oncogenic KRAS induces benign pancreatic intraepithelial neoplasias (PanINs), which exhibit features of oncogene-induced senescence. We found that the bypass of senescence in PanINs leads to malignant PDAC cells characterized by gene signatures of epithelial-mesenchymal transition, stem cells, and mitochondria. Stem cell properties were similarly acquired in PanIN cells treated with LPS, and in primary fibroblasts and mammary epithelial cells that bypassed Ras-induced senescence after reduction of ERK signaling. Intriguingly, maintenance of cells that circumvented senescence and acquired stem cell properties was blocked by metformin, an inhibitor of complex I of the electron transport chain or depletion of STAT3, a protein required for mitochondrial functions and stemness. Thus, our studies link bypass of senescence in premalignant lesions to loss of differentiation, acquisition of stemness features, and increased reliance on mitochondrial functions.

Original languageEnglish
Article numbere12889
Number of pages15
JournalAging Cell
DOIs
Publication statusPublished - 2019

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Metformin
Oncogenes
Cell Aging
Stem Cells
Neoplasms
Adenocarcinoma
Serial Passage
Telomere Shortening
Electron Transport Complex I
STAT3 Transcription Factor
Epithelial-Mesenchymal Transition
Mesenchymal Stromal Cells
Mitochondria
Breast
Fibroblasts
Epithelial Cells
Maintenance
Gene Expression
Growth
Genes

Cite this

Deschênes-Simard, X., Parisotto, M., Rowell, M. C., Le Calvé, B., Igelmann, S., Moineau-Vallée, K., ... Ferbeyre, G. (2019). Circumventing senescence is associated with stem cell properties and metformin sensitivity. Aging Cell, [e12889]. https://doi.org/10.1111/acel.12889
Deschênes-Simard, Xavier ; Parisotto, Maxime ; Rowell, Marie Camille ; Le Calvé, Benjamin ; Igelmann, Sebastian ; Moineau-Vallée, Karine ; Saint-Germain, Emmanuelle ; Kalegari, Paloma ; Bourdeau, Véronique ; Kottakis, Filippos ; Bardeesy, Nabeel ; Ferbeyre, Gerardo. / Circumventing senescence is associated with stem cell properties and metformin sensitivity. In: Aging Cell. 2019.
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Deschênes-Simard, X, Parisotto, M, Rowell, MC, Le Calvé, B, Igelmann, S, Moineau-Vallée, K, Saint-Germain, E, Kalegari, P, Bourdeau, V, Kottakis, F, Bardeesy, N & Ferbeyre, G 2019, 'Circumventing senescence is associated with stem cell properties and metformin sensitivity' Aging Cell. https://doi.org/10.1111/acel.12889

Circumventing senescence is associated with stem cell properties and metformin sensitivity. / Deschênes-Simard, Xavier; Parisotto, Maxime; Rowell, Marie Camille; Le Calvé, Benjamin; Igelmann, Sebastian; Moineau-Vallée, Karine; Saint-Germain, Emmanuelle; Kalegari, Paloma; Bourdeau, Véronique; Kottakis, Filippos; Bardeesy, Nabeel; Ferbeyre, Gerardo.

In: Aging Cell, 2019.

Research output: Contribution to journalArticle

TY - JOUR

T1 - Circumventing senescence is associated with stem cell properties and metformin sensitivity

AU - Deschênes-Simard, Xavier

AU - Parisotto, Maxime

AU - Rowell, Marie Camille

AU - Le Calvé, Benjamin

AU - Igelmann, Sebastian

AU - Moineau-Vallée, Karine

AU - Saint-Germain, Emmanuelle

AU - Kalegari, Paloma

AU - Bourdeau, Véronique

AU - Kottakis, Filippos

AU - Bardeesy, Nabeel

AU - Ferbeyre, Gerardo

PY - 2019

Y1 - 2019

N2 - Most cancers arise in old individuals, which also accumulate senescent cells. Cellular senescence can be experimentally induced by expression of oncogenes or telomere shortening during serial passage in culture. In vivo, precursor lesions of several cancer types accumulate senescent cells, which are thought to represent a barrier to malignant progression and a response to the aberrant activation of growth signaling pathways by oncogenes (oncogene toxicity). Here, we sought to define gene expression changes associated with cells that bypass senescence induced by oncogenic RAS. In the context of pancreatic ductal adenocarcinoma (PDAC), oncogenic KRAS induces benign pancreatic intraepithelial neoplasias (PanINs), which exhibit features of oncogene-induced senescence. We found that the bypass of senescence in PanINs leads to malignant PDAC cells characterized by gene signatures of epithelial-mesenchymal transition, stem cells, and mitochondria. Stem cell properties were similarly acquired in PanIN cells treated with LPS, and in primary fibroblasts and mammary epithelial cells that bypassed Ras-induced senescence after reduction of ERK signaling. Intriguingly, maintenance of cells that circumvented senescence and acquired stem cell properties was blocked by metformin, an inhibitor of complex I of the electron transport chain or depletion of STAT3, a protein required for mitochondrial functions and stemness. Thus, our studies link bypass of senescence in premalignant lesions to loss of differentiation, acquisition of stemness features, and increased reliance on mitochondrial functions.

AB - Most cancers arise in old individuals, which also accumulate senescent cells. Cellular senescence can be experimentally induced by expression of oncogenes or telomere shortening during serial passage in culture. In vivo, precursor lesions of several cancer types accumulate senescent cells, which are thought to represent a barrier to malignant progression and a response to the aberrant activation of growth signaling pathways by oncogenes (oncogene toxicity). Here, we sought to define gene expression changes associated with cells that bypass senescence induced by oncogenic RAS. In the context of pancreatic ductal adenocarcinoma (PDAC), oncogenic KRAS induces benign pancreatic intraepithelial neoplasias (PanINs), which exhibit features of oncogene-induced senescence. We found that the bypass of senescence in PanINs leads to malignant PDAC cells characterized by gene signatures of epithelial-mesenchymal transition, stem cells, and mitochondria. Stem cell properties were similarly acquired in PanIN cells treated with LPS, and in primary fibroblasts and mammary epithelial cells that bypassed Ras-induced senescence after reduction of ERK signaling. Intriguingly, maintenance of cells that circumvented senescence and acquired stem cell properties was blocked by metformin, an inhibitor of complex I of the electron transport chain or depletion of STAT3, a protein required for mitochondrial functions and stemness. Thus, our studies link bypass of senescence in premalignant lesions to loss of differentiation, acquisition of stemness features, and increased reliance on mitochondrial functions.

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U2 - 10.1111/acel.12889

DO - 10.1111/acel.12889

M3 - Article

JO - Aging Cell

JF - Aging Cell

SN - 1474-9718

M1 - e12889

ER -

Deschênes-Simard X, Parisotto M, Rowell MC, Le Calvé B, Igelmann S, Moineau-Vallée K et al. Circumventing senescence is associated with stem cell properties and metformin sensitivity. Aging Cell. 2019. e12889. https://doi.org/10.1111/acel.12889