Phenotypic plasticity in the pancreas: new triggers, new players

Demcollari, T.; Cujba, Ana-Maria; Sancho, Rocı́o

doi:10.1016/j.ceb.2017.11.014

Cited by 16 publications

(14 citation statements)

References 51 publications

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“…The pancreas is composed of functionally distinct compartments of epithelial cells derived from common progenitors. 19 Exocrine acinar cells produce and secrete digestive enzymes that travel to the gut via ductal networks. Endocrine cells of the islets of Langerhans produce and secrete hormones that regulate blood glucose.…”

Section: Introductionmentioning

confidence: 99%

EPHA2-dependent outcompetition of KRASG12D mutant cells by wild-type neighbors in the adult pancreas

et al. 2021

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Summary As we age, our tissues are repeatedly challenged by mutational insult, yet cancer occurrence is a relatively rare event. Cells carrying cancer-causing genetic mutations compete with normal neighbors for space and survival in tissues. However, the mechanisms underlying mutant-normal competition in adult tissues and the relevance of this process to cancer remain incompletely understood. Here, we investigate how the adult pancreas maintains tissue health in vivo following sporadic expression of oncogenic Kras ( KrasG12D ), the key driver mutation in human pancreatic cancer. We find that when present in tissues in low numbers, KrasG12D mutant cells are outcompeted and cleared from exocrine and endocrine compartments in vivo . Using quantitative 3D tissue imaging, we show that before being cleared, KrasG12D cells lose cell volume, pack into round clusters, and E-cadherin-based cell-cell adhesions decrease at boundaries with normal neighbors. We identify EphA2 receptor as an essential signal in the clearance of KrasG12D cells from exocrine and endocrine tissues in vivo . In the absence of functional EphA2, KrasG12D cells do not alter cell volume or shape, E-cadherin-based cell-cell adhesions increase and KrasG12D cells are retained in tissues. The retention of KRasG12D cells leads to the early appearance of premalignant pancreatic intraepithelial neoplasia (PanINs) in tissues. Our data show that adult pancreas tissues remodel to clear KrasG12D cells and maintain tissue health. This study provides evidence to support a conserved functional role of EphA2 in Ras-driven cell competition in epithelial tissues and suggests that EphA2 is a novel tumor suppressor in pancreatic cancer.

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Section: Introductionmentioning

confidence: 99%

EPHA2-dependent outcompetition of KRASG12D mutant cells by wild-type neighbors in the adult pancreas

et al. 2021

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“…There are also many examples of exploiting transcription factors to induce plasticity by modulating gene expression cell autonomously. This is evident in the pancreas, which exhibits very limited regenerative potential under homeostatic conditions yet in which a latent multipotent cell type can be uncovered within the adult pancreas 32 .…”

Section: Cell Intrinsic Mechanisms Of Plasticitymentioning

confidence: 99%

Diverse mechanisms for endogenous regeneration and repair in mammalian organs

Wells¹,

Watt²

2018

Nature

145

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Mammalian organs comprise an extraordinary diversity of cell and tissue types. Regenerative organs, such as the skin and gastrointestinal tract, use resident stem cells to maintain tissue function. Organs with a lower cellular turnover, such as the liver and lungs, mostly rely on proliferation of committed progenitor cells. In many organs, injury reveals the plasticity of both resident stem cells and differentiated cells. The ability of resident cells to maintain and repair organs diminishes with age, whereas, paradoxically, the risk of cancer increases. New therapeutic approaches aim to harness cell plasticity for tissue repair and regeneration while avoiding the risk of malignant transformation of cells.

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“…The pancreas is composed of two functionally distinct compartments of epithelial cells derived from common progenitors 22 . Exocrine acinar cells produce and secrete digestive enzymes that travel to the gut via ductal networks.…”

Section: Introductionmentioning

confidence: 99%

KRASG12D mutant cells are outcompeted by wild type neighbours in adult pancreas in an EPHA2-dependent manner

Hill

Ζαραγκούλιας

Salvador

et al. 2020

Preprint

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As we age, our tissues are repeatedly challenged by mutational insult, yet cancer occurrence is a relatively rare event. Cells carrying cancer-causing genetic mutations compete with normal neighbours for space and survival in tissues. However, the mechanisms underlying mutant-normal competition in adult tissues and the relevance of this process to cancer remain incompletely understood. Here, we investigate how the adult pancreas maintains tissue health in vivo following sporadic expression of oncogenic Kras (KrasG12D), the key driver mutation in human pancreatic cancer. We find that when present in tissues in low numbers, KrasG12D mutant cells are outcompeted and cleared from exocrine and endocrine compartments in vivo. Using quantitative 3D tissue imaging, we show that prior to being cleared, KrasG12D cells lose cell volume, segregate from normal cells and decrease E-cadherin-based cell-cell adhesions with normal neighbours. We identify EphA2 receptor is an essential signal in the clearance of KrasG12D cells from exocrine and endocrine tissues in vivo. In the absence of functional EphA2, KrasG12D cells no longer segregate, E-cadherin-based cell-cell adhesions increase and KrasG12D cells are retained in tissues. Retention of KRasG12D cells leads to an increased burden of premalignant pancreatic intraepithelial neoplasia (PanINs) in tissues. Our data show that adult pancreas tissues remodel to clear KrasG12D cells and maintain tissue health. This study provides evidence to support a conserved functional role of EphA2 in Ras-driven cell competition in epithelial tissues and suggests that EphA2 is a novel tumour suppressor in pancreatic cancer.

show abstract

Phenotypic plasticity in the pancreas: new triggers, new players

Cited by 16 publications

References 51 publications

EPHA2-dependent outcompetition of KRASG12D mutant cells by wild-type neighbors in the adult pancreas

EPHA2-dependent outcompetition of KRASG12D mutant cells by wild-type neighbors in the adult pancreas

Diverse mechanisms for endogenous regeneration and repair in mammalian organs

KRASG12D mutant cells are outcompeted by wild type neighbours in adult pancreas in an EPHA2-dependent manner

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