Active elimination of intestinal cells drives oncogenic growth in organoids.

Huy Quang Le,Tamsin Rosemary Margaret Lannagan,Arianna Fumagalli,Ana Krotenberg Garcia,Rene Jackstadt,Saskia Jacoba Elisabeth Suijkerbuijk,Owen James Sansom,Jacco van Rheenen

doi:10.1016/j.celrep.2021.109307

Abstract

SummaryCompetitive cell interactions play a crucial role in quality control during development and homeostasis. Here, we show that cancer cells use such interactions to actively eliminate wild-type intestine cells in enteroid monolayers and organoids. This apoptosis-dependent process boosts proliferation of intestinal cancer cells. The remaining wild-type population activates markers of primitive epithelia and transits to a fetal-like state. Prevention of this cell-state transition avoids elimination of wild-type cells and, importantly, limits the proliferation of cancer cells. Jun N-terminal kinase (JNK) signaling is activated in competing cells and is required for cell-state change and elimination of wild-type cells. Thus, cell competition drives growth of cancer cells by active out-competition of wild-type cells through forced cell death and cell-state change in a JNK-dependent manner.

Highlights

Over the past years, it became evident that the internal proliferative potential of tumor cells is not sufficient for their expansion
Cancer cells out-compete WT small intestine cells In order to investigate whether cell competition plays a role in mammalian intestinal cancer, we exploited the 3D organoid system (Sato et al, 2009), which closely resembles the architecture of the intestinal tissue
Two different types of organoid cultures were derived from mouse small intestines: membrane-bound tdTomato-labeled WT cells and Dendra2-labeled intestinal cancer cells derived from VillinCreERT2:Apcfl/flKrasG12D/WTTrp53fl/R172H transgenic mice (Fumagalli et al, 2017)

Summary

Introduction

It became evident that the internal proliferative potential of tumor cells is not sufficient for their expansion. Tumor cells need to acquire multiple hallmarks of cancer, including growth-supporting interplay of tumor cells and their environment in order to sustain their proliferation (Hanahan and Weinberg, 2011). The basis of this interaction is often formed by processes that are, in origin, essential for normal early development and homeostasis (Suijkerbuijk and van Rheenen, 2017). In tissues built by heterogeneous populations, weaker cells will be removed by surrounding stronger cells These features provide a strong mechanism that controls overall tissue and organismal fitness (Bowling et al, 2019; Claverıa and Torres, 2016). Quality control by cell competition starts in the early mouse embryo (Claverıa et al, 2013; Sancho et al, 2013) and continues to impact physiology up to late adulthood by determining the speed of aging (Merino et al, 2015)

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