MYC, Cell Competition, and Cell Death in Cancer: The Inseparable Triad

Simone Di Giacomo,Simona Paglia,Daniela Grifoni,Manuela Sollazzo

doi:10.3390/genes8040120

Abstract

Deregulation of MYC family proteins in cancer is associated with a global reprogramming of gene expression, ultimately promoting glycolytic pathways, cell growth, and proliferation. It is well known that MYC upregulation triggers cell-autonomous apoptosis in normal tissues, while frankly malignant cells develop resistance to apoptotic stimuli, partly resulting from MYC addiction. As well as inducing cell-autonomous apoptosis, MYC upregulation is able to trigger non cell-autonomous apoptotic death through an evolutionarily conserved mechanism known as “cell competition”. With regard to this intimate and dual relationship between MYC and cell death, recent evidence obtained in Drosophila models of cancer has revealed that, in early tumourigenesis, MYC upregulation guides the clonal expansion of mutant cells, while the surrounding tissue undergoes non-cell autonomous death. Apoptosis inhibition in this context was shown to restrain tumour growth and to restore a wild-type phenotype. This suggests that cell-autonomous and non cell-autonomous apoptosis dependent on MYC upregulation may shape tumour growth in different ways, soliciting the need to reconsider the role of cell death in cancer in the light of this new level of complexity. Here we review recent literature about MYC and cell competition obtained in Drosophila, with a particular emphasis on the relevance of cell death to cell competition and, more generally, to cancer. Possible implications of these findings for the understanding of mammalian cancers are also discussed.

Highlights

Organs are composed of several cell typologies that experience complex relationships and modify their behaviour to survive in the changing context
The oncoprotein c-MYC is known to regulate a number of cellular processes, from cell growth to apoptosis and metabolism [1]
The downstream effector of the Hpo pathway is Yorkie (Yki), encoded by the Drosophila homologue of the human YAP (Yes-Associated-Protein) oncogene, which, following deregulation of upstream components of the pathway, activates, besides MYC, transcription of several genes involved in cell growth, proliferation, and survival such as cyc E, dIAP1 (Drosophila Inhibitor of APoptosis 1), and the miRNA bantam [20]

Summary

Introduction

Organs are composed of several cell typologies that experience complex relationships and modify their behaviour to survive in the changing context. Cancer itself can be seen as an evolving landscape, in which tumour cells may be either hampered or supported by different neighbours in the disruption of tissue homeostasis. Understanding the molecular basis of the social cell biology of cancer is indispensable to develop novel therapeutic approaches targeting the whole cancer community. The oncoprotein MYC plays instrumental roles in development and cancer, strictly dependent on its ability to promote both cell growth and cell death in different genetic backgrounds. In recent years, these two intrinsic features of the MYC protein were shown to merge in a unique trait named “cell competition”, an evolutionarily conserved mechanism governing cell selection in organ development and, possibly, in cancer

MYC and Cell Growth

MYC and Cell Death

MYC Enters Cell Competition

Apoptotic Cell Death in Cancer

Final Remarks