Abstract

The term “field cancerisation” describes the formation of tissue sub-areas highly susceptible to multifocal tumourigenesis. In the earlier stages of cancer, cells may indeed display a series of molecular alterations that allow them to proliferate faster, eventually occupying discrete tissue regions with irrelevant morphological anomalies. This behaviour recalls cell competition, a process based on a reciprocal fitness comparison: when cells with a growth advantage arise in a tissue, they are able to commit wild-type neighbours to death and to proliferate at their expense. It is known that cells expressing high MYC levels behave as super-competitors, able to kill and replace less performant adjacent cells; given MYC upregulation in most human cancers, MYC-mediated cell competition is likely to pioneer field cancerisation. Here we show that MYC overexpression in a sub-territory of the larval wing epithelium of Drosophila is sufficient to trigger a number of cellular responses specific to mammalian pre-malignant tissues. Moreover, following induction of different second mutations, high MYC-expressing epithelia were found to be susceptible to multifocal growth, a hallmark of mammalian pre-cancerous fields. In summary, our study identified an early molecular alteration implicated in field cancerisation and established a genetically amenable model which may help study the molecular basis of early carcinogenesis.

Highlights

  • The molecular events underlying cancer initiation are largely unknown

  • As described in the Introduction, we previously showed that hyperplastic TSGs exploit excess MYC to grow more rapidly, but are not able to initiate malignant transformation (Ziosi et al, 2010); we aimed at exploring MYC overexpression (MYCOVER)’s effect on the clonal behaviour of neoplastic TSGs

  • It is recognised that many types of cancers start from cells owing some, but not all, phenotypic traits necessary for malignancy, and those traits may result from various mutagenic insults, on the basis of which the most performant cells are selected for clonal expansion (Curtius et al, 2018). This process may be driven by cell competition, which is intensively studied both in Drosophila (Merino et al, 2016) and mammals (Di Gregorio et al, 2016)

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Summary

Introduction

It is commonly accepted that most cancers are monoclonal in origin, evolving from a single cell whose lineage accumulates in time multiple molecular insults (Michor et al, 2004; Vogelstein et al, 2013; Feinberg et al, 2016). In the 1950s, Slaughter introduced the concept of “field cancerisation”: while studying oral cancers, he observed that they recurred more frequently adjacent to a resected tumour (Slaughter et al, 1953). Successive studies, fostered by the development of post-genomic technologies (Metzker, 2010), have demonstrated that this phenomenon is not specific to the oral mucosa, being rather a common feature of epithelial organs

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