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Tomeu Colom, Sanger Institute
Title: Clonal competition in the normal oesophageal epithelium during early tumorigenesis
Keywords: Cell competition, tumour, oesophageal epithelium, mutations
Abstract
Human epithelial tissues accumulate cancer-driver mutations with age, yet tumour formation remains rare. The positive selection of these mutations argues they alter the behaviour and fitness of proliferating cells. Hence, normal adult tissues become a patchwork of mutant clones competing for space and survival, with the fittest clones expanding by eliminating their less-competitive neighbours. However, little is known about how such dynamic competition in normal epithelia influences early tumorigenesis. Here we show that the majority of newly formed oesophageal tumours are eliminated through competition with mutant clones in the adjacent normal epithelium. We followed the fate of nascent, microscopic, pre-malignant tumours in a mouse model of oesophageal carcinogenesis, finding most are rapidly lost with no indication of tumour cell death, decreased proliferation, or an anti-tumour immune response. However, deep-sequencing of 10-day and 1-year-old tumours showed evidence of genetic selection on the surviving neoplasms. Induction of highly competitive clones in transgenic mice increased early tumour removal, while pharmacologically inhibiting clonal competition reduced tumour loss. These results support a model where survival of early neoplasms depends on their competitive fitness relative to that of mutant clones in the surrounding normal tissue. Mutant clones in normal epithelium have an unexpected anti-tumorigenic role in purging early tumours through cell competition, thereby preserving tissue integrity.
Biosketch
Bartomeu Colom graduated in Biochemistry in 2002 and in Biology in 2004 from the University of the Balearic Islands in Spain, and obtained his PhD from the same University in 2007. He then moved to London to join the laboratory of Prof. Sussan Nourshargh at the William Harvey Research Institute (QMUL) as a postdoctoral researcher, where he studied the mechanisms regulating leukocyte migration into inflamed tissues. Since 2015 Bartomeu is a Senior Staff Scientist in the lab of Prof. Phil jones at the Sanger Institute in Cambridge, investigating how competition between mutant clones in the normal epithelium impacts on early tumorigenesis.