A team of researchers has developed a laboratory system to dissect pre-cancerous steps that previously remained undetectable.
The tumour microenvironment
The tumour microenvironment (TME) is a complex ecosystem that comprises of mutant and wild-type cells, as well as endothelial, immune and mesenchymal cells. During the earliest phases of tumour initiation, the TME has to adapt to signals from tumour cells. However, our understanding of how these changes impact non-malignant cells is still unclear.
Most of our understanding from this space comes from studies in Drosophila. Studies have shown that wild-type cells eliminate less ‘fit’ cells through cell competition. Whereas, tumour cells with driver mutations become ‘super-competitors’ and eliminate their wild-type neighbours. Studying the crosstalk between mutant and wild-type cells in mammals has proven difficult. Various mosaic labelling approaches have had limited potential.
Tracing mutant and wild-type cells
To circumvent these barriers, researchers developed an oncogene-associated, multicolour report mouse model – Red2Onco system. This system allows differential tracing of mutant and wild-type cells in the same tissue.
In their study, published in Nature, researchers applied the system to the small intestine. They showed that oncogene-expressing mutant crypts altered the cellular organisation of neighbouring wild-type crypts. This accelerated clonal drift, whereby wild-type clones are lost. They specifically studied the mechanisms initiated by two separate first oncogenic hits – KRAS and PI3K. Here, that found that crypts expressing these oncogenes secreted BMP (Bone Morphogenic Protein) ligands that suppressed local stem cell activity. This consequently favoured the expansion of oncogenic mutant stem cells and their progenies.
First author, Min Kyu Yum of the Gurdon Institute, explained:
“Oncogenic mutant cells influence the fate behaviour of their wild-type neighbours both directly, through secretion of signalling factors, and indirectly through induced changes in the shared tissue environment.”
Together, these findings show that oncogene-driven remodelling creates a niche environment that has a negative impact of the maintenance of wild-type tissue, while promoting dominance of oncogenic clones. Their discovery also paves the way for intervention strategies that target important crosstalk mechanisms, such as inhibiting BMP.
Image credit: By JOSE LUIS CALVO MARTIN & JOSE ENRIQUE GARCIA-MAURIÑO MUZQUIZ – canva