GIGA-Conference

Where cancer phenotypes come from and how to make them go away

Gerard Evan (Cambridge, UK)


Infos

Dates
26th February - 12:30
Lieu
Léon Fredericq Auditorium
Durée
1h
Horaires
12:30-13:30

Where cancer phenotypes come from and how to make them go away

Gerard I. Evan, Trevor Littlewood, Roderik Kortlever, Nicole Sodir, Luca Pellegrini, Cathy Wilson and Tania Campos, Department of Biochemistry and CR UK Cambridge Cancer Centre, University of Cambridge, Europe

https://www.bioc.cam.ac.uk/research/uto/evan

Adult cancers arise through random mutation exhibit and consequently exhibit astonishing genetic diversity. This has occasioned huge efforts to catalogue and categorize them and, on the basis of their idiosyncrasies, develop tailored precision therapies. However, a preoccupation with the differences between, and within, cancers overlooks the equally remarkable fact that cancers of a particular tissue type exhibit great similarity in the way they look, behave and respond to therapy. Such phenotypic commonality suggests they share a common underpinning evolution and oncogenic mechanism that may indicate common therapeutic vulnerabilities. To explore the source of this tissue-specific commonality, we have developed switchable genetic mouse models that allow for the real time reversible toggling of Ras and Myc function in the epithelial compartments of different target tissues in vivo. However, over 30 years on from the discovery of Ras/Myc cooperation, there is still no consensus as to the mechanisms that underlie that cooperation. Oncogenic Ras and Myc are each, alone, weak oncogenes but when combined they potently synergize to drive tumourigenesis. The oncogenic capacity of Ras+Myc is tissue-agnostic, driving tumourigenesis in all tested tissues and indicating that they interact with a common, tissue-independent interface. However, the tumours they induce are distinct in each target tissue type and, moreover, perfectly phenocopy spontaneous cancers, with all their diverse oncogenic mutations, that arise in those same tissues. Hence, the signature phenotypes of cancers of different tissues of origin are inherent properties of each cell/tissue type, not of the oncogenes driving them. Moreover, those same complex tumour phenotypes are engaged by a single, common, Myc oncogenic switch. The reason for such tissue specificity is that Myc “hacks” the regenerative programme of each tissue type used to rebuild after injury. Furthermore, by toggling Myc function on and off in the epithelial compartment of tumours in lung, pancreas and liver, we can disentangle the plethora of tissue-specific effector signals and stromal programmes by which Myc drives and maintains each tumour type: Myc induces instructive signals in tumour epithelia that immediately engage tissue-resident inflammatory, immune suppressive and stromal remodelling programmes. Remarkably, subsequent blockade of Myc triggers immediate tumour regression through meticulous dismantling of each complex tumour phenotype. It appears that turning Myc off hacks tissue-resident physiological programmes that resolve and “re-normalize” tissue after injury-induced regeneration. Hence, not only is tumour formation driven by a unitary common switch but so too is tumour regression.

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