Title: OncoLive | Optogenetic control and measurement of oncogenic mutations and signalling in organoid cultures for the biophysical modelling of early oncogenesis
Funder: Cancer Research UK

Abstract: Tumour initiation is a process of sequential genetic and biochemical alterations occurring over time in a three-dimensional environment. However, cooperation and competition of cellular populations within a living tissue are also fundamental, yet not fully understood, mechanisms underlying tumour initiation and promotion. Therefore, more accurate observations and modelling of these heterogeneous cellular populations are of strategic importance for the understanding of cancer and, consequently, to design future therapeutic interventions. Unfortunately, techniques typically used for in vivo cell tracing often present critical limitations: i) phototoxicity constrains time resolution and observational times, ii) the occurrence of oncogenic events in defined places and times within a tissue is extremely difficult to control and iii) how communication between different populations of cells contributes towards mutant cell competition is arduous to characterize. OncoLive will integrate a three-dimensional organoid culturing system, cell genetics, optogenetic, biochemical imaging and light-sheet microscopy to control and visualize the early steps leading to oncogenic transformation. Our working hypothesis is that cooperation and competition between different mutant clonal populations contribute towards oncogenic tissue transformation and we will attempt to test this hypothesis by investigating clonal fitness, cellular cross-talk and cell fate dynamics within a three-dimensional culture controlling oncogenic events in space and time, as well as the cellular response to specific signalling cues. Our combined expertise will provide the means to overcome existing methodological barriers and thus offer new insights about oncogenesis. The study of cooperation and competition between heterogeneous cell populations during early stages of tumour formation is of fundamental importance to inform the community on how to better target tumour prevention and therapeutic strategies.

Lay abstract: Tumour initiation is a process of sequential genetic and biochemical alterations occurring over time in a three-dimensional environment. However, cooperation and competition of cellular populations within a living tissue are also fundamental, yet not fully understood, mechanisms underlying tumour initiation and promotion. Therefore, more accurate observations and modelling of these heterogeneous cellular populations are of strategic importance for the understanding of cancer and, consequently, to design future therapeutic interventions. Unfortunately, techniques typically used for in vivo cell tracing often present critical limitations: i) phototoxicity constrains time resolution and observational times, ii) the occurrence of oncogenic events in defined places and times within a tissue is extremely difficult to control and iii) how communication between different populations of cells contributes towards mutant cell competition is arduous to characterize. OncoLive will integrate a three-dimensional organoid culturing system, cell genetics, optogenetic, biochemical imaging and light-sheet microscopy to control and visualize the early steps leading to oncogenic transformation. Our working hypothesis is that cooperation and competition between different mutant clonal populations contribute towards oncogenic tissue transformation and we will attempt to test this hypothesis by investigating clonal fitness, cellular cross-talk and cell fate dynamics within a three-dimensional culture controlling oncogenic events in space and time, as well as the cellular response to specific signalling cues. Our combined expertise will provide the means to overcome existing methodological barriers and thus offer new insights about oncogenesis. The study of cooperation and competition between heterogeneous cell populations during early stages of tumour formation is of fundamental importance to inform the community on how to better target tumour prevention and therapeutic strategies.

Research activity codes: 2.1 BIOLOGICAL AND ENDOGENOUS FACTORS;2.6 RESOURCES AND INFRASTRUCTURE (AETIOLOGY)
Health categories: CANCER AND NEOPLASMS