Cecilia Toscani

Colorectal cancer arises from a multi-step process leading to the progressive accumulation of genetic and epigenetic mutations, causing deregulation in homeostasis and neoplastic transformation. Epigenetic and genetic alterations are able to induce a constitutive activation of the WNT signaling pathway, whose aberrant activity converges into deregulation of proliferation, differentiation and cell death pathways. Despite this knowledge of aberrant WNT activity, upstream interference with this signaling pathway induces adverse effects due to high cross-talk with other pathways, highlighting a need to find alternative ways to indirectly target the effectors of this pathway.

In recent years, several studies have been focused on epigenetic players, which act by depositing specific and reversible post-translational modifications. For this reason, they are being recognized as promising new targets for the development of cancer therapeutic strategies. In this context, my project takes advantage of 3D intestinal organoid cultures carrying oncogenic deregulations of the WNT pathway, as a platform for pooled and arrayed RNA interference screens to identify novel regulators controlling the transcriptional aspect of this oncogenic pathway. I also implemented the validation of selected targets in human metastatic colorectal cancer organoids to highlight their clinical relevance. Finally, this project generated important technical knowledge through this pioneering approach that will open up the possibility of performing functional screens in other tissues from which organoid cultures have already been established.