Oncogenic competence during development – When, Where and Why?

Introduction

Childhood cancers are believed to be rooted in aberrant development, a notion supported by their:

1. Generally low mutational burden
2. High prevalence of single (often epigenetic) driver events
3. Occurrence during confined developmental periods

Yet, the exact origins of developmental tumours remain one of the principal enigmas of pediatric oncology.

Malignant Rhabdoid Tumours

A prime example are malignant rhabdoid tumours (MRTs): they are astoundingly genomically simple but extremely deadly childhood cancers that arise almost exclusively in the first two years of life. MRTs are driven by biallelic inactivation of the SWI/SNF chromatin remodelling complex subunit SMARCB1 (>95% of cases).

Research Questions

We still do not know what determines oncogenic competence upon SMARCB1 loss. In particular, we wonder:

1. What are the cell(s)-of-origin of rhabdoid tumours and what is their normal differentiation potential?
2. What is the molecular framework that facilitates oncogenic transformation upon SMARCB1 loss?
3. What is the contribution of the niche (local and systemic) to the acquisition of oncogenic competence?
4. Considering the epigenetic nature of the oncogenic event, is the oncogenic MRT state reversible, and how?

Methodology

To answer these questions, we will combine state-of-the-art lineage-barcoded single-cell genomics, spatial transcriptomics, single-cell resolution wholemount imaging, CRISPR/Cas9 and epigenomic approaches, as well as integrative computational analyses, using transgenic mouse, induced pluripotent stem cell and patient-derived xenograft rhabdoid tumour models.

Expected Outcomes

This project will provide fundamental insights into the cell autonomous and non-autonomous determinants of oncogenic competence upon SMARCB1 loss. Based on our findings, we hope to unlock targeted treatments for MRT patients. Importantly, the conceptual and experimental framework we establish will open up new investigative opportunities for a multitude of developmental cancers.