Mice, organoids and single cells: computational methods for cancer treatment

Hereditary Diffuse Gastric Cancer (HDGC) affects hundreds of people in New Zealand, many from Māori families. An inherited mutation in the E-cadherin gene (CDH1) is a strong driver of HDGC, affecting individuals as young as 15 years old. A promising way of combatting HDGC involves finding a synthetic lethal (SL) partner to the HDGC-defining gene, CDH1. Synthetic lethality is defined as a specific relationship between two genes where a loss of one is tolerated by the cell but the loss of both is lethal. An innovative way of mixing computational approaches with experimental data offers a method of identifying a range of prospective drug targets and treatments. Generation of mouse gastric organoids (simplified versions of a mouse stomach produced from mouse stem cells with a micro-anatomy that is close to that of a real stomach) with and without CDH1 loss, provide a realistic model for HDGC, and single-cell RNA sequencing (scRNA-seq) then provides whole-transcriptome data for these organoid samples. Here I will present an analysis of the organoid scRNA-seq data, utilizing linkage to existing SL gene and pathway data (including siRNA studies done previously in our lab) as well as integration of publicly accessible data sets derived from patient tumours.