Cell Stem Cell 22, 454–467 (2018).

Pancreatic ductal adenocarcinoma (PDAC) is highly chemoresistant due to extensive mutational heterogeneity and a dense stromal environment. As some patients benefit more from current therapies than others, there is a need to characterise and stratify individual tumours to predict clinical responses. Sato and colleagues used patient-derived PDAC organoids to recapitulate cancer features, modulate them and study tumour dependence on the niche.

The authors established a library of 39 PDAC-derived organoid lines, assessed driver gene mutations and, using xenografts, confirmed resemblance to parental tumours. They found that different driver gene mutations initiated the requirement of different niche factors to sustain organoid growth.

Three functional PDAC organoid subtypes were identified based on their reliance on Wnt ligands from the niche. Cancer-associated fibroblasts could act as ligand sources for PDAC organoids that critically depended on them, as demonstrated by co-transplantation experiments. A subtype that cell-autonomously expressed epithelial Wnts was niche-independent and associated with a more aggressive phenotype. PDAC organoids could acquire Wnt niche independency by downregulating GATA6, which initiated epithelial Wnt expression. Using engineered organoids with four PDAC driver mutations alone or in combination, acquisition of mutation-specific niche independence could be verified.

This study elegantly demonstrates the value of organoids as functional platforms to study adaptive responses and progression of pancreatic tumours with different molecular profiles.