Pancreatic ductal adenocarcinoma (PDAC) is an aggressive disease and patients diagnosed with PDAC have a very poor prognosis. It has been speculated that a rare population of cancer stem cells (CSCs) are responsible for tumor growth, therapy resistance, and rapid metastatic progression in PDAC. The purported CSC populations were discovered by in vitro clonogenic assays and transplantation assays in mice. However, their relevance in established PDAC tissue has not been determined. Importantly these assays were mostly dependent on the expression of a specific marker, therefore the functionality of cell populations not expressing these markers remained untested. A new study by Oncode Investigator Louis Vermeulen and co-investigators Sophie Lodestijn and Maarten Bijlsma (all Amsterdam UMC), published today in Cell Reports, changes that. Their results can have important implications for the treatment of PDAC.

In the study, the researchers used a method their group previously established, in which tumor cells were randomly labelled within an established tumor. The elegance of this method is the independence of a specific marker, in this way the properties of all tumor cells could be analyzed. Using the resulting clonal data in combination with quantitative modelling of tumor expansion, they were able to uncover the tissue growth dynamics of PDAC.

What they found is that all PDAC cells display clonogenic potential within an expanding tumor. Furthermore, the tumor cells that were in close proximity to activated cancer-associated fibroblasts showed higher clonogenicity. This indicates that the microenvironment drives clonogenic activity of PDAC cells. Indeed, inhibiting the stroma by Hedgehog pathway inhibition altered the tumor growth mode, resulting in inhibition of excessive clonal expansion (fewer large clones). This implies that tumor-stroma crosstalk shapes tumor growth dynamics and clonal architecture in PDAC.

“I hope our fundamental work will contribute to improved therapies for this lethal disease in the future” says Oncode Investigator Louis Vermeulen. The findings can have important implications for the treatment of PDAC. For instance, targeted therapy of cancer cells, based on phenotypic properties, are likely to fail, because non-clonogenic cells will become clonogenic when they gain access to the right niche, like being in close contact to activated fibroblasts. Therefore, changing the favourable clonogenic niche to a clonogenic restraining niche might be more effective to target cancer tissue and prevent regrowth of the malignancy by remaining cancer cells.

This work was supported by Oncode, Amsterdam UMC, KWF and the European Research Council.