Nil Ege, The Institute of Cancer Research: Royal Cancer Hospital, UK

Pancreatic ductal adenocarcinoma (PDAC) is a devastating disease with poor prognosis and resistance to conventional chemotherapy remains the main challenge in PDAC treatment.  One explanation for the failure of drug discovery programs on pancreatic cancer is the use of physiologically irrelevant pre-clinical models lacking the complexity of the tumours observed in vivo. PDAC tumours are hetero-cellular system where cancer associated pancreatic stellate cells (PSCs) are highly abundant and contribute to a desmoplastic microenvironment influencing tumour progression and drug resistance.

To answer the need for more complex in vitro models, we have designed a hetero-cellular 3D screening model, co-culturing cancer cells with PSCs, and have managed to mimic the desmoplasia observed in PDAC tumours. Furthermore, we have successfully multiplexed several read-outs allowing us to differentiate mechanisms of action of compounds: cell death, metabolic arrest, spheroid growth and dispersion. By comparing results from monoculture (cancer cells only) and in coculture conditions, we are now able to detect stroma-mediated resistance and identify compounds showing activity even in presence of a desmoplastic stroma.  Selected hit compounds are then validated in a panel of PDAC cell lines and PSCs and target deconvolution is performed using proteomic-based approaches.

In conclusion, we have developed a reliable 3D large-scale phenotypic screen for PDAC, enabling the identification of novel targets and pathways of consequence as well as stroma-induced resistance mechanisms.