Histological fidelity and microenvironmental kinome signatures of metastatic patient-derived organoids

Metastatic cancer remains the greatest clinical challenge due to ineffective treatments and limited reliable models for drug testing. Patient-derived organoids (PDOs) and their subsequent culture as patient-derived-organoid xenograft (PDOX) tumours have transformed cancer research by replicating the genetic and histological characteristics of primary tumours. However, less focus has been given to metastatic tumours. Here, we investigated how well kinase signalling was conserved in PDOs grown from core-needle biopsies isolated from metastatic tumour lesions of five cancer patients. We further compared changes in kinase signalling when these PDOs were grown as metastatic PDOX tumours in mice. Strikingly, PDOs retained much kinase signalling observed in the original tumour. Even more remarkable was the ability of the metastatic PDOX tumours to match both the signalling and morphological features of the original biopsy. Cross-sample analysis revealed lost Src Family Kinase signalling in PDO cultures, highlighting the important influence of the tumour microenvironment on signalling and demonstrating this can be partially restored in the in vivo setting. Together, these studies support the use of PDOs and derived PDOX in mimicking and modelling human metastatic tumour biology.