Histological Fidelity and Microenvironmental Kinome Signatures of Metastatic Patient-Derived Organoids

Abstract

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) tumors have transformed cancer research by replicating the genetic and histological characteristics of primary tumors. However, less focus has been given to metastatic tumors. Here, we investigated how well kinase signaling was conserved in PDOs grown from core-needle biopsies isolated from metastatic tumors of five cancer patients. We further compared changes in kinase signaling when these PDOs were grown as metastatic PDOX tumors in mice. Strikingly, PDOs retained much kinase signaling observed in the original tumor. Even more remarkable was the ability of the metastatic PDOX tumors to match both the signaling and morphological features of the original biopsy. Cross-sample analysis revealed lost Src Family Kinase signaling in PDO cultures, highlighting the important influence of the tumor microenvironment on signaling 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 tumor biology.