A combinatorial culture strategy to develop pseudomyxoma peritonei organoid models

Abstract

Appendiceal tumors; Organoids; Pseudomyxoma peritonei

Tumors apendiculars; Organoides; Pseudomixoma peritonei

Tumores apendiculares; Organoides; Pseudomixoma peritoneal

Background and Objectives Few preclinical models of pseudomyxoma peritonei (PMP) have been developed, probably due to the tumor's low incidence and its peculiar characteristics of slow growth. Therefore, there is a need to develop more refined PMP models that better reflect its characteristics. The aim of the study is to develop a culture strategy to generate organoid models derived from PMP patient samples. Methods We followed a strategy based on combinatorial culture conditions that include the different factors essential for PMP growth and that mimic the microenvironment present in the patients. Results We cultured PMP samples in the presence of the various factors produced by the niche environment of PMP. We obtained 12 PMP organoid models, each of which grows under specific culture conditions. PMP-derived organoids show long-term expansion capacity and reproduce the genetic landscape and histological phenotype of the tumor of origin. Conclusion The organoids we developed faithfully reproduce the key features of PMP disease and will allow us to understand the biology of PMP. With them, we will be able to identify key regulatory networks that support PMP progression, providing a platform for multilevel preclinical testing, identify novel diagnostic biomarkers, and generate novel targets for patient treatments.

We are grateful to Drs. Federica Perrone, Elena Conca, Adele Busico, and Iolanda Capone for their help in the NGS analyses, and thank the patients for participating in the study. This work was supported by Accelerator Award 2019 AIRC 24285 to M. D. and M. G., AIRC IG 27619 to S. K., Ministry of Health Ricerca Corrente funds, and 5xmille funds for healthcare research. Open access funding provided by BIBLIOSAN.