Organoid Models of Human and Mouse Ductal Pancreatic Cancer

Abstract

SUMMARY Pancreatic cancer is one of the most lethal malignancies due to its late diagnosis and limited response to treatment. Tractable methods to identify and interrogate pathways involved in pancreatic tumorigenesis are urgently needed. We established organoid models from normal and neoplastic murine and human pancreas tissues. Pancreatic organoids can be rapidly generated from resected tumors and biopsies, survive cryopreservation and exhibit ductal- and disease stage-specific characteristics. Orthotopically transplanted neoplastic organoids recapitulate the full spectrum of tumor development by forming early-grade neoplasms that progress to locally invasive and metastatic carcinomas. Due to their ability to be genetically manipulated, organoids are a platform to probe genetic cooperation. Comprehensive transcriptional and proteomic analyses of murine pancreatic organoids revealed genes and pathways altered during disease progression. The confirmation of many of these protein changes in human tissues demonstrates that organoids are a facile model system to discover characteristics of this deadly malignancy.

Concepts to Target MYC in Pancreatic Cancer

“…However, testing of these findings in novel human cancer models reflecting the whole heterogeneity spectrum of the disease is necessary. Here, the recent development of human organoid PDAC models (82,83) will provide an appropriate platform to further develop MYC inhibitors and MYC-based therapeutic concepts in human disease models.…”

Organoids reveal cancer dynamics

“…Organoid techniques were initially developed to grow normal tissues in vitro in 3D, but have proved equally useful for propagating clinical tumour specimens [8][9][10][11][12] . Roerink et al set out to examine intratumoral hetero geneity using organoids.…”

“…The authors used genetically engineered mice that provide a model system in which to study skin carcinoma and have tumour cells 10 that are known to exhibit EMT. Pastushenko et al studied cells that had lost expression of the epithelial-cell marker EpCAM, and analysed the expression of more than 170 cell-surface proteins to try to identify useful markers of cell subpopulations.…”

Functional Optical Imaging of Primary Human Tumor Organoids: Development of a Personalized Drug Screen

“…Hundreds to thousands of organoids can be generated from a single biopsy or resected tumor section, enabling medium-to high-throughput testing of potential drugs, drug combinations, and drug doses. (Additional details on organoids can be found in reviews by Boj et al (5) and Fatehullah et al (6). )…”