Whole genomes define concordance of matched primary, xenograft, and organoid models of pancreas cancer

Abstract

Pancreatic ductal adenocarcinoma (PDAC) has the worst prognosis among solid malignancies and improved therapeutic strategies are needed to improve outcomes. Patient-derived xenografts (PDX) and patient-derived organoids (PDO) serve as promising tools to identify new drugs with therapeutic potential in PDAC. For these preclinical disease models to be effective, they should both recapitulate the molecular heterogeneity of PDAC and validate patient-specific therapeutic sensitivities. To date however, deep characterization of the molecular heterogeneity of PDAC PDX and PDO models and comparison with matched human tumour remains largely unaddressed at the whole genome level. We conducted a comprehensive assessment of the genetic landscape of 16 whole-genome pairs of tumours and matched PDX, from primary PDAC and liver metastasis, including a unique cohort of 5 ‘trios’ of matched primary tumour, PDX, and PDO. We developed a pipeline to score concordance between PDAC models and their paired human tumours for genomic events, including mutations, structural variations, and copy number variations. Tumour-model comparisons of mutations displayed single-gene concordance across major PDAC driver genes, but relatively poor agreement across the greater mutational load. Genome-wide and chromosome-centric analysis of structural variation (SV) events highlights previously unrecognized concordance across chromosomes that demonstrate clustered SV events. We found that polyploidy presented a major challenge when assessing copy number changes; however, ploidy-corrected copy number states suggest good agreement between donor-model pairs. Collectively, our investigations highlight that while PDXs and PDOs may serve as tractable and transplantable systems for probing the molecular properties of PDAC, these models may best serve selective analyses across different levels of genomic complexity.

Organoids from the Human Fetal and Adult Pancreas

“…Moreover, tumor-specific drug responses could be evaluated in assays, with an in vivo differential drug response to drug treatments of patient-derived xenografts that could be recapitulated in vitro with matched PDAC organoids [81]. These comparative results are in line with findings obtained by other groups that have compared PDAC organoids with the primary tumor and patient-derived xenograft models [38••, 82], and drug sensitivity studies performed by other groups on mouse and human PDAC organoids [38••, 83, 84••]. Novel tools have also been developed to assess drug response of PDAC organoids.…”

The fidelity of cancer cells in PDX models: Characteristics, mechanism and clinical significance

“…In addition, the dominant mutations in these genes correlated with the poor prognosis of donor patients . Genomic rearrangements and CNAs in xenograft tumors were positively correlated with metastasis in patients and were identical in comparisons of metastasis‐PDX pairs . The selective pressure in immunodeficient mice, neutral genetic drift and de novo events may contribute to genomic alterations, as observed in PDX tumors.…”

“…In addition, both genome‐wide and chromosome‐specific SV showed poor agreement between most parental tumor–PDX pairs. In chromosomes with chromothripsis, the rearrangement of clusters of SVs appeared to be different between tumors and matched PDX models …”

“…At the chromosomal level, aneuploidy and structural variations (SVs) are deviated in xenograft tumors. Polyploidization events have been found in several pancreatic ductal adenocarcinoma (PDAC) PDX models, which eventually resulted in the exclusion of these samples from the study . In addition, both genome‐wide and chromosome‐specific SV showed poor agreement between most parental tumor–PDX pairs.…”

An Organotypic Microcosm for the Pancreatic Tumor Microenvironment

“…PDAC organoids also harbor pancreatic cancer markers CK7, CK19, P53, and lack of CK20, consistent with paired tumor tissues [12,13]. Furthermore, organoids are representative models of the genetic landscape of the tumor of origin and have been indicated as a beneficial drug sensitivity model for PDAC patients [17,18]. Organoids serve as a valuable model for translational cancer research.…”