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ID: 682 (Conflict of Interest: K)

Detaillierte molekulare Charakterisierung des duktalen Adenokarzinom des Pankreas basierend auf primären Tumor-Organoiden

S. Le Blanc1, T. Bauer1, N. Ishaque2, S. Schuth1, A.-K. König1, M. Volkmar1, M. Schenk1, J. Jabs1, N. Giese1, R. Offringa1, C. Conrad1, M. W. Büchler1, M. Schlesner1, R. Eils2, O. Strobel1
1Universitätsklinikum Heidelberg, Heidelberg
2Charité - Unversitätsmedizin Berlin - CBF, Berlin

Einleitung

Pancreatic ductal adenocarcinoma (PDAC) is an aggressive tumor with poor prognosis. Due to low tumor cellularity and high content of stroma, molecular characterization of PDAC by next generation sequencing approaches is extremely challenging. Tumor organoids have emerged as models that reflect the genetic complexity of human cancers, which can be used to overcome the limitations of whole genome sequencing (WGS) and RNAseq analyses of PDAC tumors.

Material und Methoden

PDAC organoid cultures were generated from surgically resected tumors using an adaptation of the protocol described by Boj et al. (2015). Morphological analyses, WGS and RNAseq were performed. For selected cases, matching primary tumors were analyzed for comparison.

Ergebnisse

We have established 50 PDAC organoid lines from 43 patients that underwent surgical resection. Comparisons of organoids with matching original tumors suggest that organoids are genetically representative of the original tumor. WGS analyses revealed several recurrently altered genes, mainly affected by copy number alterations and structural variations, which have not been previously described as frequently altered in PDAC. According to transcriptomic analysis, classical and basal-like subtypes remain reflected in organoids. The high tumor cell purity of PDAC organoids allows to directly relate genomic alterations to RNA expression levels, which can be used to identify candidates for precision therapies without the contaminating effects of non-tumor cells.

Schlussfolgerung

Patient-derived organoids deepen our understanding of the molecular landscape of PDAC and offer the potential to identify patient-specific vulnerabilities that may be exploitable for personalized cancer therapy. The organoid repository offers the opportunity to functionally validate candidate targets by in vitro drug sensitivity testing.