Abstract 4272: Organoids and patient-derived tumor xenograft of pancreatic adenocarcinoma share morphological and genetic features with the primary tumor
Authors: Romero Calvo Isabel , Akki Ashwin , Ugolkov Andrey , Buschmann Mary M. , Sparrow Samantha M. , Barry Teresa , Eber Margaret , Gu Tongjun , Zhang Shuang Qin , Kindler Hedy , Dale William , Roggin Kevin , Mazar Andrew P. , White Kevin P. , Weber Christopher R. 
Published: July 2016

Abstract
Pancreatic ductal adenocarcinoma (PDAC) is the fourth leading cause of cancer death, with a 5-year overall survival rate &lt;7%. Several active systemic therapies are now available for PDAC. Personalizing therapy may be improved with the development of realistic tumor models from a patient's explanted tumoral tissue. Human pancreatic tumor patient-derived xenografts (PDX) implanted into immunodeficient mice and tumor organoids grown in vitro 3D culture are two promising models. However, it is uncertain if these models are histopathologically and genetically similar to the primary PDAC.
Histopathological comparison of sections from PDX tumor, organoids, and primary PDAC from a 63-year-old female patient were performed on paraffin embedded tissue. H&E and immunohistochemical staining for cytokeratins (CK7, CK20), p53, Claudin-4, and CEA were performed. DNA and mRNA sequencing was performed. Both PDX and organoids exhibited histopathological features remarkably consistent with the original patient tumor including the histologic grade (moderately differentiated), cytological appearance (irregular nuclear membranes, open chromatin and prominent nucleoli), mitotic activity (5 -7/10 HPF), and immunohistochemical profile. The PDX and organoids demonstrated diffuse moderate-to-strong positivity for CK7, CEA, p53, and Claudin-4 and focal weak positivity for CK20 - all similar to the primary tumor. The immunohistochemical staining pattern was consistent with mRNA sequencing of the primary tumor which showed that CEA, Claudin-4 and p53 expression were ∼960-fold, ∼27-fold and ∼3 fold higher respectively (vs. benign pancreatic tissue). DNA sequencing revealed somatic mutations in KRAS and TP53 genes seen in &gt;90% and ∼70% of PDACs respectively, and a few rare somatic mutations, such as a sodium leak channel (NALCN) mutation, seen in ∼3% of PDAC.
Both PDX and organoid models of PDAC maintain key histological features, immunohistochemical profile and basic gene expression pattern akin to the primary tumor. These findings suggest that PDXs and organoids have the potential to serve as reliable pathophysiological models for optimizing individual therapy for patients with PDAC.
Citation Format: Isabel Romero Calvo, Ashwin Akki, Andrey Ugolkov, Mary M. Buschmann, Samantha M. Sparrow, Teresa Barry, Margaret Eber, Tongjun Gu, Shuang Qin Zhang, Hedy Kindler, William Dale, Kevin Roggin, Andrew P. Mazar, Kevin P. White, Christopher R. Weber. Organoids and patient-derived tumor xenograft of pancreatic adenocarcinoma share morphological and genetic features with the primary tumor. [abstract]. In: Proceedings of the 107th Annual Meeting of the American Association for Cancer Research; 2016 Apr 16-20; New Orleans, LA. Philadelphia (PA): AACR; Cancer Res 2016;76(14 Suppl):Abstract nr 4272.