Patient-Derived Xenograft Models for Pancreatic Adenocarcinoma Demonstrate Retention of Tumor Morphology through Incorporation of Murine Stromal Elements

Abstract

Direct implantation of viable surgical specimens provides a representative preclinical platform in pancreatic adenocarcinoma. Patient-derived xenografts consistently demonstrate retained tumor morphology and genetic stability. However, the evolution of the tumor microenvironment over time remains poorly characterized in these models. This work specifically addresses the recruitment and incorporation of murine stromal elements into expanding patient-derived pancreatic adenocarcinoma xenografts, establishing the integration of murine cells into networks of invading cancer cells. In addition, we provide methods and observations in the establishment and maintenance of a patient-derived pancreatic adenocarcinoma xenograft model. A total of 25 histologically confirmed pancreatic adenocarcinoma specimens were implanted subcutaneously into nonobese diabetic severe combined immunodeficiency mice. Patient demographics, staging, pathological analysis, and outcomes were analyzed. After successful engraftment of tumors, histological and immunofluorescence analyses were performed on explanted tumors. Pancreatic adenocarcinoma specimens were successfully engrafted in 15 (60%) of 25 attempts. Successful engraftment does not appear to correlate with clinicopathologic factors or patient survival. Tumor morphology is conserved through multiple passages, and tumors retain metastatic potential. Interestingly, despite morphological similarity between passages, human stromal elements do not appear to expand with invading cancer cells. Rather, desmoplastic murine stroma dominates the xenograft microenvironment after the initial implantation. Recruitment of stromal elements in this manner to support and maintain tumor growth represents a novel avenue for investigation into tumor-stromal interactions.

Interrogating open issues in cancer precision medicine with patient-derived xenografts

“…It is now well established that human tumour stromal cells are replaced by mouse counterparts following engraftment 155 . As a consequence of this substitution, species-specific RNA sequencing-based expression profiling of PDXs offers a unique opportunity to distinguish mouse stroma-derived transcripts from human cancer cell-derived transcripts without the need to physically separate the two components before RNA extraction.…”

Isolation of Pancreatic Cancer Cells from a Patient-Derived Xenograft Model Allows for Practical Expansion and Preserved Heterogeneity in Culture

“…21 Briefly, a viable portion of resected tissue 2 Â 2 mm in size was isolated immediately from surgically resected primary PC specimens with care to minimize critical ischemia time. PC tissue was then implanted subcutaneously into an 8-weekold female nonobese diabetic.Cg-Prkdc scid Il2rg tm1Wjl /SzJ (NSG) mouse (The Jackson Laboratory, Bar Harbor, ME).…”

“…17,21 Specifically, here, we demonstrate the expansion of human PCCs through a PDX model that preserves the tumor heterogeneity with a 100% success rate. These established PDX-derived primary cell lines display uniform markers associated with a human PC origin with retained tumorigenicity.…”

Patient-Derived-Tumor-Xenograft: modeling cancer for basic and translational cancer research

“…Tumor fragments used to establish PDTX models contain tumor and stromal cells, as well as the extracellular matrix. Human stroma is detectable in early passages, but it is completely replaced along transplantations by mouse stroma [25,51]. In fact, recent studies clearly demonstrated how murine cells functionally replaced human stroma to recreate malignant niches closely mimicking the original human tumor microenvironment.…”