Subcutaneous Inoculation of 3D Pancreatic Cancer Spheroids Results in Development of Reproducible Stroma-Rich Tumors

Mikhail Durymanov; Christian Kroll; Anastasia Permyakova; Elizabeth O'Neill; Raed Sulaiman; Michael Person; Joshua Reineke

doi:10.1016/j.tranon.2018.10.003

Subcutaneous Inoculation of 3D Pancreatic Cancer Spheroids Results in Development of Reproducible Stroma-Rich Tumors

Transl Oncol. 2019 Jan;12(1):180-189. doi: 10.1016/j.tranon.2018.10.003. Epub 2018 Oct 25.

Authors

Mikhail Durymanov¹, Christian Kroll¹, Anastasia Permyakova¹, Elizabeth O'Neill², Raed Sulaiman³, Michael Person⁴, Joshua Reineke⁵

Affiliations

¹ Department of Pharmaceutical Sciences, South Dakota State University, Brookings, SD.
² Avera Medical Group Oncology and Hematology, Sioux Falls, SD.
³ Department of Pathology and Laboratory Medicine, Avera McKennan Hospital, Sioux Falls, SD.
⁴ Surgical Institute of South Dakota, Sioux Falls, SD.
⁵ Department of Pharmaceutical Sciences, South Dakota State University, Brookings, SD. Electronic address: joshua.reineke@sdstate.edu.

Abstract

Pancreatic ductal adenocarcinoma (PDAC) is a deadly disease characterized by high expression of extracellular matrix in tumor tissue, which contributes to chemoresistance and poor prognosis. Here, we developed 3D pancreatic cancer spheroids, based on pancreatic cancer cells and fibroblast co-culture, which demonstrate innate desmoplastic properties and stay poorly permeable for model nanoparticles. Our study revealed that establishment of tumors by transplantation of spheroids significantly improved subcutaneous xenograft model of PDAC, which stays the most widely used animal model for testing of new drugs and drug delivery approaches. Spheroid based tumors abundantly produced different extracellular matrix (ECM) components including collagen I, fibronectin, laminin and hyaluronic acid. These tumors were highly reproducible with excellent uniformity in terms of ECM architecture recapitulating clinical PDAC tumors, whereas in more common cell based xenografts a significant intertumor heterogeneity in extracellular matrix production was found. Moreover, spheroid based xenografts demonstrated higher expression of pro-fibrotic and pro-survival PDAC hallmarks in opposite to cell based counterparts. We believe that future development of this model will provide an effective instrument for testing of anti-cancer drugs with improved predictive value.