3D pancreatic carcinoma spheroids induce a matrix-rich, chemoresistant phenotype offering a better model for drug testing
Open accessAbstract
Background: Pancreatic ductal adenocarcinoma (PDAC) is the fourth most common cause of cancer related death. It is lethal in nearly all patients, due to an almost complete chemoresistance. Most if not all drugs that pass preclinical tests successfully, fail miserably in the patient. This raises the question whether traditional 2D cell culture is the correct tool for drug screening. The objective of this study is to develop a simple, high-throughput 3D model of human PDAC cell lines, and to explore mechanisms underlying the transition from 2D to 3D that might be responsible for chemoresistance. Methods: Several established human PDAC and a KPC mouse cell lines were tested, whereby Panc-1 was studied in more detail. 3D spheroid formation was facilitated with methylcellulose. Spheroids were studied morphologically, electron microscopically and by qRT-PCR for selected matrix genes, related factors and miRNA. Metabolic studies were performed, and a panel of novel drugs was tested against gemcitabine. Results: Comparing 3D to 2D cell culture, matrix proteins were significantly increased as were lumican, SNED1, DARP32, and miR-146a. Cell metabolism in 3D was shifted towards glycolysis. All drugs tested were less effective in 3D, except for allicin, MT100 and AX, which demonstrated effect. Conclusions: We developed a high-throughput 3D cell culture drug screening system for pancreatic cancer, which displays a strongly increased chemoresistance. Features associated to the 3D cell model are increased expression of matrix proteins and miRNA as well as stromal markers such as PPP1R1B and SNED1. This is supporting the concept of cell adhesion mediated drug resistance.
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Ex vivo 3D models of tumor growth are being increasingly adopted, as a number of comparative studies between 3D spheroids and 2D monolayer cultures have shown that 3D culture more faithfully recapitulates in vivo biology.
“Ex vivo 3D models of tumor growth are being increasingly adopted, as a number of comparative studies between 3D spheroids and 2D monolayer cultures have shown that 3D culture more faithfully recapitulates in vivo biology38–40.”
From Occult polyclonality of preclinical pancreatic cancer models drives in vitro evolution (2022) · cites this paper as [40]
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- Authors
- Longati, P., Jia, X., Eimer, J., Wagman, A., Witt, M.-R., Rehnmark, S., Verbeke, C., Toftgård, R., Löhr, M., & Heuchel, R. L.
- Affiliations
- Karolinska Institutet (SE)
- Axcentua (Sweden) (SE)
- Corresponding author
- Löhr, Matthias
- Venue
- BMC Cancer
- Published
- 2013-02-27
- Volume
- 13
- Issue
- 1
- Pages
- 95-95
- ISSN
- 1471-2407 (ISSN-L)
- PMC
- PMC3617005
- OpenAlex
- W2057280155
- Cited by
- 394
- References
- 60
- Citations by year
- 2026: 17 · 2025: 27 · 2024: 28 · 2023: 19 · 2022: 30 · 2021: 39 · 2020: 51 · 2019: 38 · 2018: 34 · 2017: 34 · 2016: 32 · 2015: 19 · 2014: 20 · 2013: 5 · 2012: 1
- FWCI
- 13.48
- Type
- journal article
- Language
- en
- Open access
- gold
- doi.org
- Licence
- Locations
- BMC Cancer (publishedVersion, cc-by)
- Europe PMC (PubMed Central) (publishedVersion, cc-by)
- PubMed Central (publishedVersion, cc-by)
- PubMed (publishedVersion)
- Funders
- Cancerfonden
- Nella and Leon Benoziyo Center for Neurological Diseases, Weizmann Institute of Science
- Karolinska Institutet
- Vetenskapsrådet
- Topics
- Health Sciences › Medicine › Oncology › Pancreatic and Hepatic Oncology Research
- Health Sciences › Medicine › Oncology › Cancer Cells and Metastasis
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Cell Biology › Cellular Mechanics and Interactions
- Keywords
- pancreatic ductal adenocarcinoma, multicellular spheroids, chemoresistance, gemcitabine, drug screening, extracellular matrix, miR-146a, DARPP-32, cell adhesion, glycolysis, stroma, PANC-1 cells, KPC mouse model, allicin
- MeSH terms
- Animals, Antineoplastic Agents, Disease Models, Animal, Drug Screening Assays, Antitumor, Energy Metabolism, Humans, Pancreatic Neoplasms, Phenotype, Tumor Cells, Cultured, Extracellular Matrix Proteins, Spheroids, Cellular, Drug Resistance, Neoplasm, Lactic Acid, Carcinoma, Pancreatic Ductal, Cell Line, Tumor, Mice
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