Next Article in Journal
A Phase Ib Clinical Trial of Metformin and Chloroquine in Patients with IDH1-Mutated Solid Tumors
Previous Article in Journal
Thymic Carcinomas and Second Malignancies: A Single-Center Review
Article

Exploring the Complementarity of Pancreatic Ductal Adenocarcinoma Preclinical Models

1
Cancer Research Center of Marseille, CRCM, Inserm, CNRS, Paoli-Calmettes Institut, Aix-Marseille University, 13288 Marseille, France
2
Tumour Identity Card Program (CIT), French League Against Cancer, 75013 Paris, France
3
CTIBIOTECH, Cell Therapy Research Institute, 69330 Lyon, France
4
Centre Léon Bérard, 69008 Lyon, France
5
Ipsen Innovation, 91940 Les Ulis, France
6
Oncodesign, 21000 Dijon, France
7
Paoli-Calmettes Institut, 13009 Marseille, France
*
Authors to whom correspondence should be addressed.
Denotes co-corresponding authors.
Academic Editor: Marco J. Bruno
Cancers 2021, 13(10), 2473; https://doi.org/10.3390/cancers13102473
Received: 13 April 2021 / Revised: 8 May 2021 / Accepted: 11 May 2021 / Published: 19 May 2021
Pancreatic ductal adenocarcinoma (PDAC) patient care lacks well-established molecular characterization of the tumors, which would allow for better-personalized treatment selection if improved. To overcome this problem, preclinical models are frequent-ly adopted tools used to elucidate the molecular characterization of PDAC tumors. Unfortunately, the vast majority of studies using these preclinical models fail when transferred to patients despite initially promising results. This study presents for the first time a comparison between three preclinical matched models directly derived from patient tumors. We show that their applicability to preclinical studies should be considered with a complementary focus, avoiding tumor-based direct extrapolations, which might generate misleading conclusions and consequently the overlook of clinically relevant features. We finally highlight the importance of validating and refining predictive transcriptomic signatures using a combination of these models.
Purpose: Compare pancreatic ductal adenocarcinoma (PDAC), preclinical models, by their transcriptome and drug response landscapes to evaluate their complementarity. Experimental Design: Three paired PDAC preclinical models—patient-derived xenografts (PDX), xenograft-derived pancreatic organoids (XDPO) and xenograft-derived primary cell cultures (XDPCC)—were derived from 20 patients and analyzed at the transcriptomic and chemosensitivity level. Transcriptomic characterization was performed using the basal-like/classical subtyping and the PDAC molecular gradient (PAMG). Chemosensitivity for gemcitabine, irinotecan, 5-fluorouracil and oxaliplatin was established and the associated biological pathways were determined using independent component analysis (ICA) on the transcriptome of each model. The selection criteria used to identify the different components was the chemosensitivity score (CSS) found for each drug in each model. Results: PDX was the most dispersed model whereas XDPO and XDPCC were mainly classical and basal-like, respectively. Chemosensitivity scoring determines that PDX and XDPO display a positive correlation for three out of four drugs tested, whereas PDX and XDPCC did not correlate. No match was observed for each tumor chemosensitivity in the different models. Finally, pathway analysis shows a significant association between PDX and XDPO for the chemosensitivity-associated pathways and PDX and XDPCC for the chemoresistance-associated pathways. Conclusions: Each PDAC preclinical model possesses a unique basal-like/classical transcriptomic phenotype that strongly influences their global chemosensitivity. Each preclinical model is imperfect but complementary, suggesting that a more representative approach of the clinical reality could be obtained by combining them. Translational Relevance: The identification of molecular signatures that underpin drug sensitivity to chemotherapy in PDAC remains clinically challenging. Importantly, the vast majority of studies using preclinical in vivo and in vitro models fail when transferred to patients in a clinical setting despite initially promising results. This study presents for the first time a comparison between three preclinical models directly derived from the same patients. We show that their applicability to preclinical studies should be considered with a complementary focus, avoiding tumor-based direct extrapolations, which might generate misleading conclusions and consequently the overlook of clinically relevant features. View Full-Text
Keywords: pancreatic cancer; chemosensitivity prediction; personalized medicine; in vivo models; in vitro models pancreatic cancer; chemosensitivity prediction; personalized medicine; in vivo models; in vitro models
Show Figures

Figure 1

MDPI and ACS Style

Hoare, O.; Fraunhoffer, N.; Elkaoutari, A.; Gayet, O.; Bigonnet, M.; Roques, J.; Nicolle, R.; McGuckin, C.; Forraz, N.; Sohier, E.; Tonon, L.; Wajda, P.; Boyault, S.; Attignon, V.; Tabone-Eglinger, S.; Barbier, S.; Mignard, C.; Duchamp, O.; Iovanna, J.; Dusetti, N.J. Exploring the Complementarity of Pancreatic Ductal Adenocarcinoma Preclinical Models. Cancers 2021, 13, 2473. https://doi.org/10.3390/cancers13102473

AMA Style

Hoare O, Fraunhoffer N, Elkaoutari A, Gayet O, Bigonnet M, Roques J, Nicolle R, McGuckin C, Forraz N, Sohier E, Tonon L, Wajda P, Boyault S, Attignon V, Tabone-Eglinger S, Barbier S, Mignard C, Duchamp O, Iovanna J, Dusetti NJ. Exploring the Complementarity of Pancreatic Ductal Adenocarcinoma Preclinical Models. Cancers. 2021; 13(10):2473. https://doi.org/10.3390/cancers13102473

Chicago/Turabian Style

Hoare, Owen, Nicolas Fraunhoffer, Abdessamad Elkaoutari, Odile Gayet, Martin Bigonnet, Julie Roques, Rémy Nicolle, Colin McGuckin, Nico Forraz, Emilie Sohier, Laurie Tonon, Pauline Wajda, Sandrine Boyault, Valéry Attignon, Séverine Tabone-Eglinger, Sandrine Barbier, Caroline Mignard, Olivier Duchamp, Juan Iovanna, and Nelson J. Dusetti. 2021. "Exploring the Complementarity of Pancreatic Ductal Adenocarcinoma Preclinical Models" Cancers 13, no. 10: 2473. https://doi.org/10.3390/cancers13102473

Find Other Styles
Note that from the first issue of 2016, MDPI journals use article numbers instead of page numbers. See further details here.

Article Access Map by Country/Region

1
Back to TopTop