{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,3,9]],"date-time":"2026-03-09T02:33:59Z","timestamp":1773023639399,"version":"3.50.1"},"reference-count":70,"publisher":"MDPI AG","issue":"1","license":[{"start":{"date-parts":[[2020,12,22]],"date-time":"2020-12-22T00:00:00Z","timestamp":1608595200000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"name":"Joint Project 2017 University of Verona","award":["none"],"award-info":[{"award-number":["none"]}]},{"name":"Ministero dell\u2019Istruzione, dell\u2019Universit\u00e0 e della Ricerca (MIUR)","award":["none"],"award-info":[{"award-number":["none"]}]},{"name":"European Union\u2019s Horizon 2020 research and innovation programme under the Marie Sk\u0142odowska-Curie","award":["813834"],"award-info":[{"award-number":["813834"]}]},{"name":"pHioniC - H2020-MSCA-ITN-2018","award":["754345"],"award-info":[{"award-number":["754345"]}]},{"name":"PRIN-2017 \u201cLioness\u201d from Italian Ministry for Education, University and Research (MIUR)","award":["none"],"award-info":[{"award-number":["none"]}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["IJMS"],"abstract":"<jats:p>Background: Pancreatic ductal adenocarcinoma (PDAC) is a highly lethal disease. Gemcitabine (GEM) is used as the gold standard drug in PDAC treatment. However, due to its poor efficacy, it remains urgent to identify novel strategies to overcome resistance issues. In this context, an intense stroma reaction and the presence of cancer stem cells (CSCs) have been shown to influence PDAC aggressiveness, metastatic potential, and chemoresistance. Methods: We used three-dimensional (3D) organotypic cultures grown on an extracellular matrix composed of Matrigel or collagen I to test the effect of the new potential therapeutic prodrug 4-(N)-stearoyl-GEM, called C18GEM. We analyzed C18GEM cytotoxic activity, intracellular uptake, apoptosis, necrosis, and autophagy induction in both Panc1 cell line (P) and their derived CSCs. Results: PDAC CSCs show higher sensitivity to C18GEM treatment when cultured in both two-dimensional (2D) and 3D conditions, especially on collagen I, in comparison to GEM. The intracellular uptake mechanisms of C18GEM are mainly due to membrane nucleoside transporters\u2019 expression and fatty acid translocase CD36 in Panc1 P cells and to clathrin-mediated endocytosis and CD36 in Panc1 CSCs. Furthermore, C18GEM induces an increase in cell death compared to GEM in both cell lines grown on 2D and 3D cultures. Finally, C18GEM stimulated protective autophagy in Panc1 P and CSCs cultured on 3D conditions. Conclusion: We propose C18GEM together with autophagy inhibitors as a valid alternative therapeutic approach in PDAC treatment.<\/jats:p>","DOI":"10.3390\/ijms22010029","type":"journal-article","created":{"date-parts":[[2020,12,22]],"date-time":"2020-12-22T20:39:29Z","timestamp":1608669569000},"page":"29","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":17,"title":["Extracellular Matrix Composition Modulates the Responsiveness of Differentiated and Stem Pancreatic Cancer Cells to Lipophilic Derivate of Gemcitabine"],"prefix":"10.3390","volume":"22","author":[{"given":"Stefania","family":"Forciniti","sequence":"first","affiliation":[{"name":"Department of Neurosciences, Biomedicine and Movement Sciences, Biochemistry Section, University of Verona, 37134 Verona, Italy"},{"name":"Humanitas Clinical and Research Center, IRCCS, Department of Gastroenterology-Laboratory of Molecular Gastroenterology, 20089 Rozzano, Milan, Italy"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-6813-5436","authenticated-orcid":false,"given":"Elisa","family":"Dalla Pozza","sequence":"additional","affiliation":[{"name":"Department of Neurosciences, Biomedicine and Movement Sciences, Biochemistry Section, University of Verona, 37134 Verona, Italy"}]},{"given":"Maria Raffaella","family":"Greco","sequence":"additional","affiliation":[{"name":"Department of Biosciences, Biotechnology and Biopharmaceutics, University of Bari, 70126 Bari, Italy"},{"name":"Department of Biomedical Sciences and Human Oncology, School of Medicine, University of Bari Aldo Moro, 70124 Bari, Italy"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-9095-1413","authenticated-orcid":false,"given":"Tiago Miguel","family":"Amaral Carvalho","sequence":"additional","affiliation":[{"name":"Department of Biosciences, Biotechnology and Biopharmaceutics, University of Bari, 70126 Bari, Italy"}]},{"given":"Barbara","family":"Rolando","sequence":"additional","affiliation":[{"name":"Department of Drug Science and Technology, University of Torino, 10124 Torino, Italy"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-4210-8610","authenticated-orcid":false,"given":"Giulia","family":"Ambrosini","sequence":"additional","affiliation":[{"name":"Department of Neurosciences, Biomedicine and Movement Sciences, Biochemistry Section, University of Verona, 37134 Verona, Italy"}]},{"given":"Cristian Andres","family":"Carmona-Carmona","sequence":"additional","affiliation":[{"name":"Department of Neurosciences, Biomedicine and Movement Sciences, Biochemistry Section, University of Verona, 37134 Verona, Italy"}]},{"given":"Raffaella","family":"Pacchiana","sequence":"additional","affiliation":[{"name":"Department of Neurosciences, Biomedicine and Movement Sciences, Biochemistry Section, University of Verona, 37134 Verona, Italy"}]},{"given":"Daria","family":"Di Molfetta","sequence":"additional","affiliation":[{"name":"Department of Biosciences, Biotechnology and Biopharmaceutics, University of Bari, 70126 Bari, Italy"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-9224-9230","authenticated-orcid":false,"given":"Massimo","family":"Donadelli","sequence":"additional","affiliation":[{"name":"Department of Neurosciences, Biomedicine and Movement Sciences, Biochemistry Section, University of Verona, 37134 Verona, Italy"}]},{"given":"Silvia","family":"Arpicco","sequence":"additional","affiliation":[{"name":"Department of Drug Science and Technology, University of Torino, 10124 Torino, Italy"}]},{"given":"Marta","family":"Palmieri","sequence":"additional","affiliation":[{"name":"Department of Neurosciences, Biomedicine and Movement Sciences, Biochemistry Section, University of Verona, 37134 Verona, Italy"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-9757-5908","authenticated-orcid":false,"given":"Stephan Joel","family":"Reshkin","sequence":"additional","affiliation":[{"name":"Department of Biosciences, Biotechnology and Biopharmaceutics, University of Bari, 70126 Bari, Italy"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-6390-4184","authenticated-orcid":false,"given":"Ilaria","family":"Dando","sequence":"additional","affiliation":[{"name":"Department of Neurosciences, Biomedicine and Movement Sciences, Biochemistry Section, University of Verona, 37134 Verona, Italy"}]},{"given":"Rosa Angela","family":"Cardone","sequence":"additional","affiliation":[{"name":"Department of Biosciences, Biotechnology and Biopharmaceutics, University of Bari, 70126 Bari, Italy"}]}],"member":"1968","published-online":{"date-parts":[[2020,12,22]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","first-page":"7","DOI":"10.3322\/caac.21551","article-title":"Cancer statistics, 2019","volume":"69","author":"Siegel","year":"2019","journal-title":"CA Cancer J. Clin."},{"key":"ref_2","doi-asserted-by":"crossref","first-page":"2913","DOI":"10.1158\/0008-5472.CAN-14-0155","article-title":"Projecting cancer incidence and deaths to 2030: The unexpected burden of thyroid, liver, and pancreas cancers in the United States","volume":"74","author":"Rahib","year":"2014","journal-title":"Cancer Res."},{"key":"ref_3","doi-asserted-by":"crossref","first-page":"v56","DOI":"10.1093\/annonc\/mdv295","article-title":"Cancer of the pancreas: ESMO Clinical Practice Guidelines for diagnosis, treatment and follow-up","volume":"26","author":"Ducreux","year":"2015","journal-title":"Ann. Oncol."},{"key":"ref_4","doi-asserted-by":"crossref","first-page":"25","DOI":"10.1002\/jso.24623","article-title":"Current and future therapies for advanced pancreatic cancer","volume":"116","author":"Gupta","year":"2017","journal-title":"J. Surg. Oncol."},{"key":"ref_5","doi-asserted-by":"crossref","first-page":"340","DOI":"10.1097\/SLA.0000000000002753","article-title":"Survival in locally advanced pancreatic cancer after neoadjuvant therapy and surgical resection","volume":"270","author":"Gemenetzis","year":"2019","journal-title":"Ann. Surg."},{"key":"ref_6","doi-asserted-by":"crossref","unstructured":"Syed, A.R., Carleton, N.M., Horne, Z., Dhawan, A., Bedi, G., Kochhar, G., Morrissey, S., Williams, H., Atkinson, D., and Schiffman, S. (2019). Survival trends for resectable pancreatic cancer using a multidisciplinary conference: The impact of post-operative chemotherapy. J. Gastrointest. Cancer.","DOI":"10.1007\/s12029-019-00303-z"},{"key":"ref_7","doi-asserted-by":"crossref","first-page":"44","DOI":"10.1159\/000447739","article-title":"Current standard and future perspectives in first- and second-line treatment of metastatic pancreatic adenocarcinoma","volume":"94","author":"Ellenrieder","year":"2016","journal-title":"Digestion"},{"key":"ref_8","doi-asserted-by":"crossref","first-page":"1525","DOI":"10.1172\/JCI73455","article-title":"Transport properties of pancreatic cancer describe gemcitabine delivery and response","volume":"124","author":"Koay","year":"2014","journal-title":"J. Clin. Investig."},{"key":"ref_9","doi-asserted-by":"crossref","first-page":"788","DOI":"10.1158\/1535-7163.MCT-14-0420","article-title":"Mechanisms of overcoming intrinsic resistance to Gemcitabine in Pancreatic Ductal Adenocarcinoma through the Redox Modulation","volume":"14","author":"Ju","year":"2015","journal-title":"Mol. Cancer Ther."},{"key":"ref_10","first-page":"3","article-title":"Gemcitabine: Metabolism, mechanisms of action, and self-potentiation","volume":"22","author":"Plunkett","year":"1995","journal-title":"Semin. Oncol."},{"key":"ref_11","doi-asserted-by":"crossref","first-page":"e1","DOI":"10.1634\/theoncologist.2008-0135","article-title":"Fixed-dose-rate gemcitabine: A viable first-line treatment option for advanced pancreatic and biliary tract cancer","volume":"15","author":"Milella","year":"2010","journal-title":"Oncologist"},{"key":"ref_12","doi-asserted-by":"crossref","first-page":"21197","DOI":"10.1074\/jbc.M113.484576","article-title":"An undesired effect of chemotherapy: Gemcitabine promotes pancreatic cancer cell invasiveness through reactive oxygen species-dependent, nuclear factor kappaB- and hypoxia-inducible factor 1alpha-mediated up-regulation of CXCR4","volume":"288","author":"Arora","year":"2013","journal-title":"J. Biol. Chem."},{"key":"ref_13","doi-asserted-by":"crossref","first-page":"1075","DOI":"10.1016\/S0360-3016(03)01443-3","article-title":"Cell cycle effect of gemcitabine and its role in the radiosensitizing mechanism in vitro","volume":"57","author":"Pauwels","year":"2003","journal-title":"Int. J. Radiat. Oncol. Biol. Phys."},{"key":"ref_14","doi-asserted-by":"crossref","first-page":"1","DOI":"10.4103\/0973-1482.191615","article-title":"Gemcitabine inhibits proliferation and induces apoptosis in human pancreatic cancer PANC-1 cells","volume":"12","author":"Fan","year":"2016","journal-title":"J. Cancer Res. Ther."},{"key":"ref_15","doi-asserted-by":"crossref","first-page":"2259","DOI":"10.2174\/138920112802501999","article-title":"The tumor stroma as mediator of drug resistance-a potential target to improve cancer therapy?","volume":"13","author":"Sebens","year":"2012","journal-title":"Curr. Pharm. Biotechnol."},{"key":"ref_16","doi-asserted-by":"crossref","first-page":"810","DOI":"10.1016\/j.ejmech.2016.10.061","article-title":"Prodrug approach: An overview of recent cases","volume":"127","author":"Abet","year":"2017","journal-title":"Eur. J. Med. Chem."},{"key":"ref_17","doi-asserted-by":"crossref","first-page":"461","DOI":"10.2174\/1389200033489253","article-title":"Design of ester prodrugs to enhance oral absorption of poorly permeable compounds: Challenges to the discovery scientist","volume":"4","author":"Beaumont","year":"2003","journal-title":"Curr. Drug. Metab."},{"key":"ref_18","doi-asserted-by":"crossref","first-page":"E6","DOI":"10.1208\/ps020106","article-title":"Targeted prodrug design to optimize drug delivery","volume":"2","author":"Han","year":"2000","journal-title":"AAPS PharmSci"},{"key":"ref_19","doi-asserted-by":"crossref","first-page":"331","DOI":"10.1016\/j.jconrel.2004.09.001","article-title":"Preparation, characterization, cytotoxicity and pharmacokinetics of liposomes containing lipophilic gemcitabine prodrugs","volume":"100","author":"Immordino","year":"2004","journal-title":"J. Control Release"},{"key":"ref_20","first-page":"195","article-title":"Antitumor activity and pharmacokinetics of liposomes containing lipophilic gemcitabine prodrugs","volume":"27","author":"Brusa","year":"2007","journal-title":"Anticancer Res."},{"key":"ref_21","doi-asserted-by":"crossref","unstructured":"Malfanti, A., Miletto, I., Bottinelli, E., Zonari, D., Blandino, G., Berlier, G., and Arpicco, S. (2016). Delivery of Gemcitabine Prodrugs Employing Mesoporous Silica Nanoparticles. Molecules, 21.","DOI":"10.3390\/molecules21040522"},{"key":"ref_22","doi-asserted-by":"crossref","first-page":"887","DOI":"10.1002\/jcb.21209","article-title":"Stromal biology of pancreatic cancer","volume":"101","author":"Chu","year":"2007","journal-title":"J. Cell. Biochem."},{"key":"ref_23","doi-asserted-by":"crossref","first-page":"S84","DOI":"10.1016\/j.amjsurg.2007.05.004","article-title":"Pancreatic cancer-associated stroma production","volume":"194","author":"Korc","year":"2007","journal-title":"Am. J. Surg."},{"key":"ref_24","doi-asserted-by":"crossref","first-page":"839","DOI":"10.1038\/nrc1477","article-title":"Friends or foes-bipolar effects of the tumour stroma in cancer","volume":"4","author":"Mueller","year":"2004","journal-title":"Nat. Rev. Cancer"},{"key":"ref_25","doi-asserted-by":"crossref","first-page":"14","DOI":"10.1186\/s12943-018-0927-5","article-title":"Tumor-stromal crosstalk in pancreatic cancer and tissue fibrosis","volume":"18","author":"Thomas","year":"2019","journal-title":"Mol. Cancer"},{"key":"ref_26","doi-asserted-by":"crossref","first-page":"e406","DOI":"10.1038\/emm.2017.255","article-title":"Complex roles of the stroma in the intrinsic resistance to gemcitabine in pancreatic cancer: Where we are and where we are going","volume":"49","author":"Liang","year":"2017","journal-title":"Exp. Mol. Med."},{"key":"ref_27","doi-asserted-by":"crossref","first-page":"225","DOI":"10.1016\/j.stem.2015.02.015","article-title":"The cancer stem cell niche: How essential is the niche in regulating stemness of tumor cells?","volume":"16","author":"Plaks","year":"2015","journal-title":"Cell Stem Cell"},{"key":"ref_28","doi-asserted-by":"crossref","first-page":"3945","DOI":"10.1007\/s13277-013-1561-x","article-title":"The cancer stem cell niche: Cross talk between cancer stem cells and their microenvironment","volume":"35","author":"Ye","year":"2014","journal-title":"Tumour Biol."},{"key":"ref_29","doi-asserted-by":"crossref","first-page":"77","DOI":"10.1016\/j.semcancer.2010.03.004","article-title":"Cancer stem cells in solid tumors","volume":"20","author":"Hermann","year":"2010","journal-title":"Semin. Cancer Biol."},{"key":"ref_30","doi-asserted-by":"crossref","first-page":"313","DOI":"10.1016\/j.stem.2007.06.002","article-title":"Distinct populations of cancer stem cells determine tumor growth and metastatic activity in human pancreatic cancer","volume":"1","author":"Hermann","year":"2007","journal-title":"Cell Stem Cell"},{"key":"ref_31","doi-asserted-by":"crossref","first-page":"1314","DOI":"10.3892\/ijo.2012.1565","article-title":"Expression of cancer stem cell markers in pancreatic intraepithelial neoplasias and pancreatic ductal adenocarcinomas","volume":"41","author":"Kure","year":"2012","journal-title":"Int. J. Oncol."},{"key":"ref_32","doi-asserted-by":"crossref","first-page":"111","DOI":"10.1038\/nature05384","article-title":"Identification and expansion of human colon-cancer-initiating cells","volume":"445","author":"Lombardi","year":"2007","journal-title":"Nature"},{"key":"ref_33","doi-asserted-by":"crossref","first-page":"396","DOI":"10.1038\/nature03128","article-title":"Identification of human brain tumour initiating cells","volume":"432","author":"Singh","year":"2004","journal-title":"Nature"},{"key":"ref_34","first-page":"1101","article-title":"Cancer stem cells: Implications for cancer therapy","volume":"28","author":"Dawood","year":"2014","journal-title":"Oncology (Williston Park)"},{"key":"ref_35","doi-asserted-by":"crossref","first-page":"1104","DOI":"10.3389\/fonc.2019.01104","article-title":"Therapeutic strategies targeting cancer stem cells and their microenvironment","volume":"9","author":"Sun","year":"2019","journal-title":"Front. Oncol."},{"key":"ref_36","doi-asserted-by":"crossref","first-page":"2104","DOI":"10.1111\/febs.14471","article-title":"Extracellular matrix composition modulates PDAC parenchymal and stem cell plasticity and behavior through the secretome","volume":"285","author":"Biondani","year":"2018","journal-title":"FEBS J."},{"key":"ref_37","doi-asserted-by":"crossref","unstructured":"Puls, T.J., Tan, X., Whittington, C.F., and Voytik-Harbin, S.L. (2017). 3D collagen fibrillar microstructure guides pancreatic cancer cell phenotype and serves as a critical design parameter for phenotypic models of EMT. PLoS ONE, 12.","DOI":"10.1371\/journal.pone.0188870"},{"key":"ref_38","doi-asserted-by":"crossref","first-page":"e03604","DOI":"10.7554\/eLife.03604","article-title":"Structural basis of nucleoside and nucleoside drug selectivity by concentrative nucleoside transporters","volume":"3","author":"Johnson","year":"2014","journal-title":"Elife"},{"key":"ref_39","doi-asserted-by":"crossref","first-page":"1063","DOI":"10.6004\/jnccn.2017.0133","article-title":"DNA Repair Dysfunction in pancreatic cancer: A clinically relevant subtype for drug development","volume":"15","author":"Golan","year":"2017","journal-title":"J. Natl. Compr. Cancer Netw."},{"key":"ref_40","doi-asserted-by":"crossref","first-page":"e664","DOI":"10.1038\/cddis.2013.151","article-title":"Cannabinoids inhibit energetic metabolism and induce AMPK-dependent autophagy in pancreatic cancer cells","volume":"4","author":"Dando","year":"2013","journal-title":"Cell. Death Dis."},{"key":"ref_41","doi-asserted-by":"crossref","first-page":"337","DOI":"10.1007\/s10495-012-0790-6","article-title":"Autophagy induced by p53-reactivating molecules protects pancreatic cancer cells from apoptosis","volume":"18","author":"Fiorini","year":"2013","journal-title":"Apoptosis"},{"key":"ref_42","doi-asserted-by":"crossref","first-page":"6956","DOI":"10.1158\/1078-0432.CCR-04-0224","article-title":"The absence of human equilibrative nucleoside transporter 1 is associated with reduced survival in patients with gemcitabine-treated pancreas adenocarcinoma","volume":"10","author":"Spratlin","year":"2004","journal-title":"Clin. Cancer Res."},{"key":"ref_43","doi-asserted-by":"crossref","first-page":"42","DOI":"10.2174\/187152511794182855","article-title":"CD36 as a multiple-ligand signaling receptor in atherothrombosis","volume":"9","author":"Rademakers","year":"2011","journal-title":"Cardiovasc. Hematol. Agents Med. Chem."},{"key":"ref_44","doi-asserted-by":"crossref","first-page":"139","DOI":"10.1186\/s12964-019-0437-0","article-title":"Flipping the dogma-phosphatidylserine in non-apoptotic cell death","volume":"17","author":"Shlomovitz","year":"2019","journal-title":"Cell Commun. Signal"},{"key":"ref_45","doi-asserted-by":"crossref","first-page":"193","DOI":"10.1016\/j.expneurol.2009.03.020","article-title":"Poly(ADP-ribose) signals to mitochondrial AIF: A key event in parthanatos","volume":"218","author":"Wang","year":"2009","journal-title":"Exp. Neurol."},{"key":"ref_46","doi-asserted-by":"crossref","unstructured":"Hessmann, E., Buchholz, S.M., Demir, I.E., Singh, S.K., Gress, T.M., Ellenrieder, V., and Neesse, A. (2020). Microenvironmental Determinants of Pancreatic Cancer. Physiol. Rev.","DOI":"10.1152\/physrev.00042.2019"},{"key":"ref_47","doi-asserted-by":"crossref","first-page":"160","DOI":"10.1016\/j.cell.2019.05.012","article-title":"Stromal Microenvironment Shapes the Intratumoral Architecture of Pancreatic Cancer","volume":"178","author":"Ligorio","year":"2019","journal-title":"Cell"},{"key":"ref_48","doi-asserted-by":"crossref","first-page":"19761","DOI":"10.1038\/s41598-019-56268-3","article-title":"Collagen fragments quantified in serum as measures of desmoplasia associate with survival outcome in patients with advanced pancreatic cancer","volume":"9","author":"Willumsen","year":"2019","journal-title":"Sci. Rep."},{"key":"ref_49","doi-asserted-by":"crossref","first-page":"755","DOI":"10.1038\/nrc2499","article-title":"Cancer stem cells in solid tumours: Accumulating evidence and unresolved questions","volume":"8","author":"Visvader","year":"2008","journal-title":"Nat. Rev. Cancer"},{"key":"ref_50","doi-asserted-by":"crossref","first-page":"20","DOI":"10.1186\/s12929-018-0426-4","article-title":"Cancer stem cells as key drivers of tumour progression","volume":"25","author":"Ayob","year":"2018","journal-title":"J. Biomed. Sci."},{"key":"ref_51","doi-asserted-by":"crossref","first-page":"63","DOI":"10.1016\/j.jbior.2019.02.001","article-title":"Pancreatic cancer tumorspheres are cancer stem-like cells with increased chemoresistance and reduced metabolic potential","volume":"72","author":"Domenichini","year":"2019","journal-title":"Adv. Biol. Regul."},{"key":"ref_52","doi-asserted-by":"crossref","first-page":"1102","DOI":"10.1053\/j.gastro.2009.05.053","article-title":"Combined targeted treatment to eliminate tumorigenic cancer stem cells in human pancreatic cancer","volume":"137","author":"Mueller","year":"2009","journal-title":"Gastroenterology"},{"key":"ref_53","doi-asserted-by":"crossref","unstructured":"Smigiel, J.M., Parameswaran, N., and Jackson, M.W. (2018). Targeting pancreatic cancer cell plasticity: The latest in therapeutics. Cancers, 10.","DOI":"10.3390\/cancers10010014"},{"key":"ref_54","doi-asserted-by":"crossref","first-page":"7960","DOI":"10.1016\/j.biomaterials.2010.07.001","article-title":"Differences between in vitro viability and differentiation and in vivo bone-forming efficacy of human mesenchymal stem cells cultured on PCL-TCP scaffolds","volume":"31","author":"Rai","year":"2010","journal-title":"Biomaterials"},{"key":"ref_55","doi-asserted-by":"crossref","first-page":"1845","DOI":"10.1038\/s41598-020-57846-6","article-title":"Author correction: A novel 3D in vitro platform for pre-clinical investigations in drug testing, gene therapy, and immuno-oncology","volume":"10","author":"Candini","year":"2020","journal-title":"Sci. Rep."},{"key":"ref_56","doi-asserted-by":"crossref","first-page":"206","DOI":"10.1002\/bit.26845","article-title":"3D tumor spheroids as in vitro models to mimic in vivo human solid tumors resistance to therapeutic drugs","volume":"116","author":"Nunes","year":"2019","journal-title":"Biotechnol. Bioeng."},{"key":"ref_57","doi-asserted-by":"crossref","first-page":"1857","DOI":"10.1016\/0006-2952(93)90444-2","article-title":"Kinetic studies on 2\u2019,2\u2019-difluorodeoxycytidine (Gemcitabine) with purified human deoxycytidine kinase and cytidine deaminase","volume":"45","author":"Bouffard","year":"1993","journal-title":"Biochem. Pharmacol."},{"key":"ref_58","doi-asserted-by":"crossref","first-page":"319","DOI":"10.2147\/IJN.S149196","article-title":"Overcoming tumor cell chemoresistance using nanoparticles: Lysosomes are beneficial for (stearoyl) gemcitabine-incorporated solid lipid nanoparticles","volume":"13","author":"Chen","year":"2018","journal-title":"Int. J. Nanomed."},{"key":"ref_59","doi-asserted-by":"crossref","first-page":"346","DOI":"10.1016\/j.canlet.2010.10.015","article-title":"Targeting apoptosis pathways in pancreatic cancer","volume":"332","author":"Arlt","year":"2013","journal-title":"Cancer Lett."},{"key":"ref_60","doi-asserted-by":"crossref","first-page":"486","DOI":"10.1038\/s41418-017-0012-4","article-title":"Molecular mechanisms of cell death: Recommendations of the Nomenclature Committee on Cell Death 2018","volume":"25","author":"Galluzzi","year":"2018","journal-title":"Cell Death Differ."},{"key":"ref_61","doi-asserted-by":"crossref","first-page":"290","DOI":"10.3389\/fonc.2013.00290","article-title":"Beyond DNA repair: Additional functions of PARP-1 in cancer","volume":"3","author":"Weaver","year":"2013","journal-title":"Front. Oncol."},{"key":"ref_62","doi-asserted-by":"crossref","unstructured":"Ambrosini, G., Dalla Pozza, E., Fanelli, G., Di Carlo, C., Vettori, A., Cannino, G., Cavallini, C., Carmona-Carmona, C.A., Brandi, J., and Rinalducci, S. (2020). Progressively De-Differentiated Pancreatic Cancer Cells Shift from Glycolysis to Oxidative Metabolism and Gain a Quiescent Stem State. Cells, 9.","DOI":"10.3390\/cells9071572"},{"key":"ref_63","doi-asserted-by":"crossref","first-page":"101027","DOI":"10.1016\/j.molmet.2020.101027","article-title":"Mitochondrial AIF loss causes metabolic reprogramming, caspase-independent cell death blockade, embryonic lethality, and perinatal hydrocephalus","volume":"40","author":"Delavallee","year":"2020","journal-title":"Mol. Metab."},{"key":"ref_64","doi-asserted-by":"crossref","first-page":"276","DOI":"10.1158\/2159-8290.CD-17-0952","article-title":"Autophagy sustains pancreatic cancer growth through both cell-autonomous and nonautonomous mechanisms","volume":"8","author":"Yang","year":"2018","journal-title":"Cancer Discov."},{"key":"ref_65","doi-asserted-by":"crossref","first-page":"23","DOI":"10.1002\/ijc.29990","article-title":"Stress management by autophagy: Implications for chemoresistance","volume":"139","author":"Huang","year":"2016","journal-title":"Int. J. Cancer"},{"key":"ref_66","doi-asserted-by":"crossref","first-page":"723","DOI":"10.1111\/1440-1681.12581","article-title":"Molecular mechanisms for tumour resistance to chemotherapy","volume":"43","author":"Pan","year":"2016","journal-title":"Clin. Exp. Pharmacol. Physiol."},{"key":"ref_67","doi-asserted-by":"crossref","first-page":"59950","DOI":"10.18632\/oncotarget.19048","article-title":"The molecular mechanisms of chemoresistance in cancers","volume":"8","author":"Zheng","year":"2017","journal-title":"Oncotarget"},{"key":"ref_68","doi-asserted-by":"crossref","first-page":"2261","DOI":"10.1038\/onc.2012.252","article-title":"Beclin 1 and autophagy are required for the tumorigenicity of breast cancer stem-like\/progenitor cells","volume":"32","author":"Gong","year":"2013","journal-title":"Oncogene"},{"key":"ref_69","doi-asserted-by":"crossref","first-page":"2487","DOI":"10.1158\/0008-5472.CAN-13-3536","article-title":"Curcumin promotes autophagic survival of a subset of colon cancer stem cells, which are ablated by DCLK1-siRNA","volume":"74","author":"Kantara","year":"2014","journal-title":"Cancer Res."},{"key":"ref_70","doi-asserted-by":"crossref","first-page":"1099","DOI":"10.3892\/ijo.2014.2796","article-title":"Pancreatic ductal adenocarcinoma cell lines display a plastic ability to bidirectionally convert into cancer stem cells","volume":"46","author":"Dando","year":"2015","journal-title":"Int. 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