{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,8,24]],"date-time":"2026-08-24T10:27:15Z","timestamp":1787567235039,"version":"build-2736575974"},"reference-count":31,"publisher":"Springer Science and Business Media LLC","issue":"9","license":[{"start":{"date-parts":[[2026,8,24]],"date-time":"2026-08-24T00:00:00Z","timestamp":1787529600000},"content-version":"tdm","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0"},{"start":{"date-parts":[[2026,8,24]],"date-time":"2026-08-24T00:00:00Z","timestamp":1787529600000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0"}],"funder":[{"DOI":"10.13039\/501100001691","name":"Japan Society for the Promotion of Science","doi-asserted-by":"publisher","award":["23K07397"],"award-info":[{"award-number":["23K07397"]}],"id":[{"id":"10.13039\/501100001691","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/100009619","name":"Japan Agency for Medical Research and Development","doi-asserted-by":"publisher","award":["JP24ae0121057"],"award-info":[{"award-number":["JP24ae0121057"]}],"id":[{"id":"10.13039\/100009619","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":["link.springer.com"],"crossmark-restriction":false},"short-container-title":["Human Cell"],"abstract":"<jats:title>Abstract<\/jats:title>\n                  <jats:p>Pancreatic ductal adenocarcinoma features a dense, desmoplastic tumor microenvironment (TME) dominated by cancer-associated fibroblasts (CAFs). While gemcitabine plus nab-paclitaxel (approximated as gemcitabine plus paclitaxel [GP]) and gemcitabine plus S-1 (GS) are standard regimens with distinct clinical indications, their specific effects on tumor suppression and CAF-associated stromal remodeling remain unclear. Using a humanized, three-dimensional (3D) S2-013 organoid xenograft model integrating human mesenchymal stem cells (MSCs) and human endothelial cells, we investigated the histopathological and immunohistochemical alterations induced by GP and GS. We quantitatively evaluated tumor parenchymal growth using cytokeratin 19 (CK19) and CAF-associated marker profiles, including \u03b1-smooth muscle actin (\u03b1SMA), fibroblast activation protein (FAP), platelet-derived growth factor receptors (PDGFR), and interleukin-6 (IL-6). Both regimens clearly suppressed tumor growth, but only GP significantly reduced parenchymal tumor growth compared with untreated controls. Notably, the treatments selectively remodeled the peritumoral stroma in the humanized xenograft model: PDGFR-expressing CAF-like cells were significantly reduced in the GP group, whereas FAP-expressing CAF-like cells and IL-6-expressing stromal cells were significantly decreased in the GS group. \u03b1SMA expression showed a general decreasing trend in both therapeutic arms. In summary, GP and GS chemotherapies induced distinct, measurable humanized TME remodeling modalities beyond direct cytotoxicity. By successfully recapitulating drug\u2013stroma interactions and suggesting the human MSC origin of the peritumoral CAFs, this study demonstrates the robustness of our organoid xenograft model as a powerful preclinical screening platform for evaluating and predicting the efficacy of novel stroma-targeted and immunomodulatory investigative compounds.<\/jats:p>","DOI":"10.1007\/s13577-026-01443-8","type":"journal-article","created":{"date-parts":[[2026,8,24]],"date-time":"2026-08-24T08:56:33Z","timestamp":1787561793000},"update-policy":"https:\/\/doi.org\/10.1007\/springer_crossmark_policy","source":"Crossref","is-referenced-by-count":0,"title":["Chemotherapy-induced CAF-associated stromal remodeling in a humanized stroma pancreatic ductal adenocarcinoma organoid xenograft model: a comparison between GP and GS"],"prefix":"10.1007","volume":"39","author":[{"given":"Kaoru","family":"Furihata","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Waka","family":"Iwashita","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Atsushi","family":"Kurabayashi","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Mutsuo","family":"Furihata","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Kazushige","family":"Uchida","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-9165-7494","authenticated-orcid":false,"given":"Keisuke","family":"Taniuchi","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"297","published-online":{"date-parts":[[2026,8,24]]},"reference":[{"issue":"3","key":"1443_CR1","doi-asserted-by":"publisher","first-page":"261","DOI":"10.1002\/bjs.5737","volume":"94","author":"J Kleeff","year":"2007","unstructured":"Kleeff J, Friess H, B\u00fcchler MW. Neoadjuvant therapy for pancreatic cancer. Br J Surg. 2007;94(3):261\u20132.","journal-title":"Br J Surg"},{"issue":"22","key":"1443_CR2","doi-asserted-by":"publisher","DOI":"10.1172\/jci.insight.152761","volume":"7","author":"M Heiduk","year":"2022","unstructured":"Heiduk M, Plesca I, Gl\u00fcck J, et al. Neoadjuvant chemotherapy drives intratumoral T cells toward a proinflammatory profile in pancreatic cancer. JCI Insight. 2022;7(22):e152761.","journal-title":"JCI Insight"},{"issue":"2","key":"1443_CR3","doi-asserted-by":"publisher","first-page":"190","DOI":"10.1093\/jjco\/hyy190","volume":"49","author":"F Motoi","year":"2019","unstructured":"Motoi F, Kosuge T, Ueno H, et al. Randomized phase II\/III trial of neoadjuvant chemotherapy with gemcitabine and S-1 versus upfront surgery for resectable pancreatic cancer (Prep-02\/JSAP05). Jpn J Clin Oncol. 2019;49(2):190\u20134.","journal-title":"Jpn J Clin Oncol"},{"issue":"1","key":"1443_CR4","doi-asserted-by":"publisher","first-page":"57","DOI":"10.1097\/SLA.0000000000006730","volume":"283","author":"M Unno","year":"2025","unstructured":"Unno M, Motoi F, Matsuyama Y, et al. Neoadjuvant chemotherapy with gemcitabine and S-1 versus upfront surgery for resectable pancreatic cancer: results of the randomized phase II\/III Prep-02\/JSAP05 Trial. Ann Surg. 2025;283(1):57\u201364.","journal-title":"Ann Surg"},{"issue":"18","key":"1443_CR5","doi-asserted-by":"publisher","first-page":"1691","DOI":"10.1056\/NEJMoa1304369","volume":"369","author":"DD Von Hoff","year":"2013","unstructured":"Von Hoff DD, Ervin T, Arena FP, et al. Increased survival in pancreatic cancer with nab-paclitaxel plus gemcitabine. N Engl J Med. 2013;369(18):1691\u2013703.","journal-title":"N Engl J Med"},{"issue":"11","key":"1443_CR6","doi-asserted-by":"publisher","DOI":"10.3390\/cancers12113108","volume":"12","author":"K Louault","year":"2020","unstructured":"Louault K, Li RR, DeClerck YA. Cancer-associated fibroblasts: understanding their heterogeneity. Cancers (Basel). 2020;12(11):3108.","journal-title":"Cancers (Basel)"},{"issue":"2","key":"1443_CR7","doi-asserted-by":"publisher","first-page":"282","DOI":"10.1158\/2159-8290.CD-18-0710","volume":"9","author":"G Biffi","year":"2019","unstructured":"Biffi G, Oni TE, Spielman B, et al. IL1-induced JAK\/STAT signaling is antagonized by TGF\u03b2 to shape CAF heterogeneity in pancreatic ductal adenocarcinoma. Cancer Discov. 2019;9(2):282\u2013301.","journal-title":"Cancer Discov"},{"key":"1443_CR8","doi-asserted-by":"publisher","DOI":"10.3389\/fcell.2021.743907","volume":"9","author":"P Manoukian","year":"2021","unstructured":"Manoukian P, Bijlsma M, van Laarhoven H. The cellular origins of cancer-associated fibroblasts and their opposing contributions to pancreatic cancer growth. Front Cell Dev Biol. 2021;9:743907.","journal-title":"Front Cell Dev Biol"},{"issue":"8","key":"1443_CR9","doi-asserted-by":"publisher","first-page":"1254","DOI":"10.1097\/MPA.0b013e3181dbf647","volume":"39","author":"H Fujita","year":"2010","unstructured":"Fujita H, Ohuchida K, Mizumoto K, et al. alpha-smooth muscle actin expressing stroma promotes an aggressive tumor biology in pancreatic ductal adenocarcinoma. Pancreas. 2010;39(8):1254\u201362.","journal-title":"Pancreas"},{"issue":"3","key":"1443_CR10","doi-asserted-by":"publisher","first-page":"579","DOI":"10.1084\/jem.20162024","volume":"214","author":"D \u00d6hlund","year":"2017","unstructured":"\u00d6hlund D, Handly-Santana A, Biffi G, et al. Distinct populations of inflammatory fibroblasts and myofibroblasts in pancreatic cancer. J Exp Med. 2017;214(3):579\u201396.","journal-title":"J Exp Med"},{"issue":"2","key":"1443_CR11","doi-asserted-by":"publisher","first-page":"182","DOI":"10.1046\/j.1523-1747.2003.12035.x","volume":"120","author":"MA Huber","year":"2003","unstructured":"Huber MA, Kraut N, Park JE, et al. Fibroblast activation protein: differential expression and serine protease activity in reactive stromal fibroblasts of melanocytic skin tumors. J Invest Dermatol. 2003;120(2):182\u20138.","journal-title":"J Invest Dermatol"},{"issue":"3","key":"1443_CR12","doi-asserted-by":"publisher","DOI":"10.1371\/journal.pone.0116683","volume":"10","author":"F Liu","year":"2015","unstructured":"Liu F, Qi L, Liu B, et al. Fibroblast activation protein overexpression and clinical implications in solid tumors: a meta-analysis. PLoS ONE. 2015;10(3):e0116683.","journal-title":"PLoS ONE"},{"issue":"2","key":"1443_CR13","doi-asserted-by":"publisher","first-page":"168","DOI":"10.1007\/s11481-013-9479-z","volume":"9","author":"K Funa","year":"2014","unstructured":"Funa K, Sasahara M. The roles of PDGF in development and during neurogenesis in the normal and diseased nervous system. J Neuroimmune Pharmacol. 2014;9(2):168\u201381.","journal-title":"J Neuroimmune Pharmacol"},{"key":"1443_CR14","doi-asserted-by":"publisher","DOI":"10.1186\/1478-811X-11-97","volume":"11","author":"CH Heldin","year":"2013","unstructured":"Heldin CH. Targeting the PDGF signaling pathway in tumor treatment. Cell Commun Signal. 2013;11:97.","journal-title":"Cell Commun Signal"},{"issue":"6","key":"1443_CR15","doi-asserted-by":"publisher","first-page":"2037","DOI":"10.1016\/j.ajpath.2013.02.018","volume":"182","author":"O Frings","year":"2013","unstructured":"Frings O, Augsten M, Tobin NP, et al. Prognostic significance in breast cancer of a gene signature capturing stromal PDGF signaling. Am J Pathol. 2013;182(6):2037\u201347.","journal-title":"Am J Pathol"},{"issue":"13","key":"1443_CR16","doi-asserted-by":"publisher","first-page":"2388","DOI":"10.1158\/0008-5472.CAN-23-3252","volume":"85","author":"J Cumming","year":"2025","unstructured":"Cumming J, Maneshi P, Dongre M, et al. Dissecting FAP+ cell diversity in pancreatic cancer uncovers an interferon-response subtype of cancer-associated fibroblasts with tumor-restraining properties. Cancer Res. 2025;85(13):2388\u2013411.","journal-title":"Cancer Res"},{"issue":"1","key":"1443_CR17","doi-asserted-by":"publisher","DOI":"10.1016\/j.xpro.2024.103539","volume":"6","author":"K Takeuchi","year":"2025","unstructured":"Takeuchi K, Tabe S, Yamamoto Y, et al. Protocol for generating a pancreatic cancer organoid associated with heterogeneous tumor microenvironment. STAR Protoc. 2025;6(1):103539.","journal-title":"STAR Protoc"},{"issue":"2","key":"1443_CR18","doi-asserted-by":"publisher","first-page":"735","DOI":"10.1007\/s13577-022-00684-7","volume":"35","author":"C Tanaka","year":"2022","unstructured":"Tanaka C, Furihata K, Naganuma S, et al. Establishment of a mouse model of pancreatic cancer using human pancreatic cancer cell line S2-013-derived organoid. Hum Cell. 2022;35(2):735\u201344.","journal-title":"Hum Cell"},{"issue":"2","key":"1443_CR19","doi-asserted-by":"publisher","first-page":"44","DOI":"10.1007\/s13577-024-01165-9","volume":"38","author":"Y Jobu","year":"2025","unstructured":"Jobu Y, Nishigawa M, Furihata K, Furihata M, Uchida K, Taniuchi K. Inhibitory effects of the combination of rapamycin with gemcitabine plus paclitaxel on the growth of pancreatic cancer tumors. Hum Cell. 2025;38(2):44.","journal-title":"Hum Cell"},{"issue":"4","key":"1443_CR20","doi-asserted-by":"publisher","first-page":"2443","DOI":"10.3390\/cancers7040902","volume":"7","author":"K Shiga","year":"2015","unstructured":"Shiga K, Hara M, Nagasaki T, Sato T, Takahashi H, Takeyama H. Cancer-associated fibroblasts: their characteristics and their roles in tumor growth. Cancers (Basel). 2015;7(4):2443\u201358.","journal-title":"Cancers (Basel)"},{"issue":"16","key":"1443_CR21","doi-asserted-by":"publisher","first-page":"4266","DOI":"10.1158\/1078-0432.CCR-11-3114","volume":"18","author":"C Feig","year":"2012","unstructured":"Feig C, Gopinathan A, Neesse A, Chan DS, Cook N, Tuveson DA. The pancreas cancer microenvironment. Clin Cancer Res. 2012;18(16):4266\u201376.","journal-title":"Clin Cancer Res"},{"issue":"1","key":"1443_CR22","doi-asserted-by":"publisher","first-page":"147","DOI":"10.1152\/physrev.00048.2019","volume":"101","author":"G Biffi","year":"2021","unstructured":"Biffi G, Tuveson DA. Diversity and biology of cancer-associated fibroblasts. Physiol Rev. 2021;101(1):147\u201376.","journal-title":"Physiol Rev"},{"issue":"6005","key":"1443_CR23","doi-asserted-by":"publisher","first-page":"827","DOI":"10.1126\/science.1195300","volume":"330","author":"M Kraman","year":"2010","unstructured":"Kraman M, Bambrough PJ, Arnold JN, et al. Suppression of antitumor immunity by stromal cells expressing fibroblast activation protein-alpha. Science. 2010;330(6005):827\u201330.","journal-title":"Science"},{"issue":"9","key":"1443_CR24","doi-asserted-by":"publisher","first-page":"1332","DOI":"10.1038\/nm.2938","volume":"18","author":"A Ostman","year":"2012","unstructured":"Ostman A. The tumor microenvironment controls drug sensitivity. Nat Med. 2012;18(9):1332\u20134.","journal-title":"Nat Med"},{"issue":"3","key":"1443_CR25","doi-asserted-by":"publisher","first-page":"422","DOI":"10.1158\/2159-8290.CD-19-0958","volume":"10","author":"Y Zhang","year":"2020","unstructured":"Zhang Y, Lazarus J, Steele NG, et al. Regulatory T-cell depletion alters the tumor microenvironment and accelerates pancreatic carcinogenesis. Cancer Discov. 2020;10(3):422\u201339.","journal-title":"Cancer Discov"},{"issue":"1","key":"1443_CR26","doi-asserted-by":"publisher","first-page":"249","DOI":"10.1038\/s41392-020-00341-1","volume":"5","author":"A Bulle","year":"2020","unstructured":"Bulle A, Lim KH. Beyond just a tight fortress: contribution of stroma to epithelial-mesenchymal transition in pancreatic cancer. Signal Transduct Target Ther. 2020;5(1):249.","journal-title":"Signal Transduct Target Ther"},{"issue":"5","key":"1443_CR27","doi-asserted-by":"publisher","first-page":"497","DOI":"10.1038\/nm.4082","volume":"22","author":"H Laklai","year":"2016","unstructured":"Laklai H, Miroshnikova YA, Pickup MW, et al. Genotype tunes pancreatic ductal adenocarcinoma tissue tension to induce matricellular fibrosis and tumor progression. Nat Med. 2016;22(5):497\u2013505.","journal-title":"Nat Med"},{"issue":"5","key":"1443_CR28","doi-asserted-by":"publisher","first-page":"753","DOI":"10.1158\/0008-5472.CAN-22-1890","volume":"83","author":"T Akiyama","year":"2023","unstructured":"Akiyama T, Yasuda T, Uchihara T, et al. Stromal reprogramming through dual PDGFR\u03b1\/\u03b2 blockade boosts the efficacy of anti-PD-1 immunotherapy in fibrotic tumors. Cancer Res. 2023;83(5):753\u201370.","journal-title":"Cancer Res"},{"issue":"8","key":"1443_CR29","doi-asserted-by":"publisher","first-page":"1102","DOI":"10.1158\/2159-8290.CD-19-0094","volume":"9","author":"E Elyada","year":"2019","unstructured":"Elyada E, Bolisetty M, Laise P, et al. Cross-species single-cell analysis of pancreatic ductal adenocarcinoma reveals antigen-presenting cancer-associated fibroblasts. Cancer Discov. 2019;9(8):1102\u201323.","journal-title":"Cancer Discov"},{"issue":"5","key":"1443_CR30","doi-asserted-by":"publisher","first-page":"903","DOI":"10.1016\/j.immuni.2021.04.021","volume":"54","author":"MB Buechler","year":"2021","unstructured":"Buechler MB, Fu W, Turley SJ. Fibroblast-macrophage reciprocal interactions in health, fibrosis, and cancer. Immunity. 2021;54(5):903\u201315.","journal-title":"Immunity"},{"issue":"4","key":"1443_CR31","doi-asserted-by":"publisher","first-page":"1167","DOI":"10.1111\/cas.70320","volume":"117","author":"X Zhang","year":"2026","unstructured":"Zhang X, Lan R, Li D, et al. Neoadjuvant therapy-induced remodeling in pancreatic ductal adenocarcinoma: multimodal spatial analysis and prognosis. Cancer Sci. 2026;117(4):1167\u201377.","journal-title":"Cancer Sci"}],"container-title":["Human Cell"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/link.springer.com\/content\/pdf\/10.1007\/s13577-026-01443-8.pdf","content-type":"application\/pdf","content-version":"vor","intended-application":"text-mining"},{"URL":"https:\/\/link.springer.com\/article\/10.1007\/s13577-026-01443-8","content-type":"text\/html","content-version":"vor","intended-application":"text-mining"},{"URL":"https:\/\/link.springer.com\/content\/pdf\/10.1007\/s13577-026-01443-8.pdf","content-type":"application\/pdf","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2026,8,24]],"date-time":"2026-08-24T08:56:34Z","timestamp":1787561794000},"score":1,"resource":{"primary":{"URL":"https:\/\/link.springer.com\/10.1007\/s13577-026-01443-8"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2026,8,24]]},"references-count":31,"journal-issue":{"issue":"9","published-online":{"date-parts":[[2026,9]]}},"alternative-id":["1443"],"URL":"https:\/\/doi.org\/10.1007\/s13577-026-01443-8","relation":{},"ISSN":["1749-0774"],"issn-type":[{"value":"1749-0774","type":"electronic"}],"subject":[],"published":{"date-parts":[[2026,8,24]]},"assertion":[{"value":"6 June 2026","order":1,"name":"received","label":"Received","group":{"name":"ArticleHistory","label":"Article History"}},{"value":"12 August 2026","order":2,"name":"accepted","label":"Accepted","group":{"name":"ArticleHistory","label":"Article History"}},{"value":"24 August 2026","order":3,"name":"first_online","label":"First Online","group":{"name":"ArticleHistory","label":"Article History"}},{"value":"The authors declare that they have no competing interests.","order":1,"name":"Ethics","label":"Conflict of interest","group":{"name":"EthicsHeading","label":"Declarations"}},{"value":"Animal experiments were approved by the Institutional Animal Care and Use Committee of Kochi University (approval #S-00015) and conducted in accordance with its institutional guidelines. This article does not contain any studies.","order":2,"name":"Ethics","label":"Ethical approval","group":{"name":"EthicsHeading","label":"Declarations"}},{"value":"Not applicable.","order":3,"name":"Ethics","label":"Consent to participate","group":{"name":"EthicsHeading","label":"Declarations"}},{"value":"Not applicable.","order":4,"name":"Ethics","label":"Consent for publication","group":{"name":"EthicsHeading","label":"Declarations"}}],"article-number":"129"}}