{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,9,9]],"date-time":"2026-09-09T16:11:59Z","timestamp":1788970319680,"version":"build-2803163510"},"reference-count":66,"publisher":"American Chemical Society (ACS)","issue":"35","license":[{"start":{"date-parts":[[2026,8,28]],"date-time":"2026-08-28T00:00:00Z","timestamp":1787875200000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"DOI":"10.13039\/501100004281","name":"Narodowe Centrum Nauki","doi-asserted-by":"publisher","award":["2021\/43\/B\/NZ1\/00245"],"award-info":[{"award-number":["2021\/43\/B\/NZ1\/00245"]}],"id":[{"id":"10.13039\/501100004281","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":[],"published-print":{"date-parts":[[2026,9,9]]},"abstract":"<jats:title>Abstract<\/jats:title>\n                  <jats:p>Protein\u2013drug conjugates (PDCs) constitute a rapidly growing group of precise anticancer agents. Receptor-mediated endocytosis is a critical step in PDC action, which ensures the delivery of PDCs into the interior of cancer cells. Here, we report TriFHS-MMAE, the first multivalent PDC specifically targeting heparan sulfate proteoglycans (HSPGs) overexpressed by pancreatic cancer cells, which induces ultrafast and highly efficient aggregation-dependent endocytosis (ADE) of HSPGs. Using high-content screening with a near-kinome-wide library of inhibitors, we identified signaling pathways that govern ADE of HSPGs and discovered cascades that selectively operate in pancreatic cancer cells versus healthy cells. We show that priming cells with identified endocytic chemical modulators improves the targeting of the TriFHS-MMAE conjugate in vitro and in vivo. Overall, these findings provide insights into the interplay among signaling, endocytosis, and PDCs and support the development of specific therapies for pancreatic cancer.<\/jats:p>","DOI":"10.1021\/jacs.6c08409","type":"journal-article","created":{"date-parts":[[2026,9,2]],"date-time":"2026-09-02T04:30:05Z","timestamp":1788323405000},"page":"37884-37908","source":"Crossref","is-referenced-by-count":0,"title":["Priming Cells with\nModulators of Cellular Signaling\nEnsures Enhanced Selectivity of HSPG-Specific Protein\u2013Drug\nConjugate Delivery"],"prefix":"10.1021","volume":"148","author":[{"ORCID":"https:\/\/orcid.org\/0000-0002-3391-2845","authenticated-orcid":true,"given":"Aleksandra","family":"Chora\u0328z\u0307ewska","sequence":"first","affiliation":[{"name":"University of Wroclaw , , Joliot-Curie 14a , ,","place":["Wroclaw, Poland, 50-383"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Krzysztof","family":"Ciura","sequence":"additional","affiliation":[{"name":"University of Wroclaw , , Joliot-Curie 14a , ,","place":["Wroclaw, Poland, 50-383"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Magdalena","family":"Milczarek","sequence":"additional","affiliation":[{"name":"Hirszfeld Institute of Immunology and Experimental Therapy , , Weigla 12 , ,","place":["Wroclaw, Poland, 53-114"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Dagmara","family":"K\u0142opotowska","sequence":"additional","affiliation":[{"name":"Hirszfeld Institute of Immunology and Experimental Therapy , , Weigla 12 , ,","place":["Wroclaw, Poland, 53-114"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-0669-3421","authenticated-orcid":true,"given":"Adam","family":"Pomorski","sequence":"additional","affiliation":[{"name":"University of Wroclaw , , Joliot-Curie 14a , ,","place":["Wroclaw, Poland, 50-383"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Anna","family":"Wie\u0328ch-Walo\u0301w","sequence":"additional","affiliation":[{"name":"University of Wroclaw , , Joliot-Curie 14a , ,","place":["Wroclaw, Poland, 50-383"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"B\u0142az\u0307ej","family":"\u0141ukianowski","sequence":"additional","affiliation":[{"name":"Wroclaw Medical University , , T. Marcinkowskiego 1 , ,","place":["Wroclaw, Poland, 50-368"]},{"name":"Fourth Military Hospital , , Weigla 5 , ,","place":["Wroclaw, Poland, 53-114"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Pawe\u0142","family":"Gajdzis","sequence":"additional","affiliation":[{"name":"Wroclaw Medical University , , T. Marcinkowskiego 1 , ,","place":["Wroclaw, Poland, 50-368"]},{"name":"Fourth Military Hospital , , Weigla 5 , ,","place":["Wroclaw, Poland, 53-114"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-9252-5784","authenticated-orcid":true,"given":"Artur","family":"Kre\u0328z\u0307el","sequence":"additional","affiliation":[{"name":"University of Wroclaw , , Joliot-Curie 14a , ,","place":["Wroclaw, Poland, 50-383"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Rafa\u0142","family":"Bartoszewski","sequence":"additional","affiliation":[{"name":"University of Wroclaw , , Joliot-Curie 14a , ,","place":["Wroclaw, Poland, 50-383"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Joanna","family":"Wietrzyk","sequence":"additional","affiliation":[{"name":"Hirszfeld Institute of Immunology and Experimental Therapy , , Weigla 12 , ,","place":["Wroclaw, Poland, 53-114"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Liliana","family":"Schaefer","sequence":"additional","affiliation":[{"name":"Goethe University , , Theodor-Stern Kai 7 , ,","place":["Frankfurt, Germany, 605090"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-1810-0232","authenticated-orcid":true,"given":"Natalia","family":"Pore\u0328bska","sequence":"additional","affiliation":[{"name":"University of Wroclaw , , Joliot-Curie 14a , ,","place":["Wroclaw, Poland, 50-383"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-9656-8714","authenticated-orcid":true,"given":"\u0141ukasz","family":"Opalin\u0301ski","sequence":"additional","affiliation":[{"name":"University of Wroclaw , , Joliot-Curie 14a , ,","place":["Wroclaw, Poland, 50-383"]}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"316","published-online":{"date-parts":[[2026,8,28]]},"reference":[{"key":"2026090910094414200_cit1","doi-asserted-by":"publisher","first-page":"450","DOI":"10.1038\/s41568-023-00574-6","article-title":"Endocytosis\nin cancer and cancer therapy","volume":"23","author":"Banushi","year":"2023","journal-title":"Nat. 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Cancer"},{"key":"2026090910094414200_cit5","doi-asserted-by":"publisher","first-page":"62","DOI":"10.1186\/s12943-024-01963-7","article-title":"A review\nof the clinical efficacy of FDA-approved antibody\u2013drug conjugates\nin human cancers","volume":"23","author":"Liu","year":"2024","journal-title":"Mol. Cancer"},{"key":"2026090910094414200_cit6","doi-asserted-by":"publisher","first-page":"947","DOI":"10.1038\/s41467-023-36496-y","article-title":"Cell surface protein aggregation\ntriggers endocytosis\nto maintain plasma membrane proteostasis","volume":"14","author":"Paul","year":"2023","journal-title":"Nat.\nCommun."},{"key":"2026090910094414200_cit7","doi-asserted-by":"publisher","first-page":"1888","DOI":"10.1038\/mt.2015.178","article-title":"Receptor crosslinking:\na general method to trigger internalization\nand lysosomal targeting of therapeutic receptor: ligand complexes","volume":"23","author":"Moody","year":"2015","journal-title":"Mol. 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Sci."},{"key":"2026090910094414200_cit23","doi-asserted-by":"publisher","first-page":"181","DOI":"10.1038\/s41392-020-00222-7","article-title":"FGF\/FGFR\nsignaling in health and disease","volume":"5","author":"Xie","year":"2020","journal-title":"Signal Transduction\nTargeted Ther."},{"key":"2026090910094414200_cit24","doi-asserted-by":"publisher","first-page":"7134","DOI":"10.1038\/ncomms8134","article-title":"Green fluorescent protein\nnanopolygons as monodisperse supramolecular\nassemblies of functional proteins with defined valency","volume":"6","author":"Kim","year":"2015","journal-title":"Nat. Commun."},{"key":"2026090910094414200_cit25","doi-asserted-by":"publisher","first-page":"270","DOI":"10.1186\/s12964-024-01661-3","article-title":"The diverse dependence\nof galectin-1 and -8 on multivalency for the modulation of FGFR1 endocytosis","volume":"22","author":"Z\u0307ukowska","year":"2024","journal-title":"Cell Commun. 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Pharmacother."},{"key":"2026090910094414200_cit40","doi-asserted-by":"publisher","first-page":"93","DOI":"10.1038\/s41392-022-00947-7","article-title":"Antibody drug conjugate:\nthe \u201cbiological missile\u201d for targeted cancer therapy","volume":"7","author":"Fu","year":"2022","journal-title":"Signal Transduction Targeted Ther."},{"key":"2026090910094414200_cit41","doi-asserted-by":"publisher","first-page":"2555","DOI":"10.18632\/oncotarget.6679","article-title":"Computational selection\nof antibody-drug conjugate targets for breast\ncancer","volume":"7","author":"Fauteux","year":"2016","journal-title":"Oncotarget"},{"key":"2026090910094414200_cit42","doi-asserted-by":"publisher","first-page":"939","DOI":"10.1016\/j.neo.2021.07.006","article-title":"A glypican-1-targeted\nantibody-drug conjugate exhibits potent tumor\ngrowth inhibition in glypican-1-positive pancreatic cancer and esophageal\nsquamous cell carcinoma","volume":"23","author":"Munekage","year":"2021","journal-title":"Neoplasia"},{"key":"2026090910094414200_cit43","doi-asserted-by":"publisher","first-page":"1333","DOI":"10.1038\/s41416-020-0781-2","article-title":"Anti-glypican-1 antibody\u2013drug\nconjugate is a potential therapy\nagainst pancreatic cancer","volume":"122","author":"Nishigaki","year":"2020","journal-title":"Br. J. Cancer"},{"key":"2026090910094414200_cit44","doi-asserted-by":"publisher","first-page":"251","DOI":"10.1016\/bs.acr.2022.08.001","article-title":"Heparan sulfate proteoglycans\nin cancer: Pathogenesis and therapeutic\npotential","volume":"157","author":"Yang","year":"2023","journal-title":"Adv. Cancer Res."},{"key":"2026090910094414200_cit45","doi-asserted-by":"publisher","first-page":"7","DOI":"10.1038\/s41392-021-00858-z","article-title":"Overcoming unintended\nimmunogenicity in immunocompetent\nmouse models of metastasis: the case of GFP","volume":"7","author":"Schulthei\u00df","year":"2022","journal-title":"Signal Transduction Targeted Ther."},{"key":"2026090910094414200_cit46","doi-asserted-by":"publisher","first-page":"553","DOI":"10.1007\/s12015-016-9670-8","article-title":"Cellular GFP toxicity and immunogenicity: potential confounders in\nin vivo cell tracking experiments","volume":"12","author":"Ansari","year":"2016","journal-title":"Stem Cell\nRev. 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