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We analyzed transcriptomic data from 15,025 CRC tumors to evaluate gene expression in clathrin-mediated endocytosis (CME) and the endosomal sorting complexes required for transport (ESCRT) pathway. Pathway-level signatures were compared across consensus molecular subtypes (CMS) and examined in relation to oncogenic signaling programs, while individual endocytosis-related genes were evaluated for associations with clinical outcomes in an independent randomized trial cohort. Expression of CME and ESCRT pathways varied by CMS, with the highest expression in CMS4 and the lowest in CMS3. Endocytosis signatures correlated with multiple oncogenic signaling pathways, including MAPK, TGF-\u03b2, WNT, PI3K, NOTCH, and angiogenesis, suggesting broad links between endocytic activity and tumor biology. In the randomized phase III CALGB\/SWOG 80405 trial, low expression of\n                    <jats:italic>AP2M1<\/jats:italic>\n                    \u2014a core adaptor in the CME complex\u2014was significantly associated with longer overall survival and progression-free survival in patients treated with anti-EGFR agents, but not in those receiving anti-VEGF agents. These findings suggest that endocytic trafficking may be associated with oncogenic signaling and differential therapeutic benefit in patients with metastatic CRC. The endocytosis pathway reflects biologically relevant heterogeneity in CRC and may help guide therapeutic stratification.\n                  <\/jats:p>","DOI":"10.1038\/s41388-026-04019-w","type":"journal-article","created":{"date-parts":[[2026,10,19]],"date-time":"2026-10-19T08:47:02Z","timestamp":1792399622000},"page":"5048-5056","update-policy":"https:\/\/doi.org\/10.1007\/springer_crossmark_policy","source":"Crossref","is-referenced-by-count":0,"title":["Activation of the endocytosis pathway stratifies subtypes and therapeutic sensitivity in colorectal cancer"],"prefix":"10.1038","volume":"45","author":[{"ORCID":"https:\/\/orcid.org\/0000-0002-1886-7070","authenticated-orcid":false,"given":"Hiroyuki","family":"Arai","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-8494-8031","authenticated-orcid":false,"given":"Andrew","family":"Elliott","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-7883-0798","authenticated-orcid":false,"given":"Yan","family":"Yang","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Alex","family":"Farrell","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-7961-8943","authenticated-orcid":false,"given":"Joshua","family":"Millstein","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-1267-8735","authenticated-orcid":false,"given":"Fang-Shu","family":"Ou","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Federico","family":"Innocenti","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0009-0006-6931-0359","authenticated-orcid":false,"given":"Jingyuan","family":"Wang","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Francesca","family":"Battaglin","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0009-0002-2480-4057","authenticated-orcid":false,"given":"Priya","family":"Jayachandran","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Sandra","family":"Algaze","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Shivani","family":"Soni","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Wu","family":"Zhang","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-0308-8223","authenticated-orcid":false,"given":"Richard M.","family":"Goldberg","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Michael J.","family":"Hall","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Aaron James","family":"Scott","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jimmy J.","family":"Hwang","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-1607-1386","authenticated-orcid":false,"given":"Emil","family":"Lou","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Benjamin A.","family":"Weinberg","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"John","family":"Marshall","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-2798-7568","authenticated-orcid":false,"given":"Sanjay","family":"Goel","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Joanne","family":"Xiu","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"W. 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EL reports research grants from the American Cancer Society (RSG-22-022-01-CDP) 2022-2026, and the Minnesota Ovarian Cancer Alliance in 2019, 2021, and 2022; The Randy Shaver Cancer Research and Community Fund; honoraria and travel expenses for lab-based research talks 2018-21, and equipment for laboratory-based research 2018-present, Novocure, Ltd; honorarium for panel discussion organized by Antidote Education for a CME module on diagnostics and treatment of HER2+ gastric and colorectal cancers, funded by Daiichi-Sankyo, 2021 (honorarium donated to lab); compensation for scientific review of proposed printed content, Elsevier Publishing and Johns Hopkins Press; consultant, Nomocan Pharmaceuticals (no financial compensation); Scientific Advisory Board Member, Minnetronix, LLC, 2018-2019 (no financial compensation); consultant and speaker honorarium, Boston Scientific US, 2019. BAW reports an immediate family member employed by Apple (stock\/other ownership interests); honoraria from Primum and Caris Life Sciences; consulting or advisory role for Merus NV, DoMore Diagnostics, Foundation Medicine, Agenus, Regeneron, and CytoDyn; speaker\u2019s bureau for Sirtex, Seagen, Merus NV, Daiichi Sankyo\/Astra Zeneca, Natera, Jazz Pharmaceuticals, and Pfizer; research funding from Ipsen, Immune System Key, Merck, and BioXCel therapeutics; expert testimony for AstraZeneca; travel, accommodations, and expense support from Merus NV. AE, AF, JX, and WMK are employees of Caris Life Sciences. All remaining authors have declared no conflicts of interest.","order":1,"name":"Ethics","label":"Competing interests","group":{"name":"EthicsHeading","label":"Ethics"}},{"value":"For the Caris cohort, the retrospective study was conducted under Caris Life Sciences\u2019 Research Data Banking protocol, which was reviewed and granted IRB exemption by the WCG IRB (Sponsor Protocol No.: CCC-001-0320). Because the study involved retrospective analysis of de-identified data, individual informed consent was not required. Patients enrolled in the CALGB\/SWOG 80405 clinical trial provided written informed consent for molecular research, and the protocol received IRB approval at each participating institution. All study procedures were conducted in accordance with relevant ethical principles, including the Declaration of Helsinki, the Belmont Report, and the U.S. Common Rule.","order":2,"name":"Ethics","label":"Ethics approval and consent to participate","group":{"name":"EthicsHeading","label":"Ethics"}}]}}