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Here, we identify a metabolic checkpoint that controls the stability of the collagen receptor DDR1, and subsequent tumorigenesis. We show that defective Col-I remodeling deprives PDAC cells of the high affinity DDR1 ligand, \u00beCol-I, resulting in reduced ATP and activation of AMPK. AMPK phosphorylates DDR1 at T519, promoting its recognition by the E3 ubiquitin ligase adaptor FBXW2 and subsequent degradation. Importantly, this degradation pathway can be disabled by inflammatory signaling. Exposure to inflammatory cytokines induces methylation-dependent silencing of FBXW2, which establishes an inflammatory memory that preserves DDR1 stability, enabling sustained ligand-triggered receptor oligomerization and downstream NF-\u03baB-NRF2 signaling even in restrictive stromal environments. Together, these findings identify regulated receptor turnover as a mechanism through which stromal architecture, metabolic state, and inflammatory memory are integrated to control PDAC progression.<\/jats:p>","DOI":"10.64898\/2026.04.01.715820","type":"posted-content","created":{"date-parts":[[2026,4,4]],"date-time":"2026-04-04T05:00:14Z","timestamp":1775278814000},"source":"Crossref","is-referenced-by-count":0,"title":["Inflammatory memory disables a DDR1 degradation checkpoint to enable pancreatic cancer growth"],"prefix":"10.64898","author":[{"given":"Fei","family":"Yang","sequence":"first","affiliation":[{"name":"Institutes of Biomedical Sciences, Liver Cancer Institute, Zhongshan Hospital, Fudan University, Shanghai, China"},{"name":"Department of Hepatobiliary Surgery, The First Affiliated Hospital of Anhui Medical University, MOE Innovation Center for Basic Research in Tumor Immunotherapy, Anhui Province Key Laboratory of Tumor Immune Microenvironment and Immunotherapy, Hefei, Anhui, China"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Bo","family":"Lin","sequence":"additional","affiliation":[{"name":"Institutes of Biomedical Sciences, Liver Cancer Institute, Zhongshan Hospital, Fudan University, Shanghai, China"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Zihang","family":"Yuan","sequence":"additional","affiliation":[{"name":"Institutes of Biomedical Sciences, Liver Cancer Institute, Zhongshan Hospital, Fudan University, Shanghai, China"},{"name":"Department of Hepatobiliary Surgery, The First Affiliated Hospital of Anhui Medical University, MOE Innovation Center for Basic Research in Tumor Immunotherapy, Anhui Province Key Laboratory of Tumor Immune Microenvironment and Immunotherapy, Hefei, Anhui, China"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Yongkang","family":"Yuan","sequence":"additional","affiliation":[{"name":"Institutes of Biomedical Sciences, Liver Cancer Institute, Zhongshan Hospital, Fudan University, Shanghai, China"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Xiaohong","family":"Pu","sequence":"additional","affiliation":[{"name":"Department of Pathology, the Affiliated Drum Tower Hospital of Medical School, Nanjing University, Nanjing, Jiangsu, China"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Chunlan","family":"Wang","sequence":"additional","affiliation":[{"name":"Institutes of Biomedical Sciences, Liver Cancer Institute, Zhongshan Hospital, Fudan University, Shanghai, China"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Kosuke","family":"Watari","sequence":"additional","affiliation":[{"name":"Laboratory of Gene Regulation and Signal Transduction, Departments of Pharmacology and Pathology, School of Medicine, University of California San Diego, La Jolla, CA, USA"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Rongkui","family":"Luo","sequence":"additional","affiliation":[{"name":"Department of Pathology, Zhongshan Hospital, Fudan University, Shanghai, China"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Beicheng","family":"Sun","sequence":"additional","affiliation":[{"name":"Department of Hepatobiliary Surgery, The First Affiliated Hospital of Anhui Medical University, MOE Innovation Center for Basic Research in Tumor Immunotherapy, Anhui Province Key Laboratory of Tumor Immune Microenvironment and Immunotherapy, Hefei, Anhui, China"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Michael","family":"Karin","sequence":"additional","affiliation":[{"name":"Laboratory of Gene Regulation and Signal Transduction, Departments of Pharmacology and Pathology, School of Medicine, University of California San Diego, La Jolla, CA, USA"},{"name":"Center for Metabolic and Liver Diseases, SBP Medical Discovery Institute, La Jolla, CA, USA"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-2344-3886","authenticated-orcid":false,"given":"Hua","family":"Su","sequence":"additional","affiliation":[{"name":"Institutes of Biomedical Sciences, Liver Cancer Institute, Zhongshan Hospital, Fudan University, Shanghai, China"}],"role":[{"role":"author","vocabulary":"crossref"}]}],"member":"54368","reference":[{"key":"2026040705200520000_2026.04.01.715820v1.1","doi-asserted-by":"publisher","DOI":"10.1016\/j.cell.2023.02.014"},{"key":"2026040705200520000_2026.04.01.715820v1.2","doi-asserted-by":"crossref","unstructured":"Yuan Z , Lin B , Wang C , Yan Z , Yang F , Su H . 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