{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,5,8]],"date-time":"2026-05-08T15:13:47Z","timestamp":1778253227687,"version":"3.51.4"},"reference-count":50,"publisher":"Wiley","issue":"5","license":[{"start":{"date-parts":[[2025,10,27]],"date-time":"2025-10-27T00:00:00Z","timestamp":1761523200000},"content-version":"vor","delay-in-days":0,"URL":"http:\/\/creativecommons.org\/licenses\/by\/4.0\/"},{"start":{"date-parts":[[2025,10,27]],"date-time":"2025-10-27T00:00:00Z","timestamp":1761523200000},"content-version":"tdm","delay-in-days":0,"URL":"http:\/\/doi.wiley.com\/10.1002\/tdm_license_1.1"}],"funder":[{"DOI":"10.13039\/100004334","name":"Merck","doi-asserted-by":"publisher","id":[{"id":"10.13039\/100004334","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":["febs.onlinelibrary.wiley.com"],"crossmark-restriction":true},"short-container-title":["Molecular Oncology"],"published-print":{"date-parts":[[2026,5]]},"abstract":"<jats:p>\n                    Cancer\u2010associated fibroblasts (CAFs) are sought after as potential therapeutic targets due to their pro\u2010 and antitumorigenic functions, which are attributed to specializations in CAF subtypes. A precise targeting of specific subtypes would be required to design therapies that effectively modulate CAF phenotypes, necessitating translatable model systems to support target discovery efforts. However, not only is our knowledge of CAF heterogeneity in solid tumors lacking, particularly in pancreatic tumors, but the translatability of CAF models has also not been rigorously evaluated. Here, we develop a coculturing model with primary CAFs and immortalized tumor cell lines that can reliably represent CAF phenotypes observed in tumors, with correlations to immuno\u2010resistant and immunomodulatory phenotypes. Using single\u2010cell transcriptomics, we characterize the CAF subtype heterogeneity in the\n                    <jats:italic>in vitro<\/jats:italic>\n                    CAF cell lines isolated from pancreatic cancer patients and investigate the impact of perturbing potential stromal genes on different CAF subtypes. We also infer the continuum of state changes underlying the interconvertibility of CAF subtypes. Finally, we use immortalized CAF cell lines to perform single\u2010cell CRISPR perturbations of stromal targets, revealing the subtype\u2010specific effects of perturbations and the impact of model\u2010type selection on the translatability of insights.\n                  <\/jats:p>","DOI":"10.1002\/1878-0261.70153","type":"journal-article","created":{"date-parts":[[2025,10,28]],"date-time":"2025-10-28T13:11:39Z","timestamp":1761657099000},"page":"1253-1269","update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":1,"title":["<i>In vitro<\/i>\n                    models of cancer\u2010associated fibroblast heterogeneity uncover subtype\u2010specific effects of\n                    <scp>CRISPR<\/scp>\n                    perturbations"],"prefix":"10.1002","volume":"20","author":[{"given":"Elysia","family":"Saputra","sequence":"first","affiliation":[{"name":"Department of Data, AI, and Genome Sciences Merck &amp; Co., Inc.  Rahway NJ USA"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Shamsudheen Karuthedath","family":"Vellarikkal","sequence":"additional","affiliation":[{"name":"Department of Data, AI, and Genome Sciences Merck &amp; Co., Inc.  Rahway NJ USA"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Lixia","family":"Li","sequence":"additional","affiliation":[{"name":"Department of Data, AI, and Genome Sciences Merck &amp; Co., Inc.  Rahway NJ USA"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Hong","family":"Sun","sequence":"additional","affiliation":[{"name":"Department of Data, AI, and Genome Sciences Merck &amp; Co., Inc.  Rahway NJ USA"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Khoa","family":"Nguyen","sequence":"additional","affiliation":[{"name":"Department of Discovery Oncology Merck &amp; Co., Inc.  Rahway NJ USA"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Amber","family":"Montano","sequence":"additional","affiliation":[{"name":"Department of Discovery Oncology Merck &amp; Co., Inc.  Rahway NJ USA"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Suchitra","family":"Natarajan","sequence":"additional","affiliation":[{"name":"Department of Discovery Oncology Merck &amp; Co., Inc.  Rahway NJ USA"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Federica","family":"Piccioni","sequence":"additional","affiliation":[{"name":"Department of Data, AI, and Genome Sciences Merck &amp; Co., Inc.  Rahway NJ USA"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Alex Michael","family":"Tamburino","sequence":"additional","affiliation":[{"name":"Department of Data, AI, and Genome Sciences Merck &amp; Co., Inc.  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