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We identified transcriptionally distinct cancer subpopulations or cell states using unsupervised clustering and characterised\u2011 their regulatory network as well as clinical associations with treatment response, metastatic progression and survival. Findings were validated using multiple independent TNBC cohorts.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Results<\/jats:title>\n                    <jats:p>\n                      Four major transcriptionally distinct cancer cell states were identified that were shared across the PDX models. These cell states were characterised by enrichment of developmental, hypoxia, interferon signalling, chromosomal instability, and DNA-damage pathways. Hypoxia and interferon signalling cell states shared transcriptional features of drug-tolerant persister cells. Hypoxia cell states contained both cycling and non-cycling cells and were not associated with mutation status. Extensive validation in TNBC patient cohorts confirmed that dysregulated pathways enriched in residual disease were pre-existing in chemotherapy-na\u00efve patients, maintained in distant metastases and were both prognostic and predictive of treatment response.\n                      <jats:italic>In vitro<\/jats:italic>\n                      functional validation highlighted that inhibition of the lysine demethylase KDM5B suppressed the emergence of drug\u2011tolerant persister cells.\n                    <\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Conclusions<\/jats:title>\n                    <jats:p>Neoadjuvant therapy selects for epigenetically regulated, hypoxia-related cycling and non-cycling drug\u2011tolerant persister cells in TNBC. These cell states are maintained in metastatic disease and are prognostic\/predictive of therapy response.<\/jats:p>\n                  <\/jats:sec>","DOI":"10.1186\/s13073-026-01643-9","type":"journal-article","created":{"date-parts":[[2026,4,9]],"date-time":"2026-04-09T12:26:12Z","timestamp":1775737572000},"update-policy":"https:\/\/doi.org\/10.1007\/springer_crossmark_policy","source":"Crossref","is-referenced-by-count":1,"title":["Co-occurrence of transcriptionally distinct persister cell states underpins neoadjuvant therapy resistance in triple\u2011negative breast cancer"],"prefix":"10.1186","volume":"18","author":[{"given":"Yu","family":"Zhang","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Fatemeh Ahmadi","family":"Moughari","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Ioanna","family":"Mavrommati","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Nora J.","family":"Doleschall","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Kate","family":"Moore","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Gareth","family":"Muirhead","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Ram Rajaram","family":"Srinivasan","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Ping","family":"Gong","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jonathan T.","family":"Lei","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Amy","family":"Fleming","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Hwei Minn","family":"Khoo","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Naomi","family":"Guppy","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Gabrielle","family":"Elshtein","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Mohammed","family":"Inayatullah","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Vijay K.","family":"Tiwari","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Lacey E.","family":"Dobrolecki","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Michael T.","family":"Lewis","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Syed","family":"Haider","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Rachael","family":"Natrajan","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"297","published-online":{"date-parts":[[2026,4,9]]},"reference":[{"key":"1643_CR1","doi-asserted-by":"publisher","first-page":"236","DOI":"10.1093\/annonc\/mdy547","volume":"30","author":"SJ Luen","year":"2019","unstructured":"Luen SJ, Salgado R, Dieci MV, Vingiani A, Curigliano G, Gould RE, Castaneda C, D\u2019Alfonso T, Sanchez J, Cheng E, et al. 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