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The lethality of PDAC is driven by late diagnosis and inefficient therapies. The complex biology of PDAC involves various cellular components, including exosomes that carry molecular information between cells. Thus, recipient cells can be reprogrammed, impacting tumorigenesis. Rab27a is a GTPase responsible for the last step of exosomes biogenesis. Hence, dissecting the mechanisms that regulate the expression of Rab27a and that control exosomes biogenesis can provide fundamental insights into the molecular underpinnings regulating PDAC progression.<\/jats:p>\n              <\/jats:sec><jats:sec>\n                <jats:title>Methods<\/jats:title>\n                <jats:p>To assess the mechanism that regulates Rab27a expression in PDAC, we used PDAC cell lines. The biological significance of these findings was validated in PDAC genetically engineered mouse models (GEMMs) and human samples.<\/jats:p>\n              <\/jats:sec><jats:sec>\n                <jats:title>Results<\/jats:title>\n                <jats:p>In this work we demonstrate in human PDAC samples and GEMMs that Rab27a expression decreases throughout the development of the disease, and that Rab27a knockout promotes disease progression. What is more, we demonstrate that Rab27a expression is epigenetically regulated in PDAC. Treatment with demethylating agents increases Rab27a expression specifically in human PDAC cell lines. We found that SMC3, a component of the cohesin complex, regulates Rab27a expression in PDAC. SMC3 methylation is present in human PDAC specimens and treatment with demethylating agents increases SMC3 expression in human PDAC cell lines. Most importantly, high levels of SMC3 methylation are associated with a worse prognosis in PDAC. Mechanistically, we identified an enhancer region within the Rab27a gene that recruits SMC3, and modulates Rab27a expression.<\/jats:p>\n              <\/jats:sec><jats:sec>\n                <jats:title>Conclusion<\/jats:title>\n                <jats:p>Overall, we dissected a mechanism that regulates Rab27a expression during PDAC progression and impacts disease prognosis.<\/jats:p>\n              <\/jats:sec>","DOI":"10.1186\/s12967-023-04448-1","type":"journal-article","created":{"date-parts":[[2023,8,28]],"date-time":"2023-08-28T11:03:50Z","timestamp":1693220630000},"update-policy":"https:\/\/doi.org\/10.1007\/springer_crossmark_policy","source":"Crossref","is-referenced-by-count":3,"title":["SMC3 epigenetic silencing regulates Rab27a expression and drives pancreatic cancer progression"],"prefix":"10.1186","volume":"21","author":[{"given":"Nuno","family":"Bastos","sequence":"first","affiliation":[]},{"given":"St\u00e9phanie A.","family":"Castaldo","sequence":"additional","affiliation":[]},{"given":"B\u00e1rbara","family":"Adem","sequence":"additional","affiliation":[]},{"given":"Jos\u00e9 C.","family":"Machado","sequence":"additional","affiliation":[]},{"given":"Carlos A.","family":"Melo","sequence":"additional","affiliation":[]},{"ORCID":"https:\/\/orcid.org\/0000-0002-2291-4263","authenticated-orcid":false,"given":"Sonia A.","family":"Melo","sequence":"additional","affiliation":[]}],"member":"297","published-online":{"date-parts":[[2023,8,28]]},"reference":[{"issue":"3","key":"4448_CR1","doi-asserted-by":"publisher","first-page":"209","DOI":"10.3322\/caac.21660","volume":"71","author":"H Sung","year":"2021","unstructured":"Sung H, et al. 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The ethical committee of Centro Hospitalar Tondela-Viseu, Viseu (ID number 02\/07\/2018), and ethical committee of Carl Gustav Carus University Hospital, Dresden, Germany approved the use of tumor paraffin blocks. Human studies were conducted in accordance with the Declaration of Helsinki ethical guidelines. Animal protocol was approved by DGAV \u201cDire\u00e7\u00e3o Geral de Alimenta\u00e7\u00e3o e Veterin\u00e1ria\u201d.","order":2,"name":"Ethics","group":{"name":"EthicsHeading","label":"Ethics approval and consent to participate"}},{"value":"Not applicable.","order":3,"name":"Ethics","group":{"name":"EthicsHeading","label":"Consent for publication"}},{"value":"SAM hold patents in the area of exosomes biology that are licensed to Codiak Biosciences, Inc. The other authors declare no competing interests.","order":4,"name":"Ethics","group":{"name":"EthicsHeading","label":"Competing interests"}}],"article-number":"578"}}