An SRRM3-regulated neural alternative splicing program is subverted to promote tumor progression in pancreatic neuroendocrine cells

Potiri, Myrto; Moschou, Charikleia; Erpapazoglou, Zoi; Rouni, Georgia; Kotsoni, Anastasia; Andreadou, Margarita; Klavdianos, Anastasios; Dragolia, Melina; Ntafis, Vasileios; Schrader, Joerg; Juan-Mateu, Jonàs; Dedos, Skarlatos G.; Samiotaki, Martina; Kostourou, Vassiliki; Rogalska, Malgorzata; Kafasla, Panagiota

An SRRM3-regulated neural alternative splicing program is subverted to promote tumor progression in pancreatic neuroendocrine cells

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dc.contributor.author Potiri, Myrto
dc.contributor.author Moschou, Charikleia
dc.contributor.author Erpapazoglou, Zoi
dc.contributor.author Rouni, Georgia
dc.contributor.author Kotsoni, Anastasia
dc.contributor.author Andreadou, Margarita
dc.contributor.author Klavdianos, Anastasios
dc.contributor.author Dragolia, Melina
dc.contributor.author Ntafis, Vasileios
dc.contributor.author Schrader, Joerg
dc.contributor.author Juan-Mateu, Jonàs
dc.contributor.author Dedos, Skarlatos G.
dc.contributor.author Samiotaki, Martina
dc.contributor.author Kostourou, Vassiliki
dc.contributor.author Rogalska, Malgorzata
dc.contributor.author Kafasla, Panagiota
dc.date.accessioned 2025-10-07T05:36:29Z
dc.date.available 2025-10-07T05:36:29Z
dc.date.issued 2025
dc.description.abstract Pancreatic neuroendocrine tumors (PanNETs) are a heterogeneous group of neoplasms arising in pancreatic islets and altering the hormone-secreting function of neuroendocrine cells. Genome-wide approaches have revealed the genomic landscape of PanNETs but have not explained their problematic hormone secretion. We show here that alternative splicing (AS) deregulation is responsible for changes in the secretory ability of PanNET cells. We reveal that the RNA-binding protein SRRM3 is upregulated in PanNETs and favors the inclusion of a group of alternative microexons in certain mRNAs. These microexons are part of a larger neural program regulated by SRRM3, and their inclusion results in protein isoforms that change stimulus-induced insulin trafficking and secretion. By downregulating SRRM3 or inhibiting its binding to three of the microexon-bearing pre-mRNAs in animal and cellular PanNET models, we prove the necessity of SRRM3 for hormone secretion, PanNET progression, and enhancement of the neural component of PanNET tumors.
dc.description.sponsorship This study was supported by a Neuroendocrine Tumor Research Foundation (NETRF) Pilot Award (ID: 57222). M.P. was supported by the Hellenic Foundation for Research and Innovation (HFRI) (Fellowship: 11141). M.A. was supported by InfrafrontierGR/Phenotypos, NSRF 2014–2020, and MIS 5002135. M.E.R. and J.J.-M. were supported by ERC AdvG 670146. M.S. was supported by an RRF Action 16624 from the National Recovery and Resilience Plan “Greece 2.0” (Next Generation EU Grant ID: 5173820). V.K. was supported by a Fondation Santé Biomedical Research grant.
dc.format.mimetype application/pdf
dc.identifier.citation Potiri M, Moschou C, Erpapazoglou Z, Rouni G, Kotsoni A, Andreadou M, et al. An SRRM3-regulated neural alternative splicing program is subverted to promote tumor progression in pancreatic neuroendocrine cells. Cell Rep. 2025 Aug 26;44(8):116022. DOI: 10.1016/j.celrep.2025.116022
dc.identifier.doi http://dx.doi.org/10.1016/j.celrep.2025.116022
dc.identifier.issn 2211-1247
dc.identifier.uri http://hdl.handle.net/10230/71405
dc.language.iso eng
dc.publisher Elsevier
dc.relation.ispartof Cell Rep. 2025 Aug 26;44(8):116022
dc.relation.projectID info:eu-repo/grantAgreement/EC/H2020/670146
dc.rights.accessRights info:eu-repo/semantics/openAccess
dc.rights.uri http://creativecommons.org/licenses/by/4.0/
dc.subject.keyword ASOs
dc.subject.keyword CP: Cancer
dc.subject.keyword PanNETs
dc.subject.keyword SRRM3
dc.subject.keyword Alternative splicing
dc.subject.keyword Hormone secretion
dc.subject.keyword Microexons
dc.subject.keyword Neural microexons
dc.subject.keyword Pancreatic neuroendocrine tumors
dc.subject.keyword Splice-switching oligonucleotides
dc.title An SRRM3-regulated neural alternative splicing program is subverted to promote tumor progression in pancreatic neuroendocrine cells
dc.type info:eu-repo/semantics/article
dc.type.version info:eu-repo/semantics/publishedVersion

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