Exploring the role of DYRK1A in the pancreatic ductal adenocarcinoma tumour microenvironment and its potential as a therapeutic target

Tesi realitzada a l'Institut de Investigacions Biomèdiques August Pi i Sunyer (IDIBAPS)

Detalles Bibliográficos
Autor: Pascual Sabater, Silvia
Tipo de recurso: tesis doctoral
Estado:Versión publicada
Fecha de publicación:2024
País:España
Institución:CBUC, CESCA
Repositorio:TDR. Tesis Doctorales en Red
OAI Identifier:oai:www.tdx.cat:10803/693921
Acceso en línea:http://hdl.handle.net/10803/693921
Access Level:acceso abierto
Palabra clave:Càncer de pàncrees
Càncer de páncreas
Pancreas cancer
Fibroblasts
Fibroblastos
Tractament adjuvant del càncer
Tratamientos adjuvantes del cáncer
Adjuvant treatment of cancer
Ciències de la Salut
616
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oai_identifier_str oai:www.tdx.cat:10803/693921
network_acronym_str ES
network_name_str España
repository_id_str
dc.title.none.fl_str_mv Exploring the role of DYRK1A in the pancreatic ductal adenocarcinoma tumour microenvironment and its potential as a therapeutic target
title Exploring the role of DYRK1A in the pancreatic ductal adenocarcinoma tumour microenvironment and its potential as a therapeutic target
spellingShingle Exploring the role of DYRK1A in the pancreatic ductal adenocarcinoma tumour microenvironment and its potential as a therapeutic target
Pascual Sabater, Silvia
Càncer de pàncrees
Càncer de páncreas
Pancreas cancer
Fibroblasts
Fibroblastos
Tractament adjuvant del càncer
Tratamientos adjuvantes del cáncer
Adjuvant treatment of cancer
Ciències de la Salut
616
title_short Exploring the role of DYRK1A in the pancreatic ductal adenocarcinoma tumour microenvironment and its potential as a therapeutic target
title_full Exploring the role of DYRK1A in the pancreatic ductal adenocarcinoma tumour microenvironment and its potential as a therapeutic target
title_fullStr Exploring the role of DYRK1A in the pancreatic ductal adenocarcinoma tumour microenvironment and its potential as a therapeutic target
title_full_unstemmed Exploring the role of DYRK1A in the pancreatic ductal adenocarcinoma tumour microenvironment and its potential as a therapeutic target
title_sort Exploring the role of DYRK1A in the pancreatic ductal adenocarcinoma tumour microenvironment and its potential as a therapeutic target
dc.creator.none.fl_str_mv Pascual Sabater, Silvia
author Pascual Sabater, Silvia
author_facet Pascual Sabater, Silvia
author_role author
dc.contributor.none.fl_str_mv Fillat i Fonts, Cristina
Fillat i Fonts, Cristina
Universitat de Barcelona. Facultat de Medicina i Ciències de la Salut
dc.subject.none.fl_str_mv Càncer de pàncrees
Càncer de páncreas
Pancreas cancer
Fibroblasts
Fibroblastos
Tractament adjuvant del càncer
Tratamientos adjuvantes del cáncer
Adjuvant treatment of cancer
Ciències de la Salut
616
topic Càncer de pàncrees
Càncer de páncreas
Pancreas cancer
Fibroblasts
Fibroblastos
Tractament adjuvant del càncer
Tratamientos adjuvantes del cáncer
Adjuvant treatment of cancer
Ciències de la Salut
616
description Tesi realitzada a l'Institut de Investigacions Biomèdiques August Pi i Sunyer (IDIBAPS)
publishDate 2024
dc.date.none.fl_str_mv 2024
2025
2025
dc.type.none.fl_str_mv info:eu-repo/semantics/doctoralThesis
info:eu-repo/semantics/publishedVersion
format doctoralThesis
status_str publishedVersion
dc.identifier.none.fl_str_mv http://hdl.handle.net/10803/693921
url http://hdl.handle.net/10803/693921
dc.language.none.fl_str_mv Inglés
language_invalid_str_mv Inglés
dc.rights.none.fl_str_mv info:eu-repo/semantics/openAccess
eu_rights_str_mv openAccess
dc.format.none.fl_str_mv 282 p.
application/pdf
dc.publisher.none.fl_str_mv Universitat de Barcelona
publisher.none.fl_str_mv Universitat de Barcelona
dc.source.none.fl_str_mv TDX (Tesis Doctorals en Xarxa)
reponame:TDR. Tesis Doctorales en Red
instname:CBUC, CESCA
instname_str CBUC, CESCA
reponame_str TDR. Tesis Doctorales en Red
collection TDR. Tesis Doctorales en Red
repository.name.fl_str_mv
repository.mail.fl_str_mv
_version_ 1869422639872737280
spelling Exploring the role of DYRK1A in the pancreatic ductal adenocarcinoma tumour microenvironment and its potential as a therapeutic targetPascual Sabater, SilviaCàncer de pàncreesCàncer de páncreasPancreas cancerFibroblastsFibroblastosTractament adjuvant del càncerTratamientos adjuvantes del cáncerAdjuvant treatment of cancerCiències de la Salut616Tesi realitzada a l'Institut de Investigacions Biomèdiques August Pi i Sunyer (IDIBAPS)[eng] Pancreatic ductal adenocarcinoma (PDAC) is known for its poor prognosis, with mortality rates that almost equal its incidence. Surgery is currently the only potentially curative option, but less than 20% of patients are eligible for resection at diagnosis, with systemic chemotherapy being the standard treatment for both resectable and metastatic disease. Despite modest improvements in survival with newer drug combinations, the aggressive nature of PDAC demands more effective therapies. One of the most challenging features of PDAC is its tumour microenvironment (TME), which can constitute up to 90% of the tumour volume. This TME is abundant in extracellular matrix (ECM) and includes cancer-associated fibroblasts (CAFs), which contribute to tumour progression by releasing growth factors, inflammatory ligands and ECM proteins that promote cancer cell proliferation, invasion, therapy resistance, and immune exclusion. However, therapeutic targeting of CAFs has been controversial, as their total depletion or inhibition can accelerate cancer progression. Recent research has revealed significant CAF heterogeneity, emphasising the need to consider their functional diversity in developing new therapeutic strategies. The dual-specificity tyrosine-regulated kinase 1A (DYRK1A) plays critical roles in several cellular processes and signal transduction pathways relevant to cancer via multiple interactors and substrates. Recently, it has emerged as a key player in PDAC, where it exerts a protumourigenic role by stabilising c-MET and EGFR receptors in cancer cells. Histological evidence showing abundant DYRK1A expression in primary tumours from a cohort of PDAC patients prompted us to investigate the role of this kinase in PDAC CAFs to evaluate its potential as a therapeutic target for remodelling the tumour-promoting, immunosuppressive PDAC stroma. To identify DYRK1A-mediated functions of PDAC CAFs, we used short hairpin (shRNA)-based knockdown or small-molecule inhibitors to reduce its expression or activity and assessed changes in cell-intrinsic properties and paracrine communication. Our findings revealed that both aspects were altered by reduced DYRK1A function, leading to reduced migratory and contractile capabilities in these cells. Transcriptome profiling of shDYRK1A PDAC CAFs showed an enrichment in pathways associated with cytoskeletal regulation, suggesting a putative regulatory mechanism for those changes. Moreover, shDYRK1A CAFs presented altered paracrine communication with cancer cells, inducing less migration of PANC-1 cells and reducing organoid growth. Secretome analysis by mass spectrometry revealed several DYRK1A-dependent downregulated factors, among which CXCL12 appeared as an interesting candidate due to their described roles in immunosuppression and PDAC progression. With the aim to evaluate potential synergies between DYRK1A inhibition with chemotherapy and/or immunotherapy, we used patient-derived organoid (PDO) cultures and immunocompetent syngeneic xenograft KPC mouse models. Combining DYRK1A inhibitors and oxaliplatin led to modest synergistic effects in PDAC PDOs that were stronger in vivo. On the other hand, combination with α-PD-1 antibodies reduced immunosuppressive infiltration in the KPC xenograft model, but increased antitumour efficacy required the addition of oxaliplatin to the treatment regime.BiomedicinaUniversitat de BarcelonaFillat i Fonts, CristinaFillat i Fonts, CristinaUniversitat de Barcelona. Facultat de Medicina i Ciències de la Salut202520252024info:eu-repo/semantics/doctoralThesisinfo:eu-repo/semantics/publishedVersion282 p.application/pdfhttp://hdl.handle.net/10803/693921TDX (Tesis Doctorals en Xarxa)reponame:TDR. Tesis Doctorales en Redinstname:CBUC, CESCAInglésADVERTIMENT. Tots els drets reservats. L'accés als continguts d'aquesta tesi doctoral i la seva utilització ha de respectar els drets de la persona autora. Pot ser utilitzada per a consulta o estudi personal, així com en activitats o materials d'investigació i docència en els termes establerts a l'art. 32 del Text Refós de la Llei de Propietat Intel·lectual (RDL 1/1996). Per altres utilitzacions es requereix l'autorització prèvia i expressa de la persona autora. En qualsevol cas, en la utilització dels seus continguts caldrà indicar de forma clara el nom i cognoms de la persona autora i el títol de la tesi doctoral. No s'autoritza la seva reproducció o altres formes d'explotació efectuades amb finalitats de lucre ni la seva comunicació pública des d'un lloc aliè al servei TDX. Tampoc s'autoritza la presentació del seu contingut en una finestra o marc aliè a TDX (framing). Aquesta reserva de drets afecta tant als continguts de la tesi com als seus resums i índexs.info:eu-repo/semantics/openAccessoai:www.tdx.cat:10803/6939212026-06-14T12:46:07Z
score 15,81155

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