Leiden University Scholarly Publications

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Bergonzini, C. (2026)

Acquired resistance in pancreatic cancer: characterization and exploration of actionable targets of a multifactorial disease

Doctoral Thesis
Pancreatic ductal adenocarcinoma (PDAC) is among the cancers with the highest mortality rate, despite a relatively low incidence. Most patients are diagnosed at unresectable stages and response to chemotherapy is often limited due to rapid emergence of resistance. The stiff desmoplastic tumor microenvironment (TME) has been suggested to play a role in chemoresistance, but insights on this aspect are limited. Therefore, this thesis investigates molecular mechanisms of chemoresistance and the mechanobiological traits associated with them. Through a multidisciplinary approach, across multiple PDAC models with acquired resistance to paclitaxel or gemcitabine, we elucidated recurrent functional mechanisms causing resistance and identified potential targets and strategies to restore sensitivity. Furthermore, Integrin subunit α2 (ITGA2) emerged as a mechanosensitive regulator with a prognostic role, with its expression increasing with substrate stiffness and correlating with poor...Show morePancreatic ductal adenocarcinoma (PDAC) is among the cancers with the highest mortality rate, despite a relatively low incidence. Most patients are diagnosed at unresectable stages and response to chemotherapy is often limited due to rapid emergence of resistance. The stiff desmoplastic tumor microenvironment (TME) has been suggested to play a role in chemoresistance, but insights on this aspect are limited. Therefore, this thesis investigates molecular mechanisms of chemoresistance and the mechanobiological traits associated with them. Through a multidisciplinary approach, across multiple PDAC models with acquired resistance to paclitaxel or gemcitabine, we elucidated recurrent functional mechanisms causing resistance and identified potential targets and strategies to restore sensitivity. Furthermore, Integrin subunit α2 (ITGA2) emerged as a mechanosensitive regulator with a prognostic role, with its expression increasing with substrate stiffness and correlating with poor survival in gemcitabine-treated patients. Finally, resistant cells displayed enhanced traction forces and motility, independent of the resistance mechanism, highlighting the complexity of the mechanical adaptation associated with therapeutic escape. Together, these findings provide actionable insights into the complex process of PDAC acquired chemoresistance and its connection with the mechanical properties of the tumor microenvironment.Show less
Pancreatic cancer
Chemoresistance
Mechanobiology
PDAC
Tumor microenvironment
All authors
Bergonzini, C.
Supervisor
Danen, E.H.J.; Schmidt, T.
Co-supervisor
Giovannetti, E.
Committee
Eck, M. van; Lange, E.C.M. de; Heitman, L.H.; Pegtel, M.; Kuppen, P.J.K.
Qualification
Doctor (dr.)
Awarding Institution
Leiden Academic Centre for Drug Research (LACDR), Faculty of Science, Leiden University
Date
2026-01-27
ISBN (print)
9789465370484