Year: 2026
Type: preprint
Abstract: Prostate cancer (PCa) progression is accompanied by profound alterations in cell-extracellular matrix (ECM) adhesion, nuclear architecture and mechanical adaptability, yet the molecular mechanisms linking these processes remain poorly understood. Hemidesmosomes (HDs), formed by α6β4-integrins, anchor epithelial cells to the basement membrane and couple extracellular forces to the intermediate filament (IF) cytoskeleton. Here, we identify a previously unrecognized tumor-suppressive function of β4-integrins in preserving nuclear integrity in prostate epithelial cells. Loss of β4-integrins disrupted the cytokeratin-5 network and its coupling to the nucleus, leading to nuclear softening, lamin remodeling, reduced heterochromatin content and enhanced confined migration. Unexpectedly, proximity-labeling proteomics revealed that β4-integrins engage nuclear pore complex (NPC) components in an α6-independent manner, particularly upon HD disassembly. Selected interactions were validated using proximity ligation and co-immunoprecipitation assays. β4-integrin loss was associated with enlarged nuclear pores and aberrant nucleocytoplasmic transport, including nuclear accumulation of YAP1. Consistent with these findings, reduced β4-integrin expression in a large PCa tissue cohort correlated with altered nuclear morphology, adverse clinicopathological features, metastatic progression, and poor patient survival. Collectively, our study establishes β4-integrins as a critical molecular link between cell-ECM adhesion, nuclear mechanics and genome integrity.
Authors: Anette Schmidt, Rong Wei, Paulina Nastaly, Maliha Mehnaz-Enamul, Atharva Agashe, Michal Rychlowski, Katarzyna Bury, Saara Koivusalo, Qin Zhang, Crescenzo Frascogna, Carlo F Natale, Xiayun Yang, Aleksander Jarmakowicz, Anne Ahtikoski, Markku Vaarala, Xiaonan Liu, Katarzyna Ruckemann-Dziurdzinska, Markku Varjosalo, Ewa Bryl, Amrinder Nain, Gong-Hong Wei, Tomasz Wenta, Aki Manninen
Institutions: University of Oulu, University of Gdańsk, Gdańsk Medical University, Virginia Tech, Italian Institute of Technology, Center for Advanced Biomaterials for Healthcare, University of Naples Federico II, Oulu University Hospital, Medical University of Silesia, University of Helsinki, HiLIFE – Elämäntieteiden Instituutti, Shanghai Medical College of Fudan University, Chinese Academy of Medical Sciences & Peking Union Medical College, Fudan University, Fudan University Shanghai Cancer Center, Suzhou Institute of Systems Medicine
Language: English
Subfield: Immunology and Allergy
Field: Medicine
Domain: Health Sciences
Open Access status: green
Awards: G2257223166, G3217225776, EFRI BEGIN OI: Reservoid Computer - Intelligent and Evolving Mechano-Reservoir Computing with Living Spheroids on Fibers, G4323716960, G4575391396, G6209326266, G6330772937, Collaborative Research: Theory and experiment of contact inhibition of locomotion in nanofiber geometries, G7973425342, Matrix biophysics and pericyte mechanobiology in (patho)physiological angiogenesis
OpenAlex ID: W7207697739