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Targeting ROCK2 improves macromolecular permeability in a 3D fibrotic pancreatic cancer microenvironment model.
Tanaka, Hiroyoshi Y; Nakazawa, Takuya; Miyazaki, Takuya; Cabral, Horacio; Masamune, Atsushi; Kano, Mitsunobu R.
Afiliación
  • Tanaka HY; Department of Pharmaceutical Biomedicine, Graduate School of Medicine, Dentistry, and Pharmaceutical Sciences, Okayama University, 1-1-1 Tsushima-naka, Kita-ku, Okayama-shi, Okayama 700-8530, Japan.
  • Nakazawa T; Department of Pharmaceutical Biomedicine, Graduate School of Interdisciplinary Science and Engineering in Health Systems, Okayama University, 1-1-1 Tsushima-naka, Kita-ku, Okayama-shi, Okayama 700-8530, Japan.
  • Miyazaki T; Kanagawa Institute of Industrial Science and Technology (KISTEC), 705-1 Shimoimaizumi, Ebina-shi, Kanagawa 243-0435, Japan.
  • Cabral H; Department of Bioengineering, Graduate School of Engineering, The University of Tokyo, 7-3-1 Hongo, Bunkyo-ku, Tokyo 113-8656, Japan.
  • Masamune A; Division of Gastroenterology, Tohoku University Graduate School of Medicine, 1-1 Seiryo-machi, Aoba-ku, Sendai-shi, Miyagi 980-8574, Japan.
  • Kano MR; Department of Pharmaceutical Biomedicine, Graduate School of Interdisciplinary Science and Engineering in Health Systems, Okayama University, 1-1-1 Tsushima-naka, Kita-ku, Okayama-shi, Okayama 700-8530, Japan. Electronic address: mikano-tky@umin.net.
J Control Release ; 369: 283-295, 2024 May.
Article en En | MEDLINE | ID: mdl-38522816
ABSTRACT
Pancreatic cancer is characterized by a densely fibrotic stroma. The fibrotic stroma hinders the intratumoral penetration of nanomedicine and diminishes therapeutic efficacy. Fibrosis is characterized by an abnormal organization of extracellular matrix (ECM) components, namely the abnormal deposition and/or orientation of collagen and fibronectin. Abnormal ECM organization is chiefly driven by pathological signaling in pancreatic stellate cells (PSCs), the main cell type involved in fibrogenesis. However, whether targeting signaling pathways involved in abnormal ECM organization improves the intratumoral penetration of nanomedicines is unknown. Here, we show that targeting transforming growth factor-ß (TGFß)/Rho-associated kinase (ROCK) 1/2 signaling in PSCs normalizes ECM organization and concomitantly improves macromolecular permeability of the fibrotic stroma. Using a 3-dimensional cell culture model of the fibrotic pancreatic cancer microenvironment, we found that pharmacological inhibition of TGFß or ROCK1/2 improves the permeation of various macromolecules. By using an isoform-specific pharmacological inhibitor and siRNAs, we show that targeting ROCK2, but not ROCK1, alone is sufficient to normalize ECM organization and improve macromolecular permeability. Moreover, we found that ROCK2 inhibition/knockdown attenuates Yes-associated protein (YAP) nuclear localization in fibroblasts co-cultured with pancreatic cancer cells in 3D. Finally, pharmacological inhibition or siRNA-mediated knockdown of YAP normalized ECM organization and improved macromolecular permeability. Our results together suggest that the TGFß/ROCK2/YAP signaling axis may be therapeutically targeted to normalize ECM organization and improve macromolecular permeability to augment therapeutic efficacy of nanomedicines in pancreatic cancer.
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Texto completo: 1 Colección: 01-internacional Base de datos: MEDLINE Asunto principal: Neoplasias Pancreáticas / Permeabilidad / Factor de Crecimiento Transformador beta / Quinasas Asociadas a rho / Células Estrelladas Pancreáticas / Microambiente Tumoral Límite: Humans Idioma: En Revista: J Control Release Asunto de la revista: FARMACOLOGIA Año: 2024 Tipo del documento: Article País de afiliación: Japón Pais de publicación: Países Bajos
Texto completo
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Texto completo: 1 Colección: 01-internacional Base de datos: MEDLINE Asunto principal: Neoplasias Pancreáticas / Permeabilidad / Factor de Crecimiento Transformador beta / Quinasas Asociadas a rho / Células Estrelladas Pancreáticas / Microambiente Tumoral Límite: Humans Idioma: En Revista: J Control Release Asunto de la revista: FARMACOLOGIA Año: 2024 Tipo del documento: Article País de afiliación: Japón Pais de publicación: Países Bajos