2. Academic Validation
  3. Collagen Signaling via DDR1 Exacerbates Barriers to Macromolecular Drug Delivery in a 3D Model of Pancreatic Cancer Fibrosis

Collagen Signaling via DDR1 Exacerbates Barriers to Macromolecular Drug Delivery in a 3D Model of Pancreatic Cancer Fibrosis

  • Small. 2025 Dec;21(50):e06926. doi: 10.1002/smll.202506926.
Mayu Ohira 1,  Moe Kitamura 1,  Hiroyo Iwasaki 1,  Haruko Ohta-Okano 1,  Hiyori Tsujii 1,  Reika Nakamura 1,  Takuya Nakazawa 2,  Akihiro Nishiguchi 3,  Masaya Yamamoto 4 5,  Kensuke Osada 6,  Shinichi Toyooka 7,  Horacio Cabral 8,  Atsushi Masamune 9,  Mitsunobu R Kano 2,  Hiroyoshi Y Tanaka 1
Affiliations

Affiliations

  • 1 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.
  • 2 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.
  • 3 Biomaterials Field, Research Center for Macromolecules and Biomaterials, National Institute for Materials Science, 1-1 Namiki, Tsukuba-Shi, Ibaraki, 305-0044, Japan.
  • 4 Department of Materials Processing, Graduate School of Engineering, Tohoku University, 6-6-02, Aza-Aoba Aramaki, Aoba-Ku, Sendai-Shi, Miyagi, 980-8579, Japan.
  • 5 Division of Biomedical Engineering for Diagnosis and Treatment, Graduate School of Biomedical Engineering, Tohoku University, 6-6-02, Aza-Aoba Aramaki, Aoba-Ku, Sendai-Shi, Miyagi, 980-8579, Japan.
  • 6 Department of Molecular Imaging and Theranostics, Institute for Quantum Medical Science, National Institutes for Quantum Sciences and Technology (QST), 4-9-1 Anagawa, Inage-Ku, Chiba-Shi, Chiba, 263-8555, Japan.
  • 7 Department of General Thoracic Surgery and Breast and Endocrinological Surgery, Graduate School of Medicine, Dentistry and Pharmaceutical Sciences, Okayama University, 2-5-1 Shikata-cho, Kita-Ku, Okayama-Shi, Okayama, 700-8558, Japan.
  • 8 Department of Bioengineering, Graduate School of Engineering, The University of Tokyo, 7-3-1 Hongo, Bunkyo-Ku, Tokyo, 113-8656, Japan.
  • 9 Division of Gastroenterology, Graduate School of Medicine, Tohoku University, 1-1 Seiryo-machi, Aoba-Ku, Sendai-Shi, Miyagi, 980-8574, Japan.
PMID: 41170605 DOI: 10.1002/smll.202506926
Abstract

Fibrosis is a significant barrier to drug delivery in pancreatic ductal adenocarcinoma (PDAC) and contributes to its dismal prognosis. Pancreatic stellate cells (PSCs) drive fibrosis by excessively secreting extracellular matrix proteins such as Collagen I. Collagen I is thought to physically obstruct the delivery of macromolecules, such as albumin, antibodies, and nanomedicines. Apart from its structural role, Collagen signals through dedicated cell surface receptors, such as the discoidin domain receptors (DDR) 1/2. However, whether and how Collagen signaling contributes to fibrotic barrier generation remains uncharacterized. Here, a 3D culture model of PDAC fibrosis constructed from patient PSCs is used to assess the contribution of DDR1/2-mediated Collagen signaling. DDR1/2 inhibition diminishes Collagen I expression in PSCs to enhance macromolecular delivery. Moreover, MEK inhibitors exacerbate the fibrotic barrier by up-regulating Collagen I, an effect reversed by inhibiting DDR1/2. Through isoform-specific targeting, inhibiting DDR1, but not DDR2, is shown to be effective. Downstream of DDR, the involvement of the PI3K/Akt/mTOR pathway is demonstrated, particularly alternative mTOR complexes involving MEAK7 and GIT1. Altogether, the results show in vitro that DDR1-mediated Collagen signaling exacerbates the fibrotic barrier and may be targeted to enhance macromolecular drug delivery in PDAC.

Keywords

collagen; fibrosis; nanomedicine; pancreatic cancer; pancreatic stellate cell.

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