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journal article·2025-12Open access

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

Mayu Ohira, Moe Kitamura, Hiroyo Iwasaki, Haruko Ohta‐Okano, Hiyori Tsujii, Reika Nakamura, Takuya Nakazawa, Akihiro Nishiguchi, Masaya Yamamoto, Kensuke Osada, Shinichi Toyooka, Horacio Cabral, Atsushi Masamune, Mitsunobu R. Kano, Hiroyoshi Y. Tanaka

Small· Volume 21· Issue 50
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Source abstract

Abstract

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.
Source: crossref · Quality: baseline

Research context

PolymersNanomaterials

OpenAlex topics: Cell Adhesion Molecules Research · Pancreatic and Hepatic Oncology Research · Pancreatitis Pathology and Treatment

SciVX discovery tags are terminology-based. OpenAlex topics are source-provided classifications.

Affiliations

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

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

Biomaterials Field Research Center for Macromolecules and Biomaterials National Institute for Materials Science 1‐1 Namiki Tsukuba‐Shi Ibaraki 305‐0044 Japan

Department of Materials Processing Graduate School of Engineering Tohoku University 6‐6‐02, Aza‐Aoba Aramaki, Aoba‐Ku Sendai‐Shi Miyagi 980‐8579 Japan

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

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

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

Department of Bioengineering Graduate School of Engineering The University of Tokyo 7‐3‐1 Hongo Bunkyo‐Ku Tokyo 113‐8656 Japan

Division of Gastroenterology Graduate School of Medicine Tohoku University 1‐1 Seiryo‐machi, Aoba‐Ku Sendai‐Shi Miyagi 980‐8574 Japan

Funding

Japan Society for the Promotion of Science · Okayama University · Inamori Foundation · Hokuto Foundation for Bioscience · Japan Foundation for Applied Enzymology · Pancreas Research Foundation of Japan · Ryobi Teien Memory Foundation · Japan Science and Technology Agency

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