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克服肿瘤胶原障碍：一种用于 DDR1 介导的耐药结直肠癌治疗的多阶段药物递送策略。

Overcoming the Tumor Collagen Barriers: A Multistage Drug Delivery Strategy for DDR1-Mediated Resistant Colorectal Cancer Therapy.

机构信息

Department of General Surgery & Guangdong Provincial Key Laboratory of Precision Medicine for Gastrointestinal Tumor, Nanfang Hospital, Southern Medical University, Guangzhou, 510515, China.

The Tenth Affiliated Hospital of Southern Medical University, Dongguan, Guangdong, 523059, China.

出版信息

Adv Sci (Weinh). 2024 Sep;11(33):e2402107. doi: 10.1002/advs.202402107. Epub 2024 Jul 2.

DOI:10.1002/advs.202402107
PMID:38953306
原文链接:https://pmc.ncbi.nlm.nih.gov/articles/PMC11434232/
Abstract

The extracellular matrix (ECM) is critical for drug resistance in colorectal cancer (CRC). The abundant collagen within the ECM significantly influences tumor progression and matrix-mediated drug resistance (MMDR) by binding to discoidin domain receptor 1 (DDR1), but the specific mechanisms by which tumor cells modulate ECM via DDR1 and ultimately regulate TME remain poorly understand. Furthermore, overcoming drug resistance by modulating the tumor ECM remains a challenge in CRC treatment. In this study, a novel mechanism is elucidated by which DDR1 mediates the interactions between tumor cells and collagen, enhances collagen barriers, inhibits immune infiltration, promotes drug efflux, and leads to MMDR in CRC. To address this issue, a multistage drug delivery system carrying DDR1-siRNA and chemotherapeutic agents is employed to disrupt collagen barriers by silencing DDR1 in tumor, enhancing chemotherapy drugs diffusion and facilitating immune infiltration. These findings not only revealed a novel role for collagen-rich matrix mediated by DDR1 in tumor resistance, but also introduced a promising CRC treatment strategy.

摘要

细胞外基质（ECM）对于结直肠癌（CRC）的耐药性至关重要。ECM 中丰富的胶原蛋白通过与盘状结构域受体 1（DDR1）结合，显著影响肿瘤进展和基质介导的耐药性（MMDR），但肿瘤细胞通过 DDR1 调节 ECM 的具体机制以及最终调节 TME 仍知之甚少。此外，通过调节肿瘤 ECM 来克服耐药性仍然是 CRC 治疗中的一个挑战。在这项研究中，揭示了一个新的机制，即 DDR1 介导肿瘤细胞与胶原蛋白之间的相互作用，增强胶原蛋白屏障，抑制免疫浸润，促进药物外排，导致 CRC 的 MMDR。为了解决这个问题，采用了一种多阶段药物输送系统，携带 DDR1-siRNA 和化疗药物，通过沉默肿瘤中的 DDR1 来破坏胶原蛋白屏障，增强化疗药物的扩散并促进免疫浸润。这些发现不仅揭示了 DDR1 介导的富含胶原蛋白的基质在肿瘤耐药性中的新作用，还提出了一种有前途的 CRC 治疗策略。

https://cdn.ncbi.nlm.nih.gov/pmc/blobs/5f97/11434232/e4affc7bac1c/ADVS-11-2402107-g005.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/5f97/11434232/11fe4f9565e2/ADVS-11-2402107-g001.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/5f97/11434232/eb712c23ef72/ADVS-11-2402107-g007.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/5f97/11434232/2659d424bfca/ADVS-11-2402107-g006.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/5f97/11434232/6dc955742165/ADVS-11-2402107-g003.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/5f97/11434232/e8f22d33e707/ADVS-11-2402107-g008.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/5f97/11434232/3ff51819a4bc/ADVS-11-2402107-g004.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/5f97/11434232/e4affc7bac1c/ADVS-11-2402107-g005.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/5f97/11434232/11fe4f9565e2/ADVS-11-2402107-g001.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/5f97/11434232/eb712c23ef72/ADVS-11-2402107-g007.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/5f97/11434232/2659d424bfca/ADVS-11-2402107-g006.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/5f97/11434232/6dc955742165/ADVS-11-2402107-g003.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/5f97/11434232/e8f22d33e707/ADVS-11-2402107-g008.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/5f97/11434232/3ff51819a4bc/ADVS-11-2402107-g004.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/5f97/11434232/e4affc7bac1c/ADVS-11-2402107-g005.jpg

相似文献

[1]
Overcoming the Tumor Collagen Barriers: A Multistage Drug Delivery Strategy for DDR1-Mediated Resistant Colorectal Cancer Therapy.

Adv Sci (Weinh). 2024-9

[2]
Tumour DDR1 promotes collagen fibre alignment to instigate immune exclusion.

Nature. 2021-11

[3]
A highly selective humanized DDR1 mAb reverses immune exclusion by disrupting collagen fiber alignment in breast cancer.

J Immunother Cancer. 2023-6

[4]
Influences of TP53 and the anti-aging DDR1 receptor in controlling Raf/MEK/ERK and PI3K/Akt expression and chemotherapeutic drug sensitivity in prostate cancer cell lines.

Aging (Albany NY). 2020-6-3

[5]
Tumor-extrinsic discoidin domain receptor 1 promotes mammary tumor growth by regulating adipose stromal interleukin 6 production in mice.

J Biol Chem. 2018-1-3

[6]
DDR1 is a Novel Biomarker and Potential Therapeutic Target for the Combination Treatment of Liver Hepatocellular Carcinoma.

Cancer Control. 2024

[7]
Suppressing miR-199a-3p by promoter methylation contributes to tumor aggressiveness and cisplatin resistance of ovarian cancer through promoting DDR1 expression.

J Ovarian Res. 2017-7-25

[8]
Signaling by discoidin domain receptor 1 in cancer metastasis.

Cell Adh Migr. 2018-10-13

[9]
Targeting Discoidin Domain Receptors DDR1 and DDR2 overcomes matrix-mediated tumor cell adaptation and tolerance to BRAF-targeted therapy in melanoma.

EMBO Mol Med. 2022-2-7

[10]
Collagen Fibril Ultrastructure in Mice Lacking Discoidin Domain Receptor 1.

Microsc Microanal. 2016-6

引用本文的文献

[1]
Collagen disorder architecture features are associated with clinical, molecular, genetic factors and survival outcomes in colon cancer.

NPJ Precis Oncol. 2025-8-28

[2]
Targeting Resistance Pathways in Breast Cancer Through Precision Oncology: Nanotechnology and Immune Modulation Approaches.

Biomedicines. 2025-7-10

[3]
Sequential drug release system: Targeting the tumor ECM for enhanced chemotherapy efficacy.

Proc Natl Acad Sci U S A. 2025-6-10

[4]
Collagen remodeling-mediated signaling pathways and their impact on tumor therapy.

J Biol Chem. 2025-3

本文引用的文献

[1]
Molecular cartography uncovers evolutionary and microenvironmental dynamics in sporadic colorectal tumors.

Cell. 2023-12-7

[2]
Define cancer-associated fibroblasts (CAFs) in the tumor microenvironment: new opportunities in cancer immunotherapy and advances in clinical trials.

Mol Cancer. 2023-10-2

[3]
Activated fibroblasts in cancer: Perspectives and challenges.

Cancer Cell. 2023-3-13

[4]
Patient-Derived Tumor Organoids Can Predict the Progression-Free Survival of Patients With Stage IV Colorectal Cancer After Surgery.

Dis Colon Rectum. 2023-5-1

[5]
Two-Stage SN38 Release from a Core-Shell Nanoparticle Enhances Tumor Deposition and Antitumor Efficacy for Synergistic Combination with Immune Checkpoint Blockade.

ACS Nano. 2022-12-27

[6]
CD16 fibroblasts foster a trastuzumab-refractory microenvironment that is reversed by VAV2 inhibition.

Cancer Cell. 2022-11-14

[7]
Targeting the tumor stroma for cancer therapy.

Mol Cancer. 2022-11-2

[8]
Collagenolysis-dependent DDR1 signalling dictates pancreatic cancer outcome.

Nature. 2022-10

[9]
Cell-matrix interface regulates dormancy in human colon cancer stem cells.

Nature. 2022-8

[10]
Targeting extracellular matrix stiffness and mechanotransducers to improve cancer therapy.

J Hematol Oncol. 2022-3-24

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