Temporally resolved proteomics identifies nidogen-2 as a cotarget in pancreatic cancer that modulates fibrosis and therapy response

Brooke A Pereira ^1,2, Shona Ritchie ^1,2, Cecilia R Chambers ^1,2

¹Cancer Ecosystems Program, Garvan Institute of Medical Research and The Kinghorn Cancer Centre, Darlinghurst, New South Wales, Australia.
²School of Clinical Medicine, Faculty of Medicine, University of New South Wales (UNSW) Sydney, Kensington, New South Wales, Australia.
³Intravital Imaging Expertise Center, VIB Center for Cancer Biology, VIB, Leuven, Belgium.
⁴Centre for Genomic Regulation (CRG), Barcelona Institute of Science and Technology, Barcelona, Spain.
⁵Universitat Pompeu Fabra (UPF), Barcelona, Spain.
⁶Genomics and Inherited Disease Program, Garvan Institute of Medical Research and The Kinghorn Cancer Centre, Darlinghurst, New South Wales, Australia.
⁷ACRF INCITe Intravital Imaging Centre, Garvan Institute of Medical Research and The Kinghorn Cancer Centre, Darlinghurst, New South Wales, Australia.
⁸Translational Oncology Program, Garvan Institute of Medical Research and The Kinghorn Cancer Centre, Darlinghurst, New South Wales, Australia.
⁹Immune Biotherapies Program, Garvan Institute of Medical Research, Darlinghurst, New South Wales, Australia.
¹⁰Data Science Platform, Garvan Institute of Medical Research, Darlinghurst, New South Wales, Australia.
¹¹Genentech Inc., South San Francisco, CA, USA.
¹²Children's Cancer Institute, Lowy Cancer Research Centre, UNSW Sydney, Kensington, New South Wales, Australia.
¹³Histopathology Platform, Garvan Institute of Medical Research and The Kinghorn Cancer Centre, Darlinghurst, New South Wales, Australia.
¹⁴Division of Molecular Pathology, Netherlands Cancer Institute, Antoni van Leeuwenhoek Hospital, Amsterdam, Netherlands.
¹⁵Oncode Institute, Amsterdam, Netherlands.
¹⁶Centre for Advanced Histology & Microscopy, Peter MacCallum Cancer Centre, Parkville, Victoria, Australia.
¹⁷Sir Peter MacCallum Department of Oncology, The University of Melbourne, Parkville, Victoria, Australia.
¹⁸Biological Optical Microscopy Platform, The University of Melbourne, Parkville, Victoria, Australia.
¹⁹Centre for Cancer Biology, An Alliance of SA Pathology and University of South Australia, Adelaide, South Australia, Australia.
²⁰Basil Hetzel Institute for Translational Health Research, Queen Elizabeth Hospital, Woodville South, South Australia, Australia.
²¹NHMRC Clinical Trials Centre, University of Sydney, Camperdown, New South Wales, Australia.
²²Department of Medical Oncology, Chris O'Brien Lifehouse, Camperdown, New South Wales, Australia.
²³Department of Medical Oncology, Illawarra Shoalhaven Local Health District, Wollongong, New South Wales, Australia.
²⁴Centre for Cancer Research and Department of Clinical Pathology, The University of Melbourne, Parkville, Victoria, Australia.
²⁵NSW Health Pathology, Department of Anatomical Pathology, Royal North Shore Hospital, St Leonards, New South Wales, Australia.
²⁶Sydney Medical School, University of Sydney, Camperdown, New South Wales, Australia.
²⁷Department of Surgery, Royal North Shore Hospital, St Leonards, New South Wales, Australia.
²⁸Cancer Research UK Beatson Institute, Glasgow, UK.
²⁹School of Cancer Sciences, Institute of Cancer Sciences, University of Glasgow, Glasgow, UK.
³⁰Department of Biochemistry, Faculty of Medicine, Oita University, Oita, Japan.
³¹Precision Immunology Program, Garvan Institute of Medical Research, Darlinghurst, New South Wales, Australia.
³²Department of Anatomy and Physiology, University of Melbourne, Parkville, Victoria, Australia.

⁰Cancer Ecosystems Program, Garvan Institute of Medical Research and The Kinghorn Cancer Centre, Darlinghurst, New South Wales, Australia.

Science Advances +

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July 3, 2024

View abstract on PubMed

Summary

Nidogen-2 (NID2) promotes pancreatic ductal adenocarcinoma (PDAC) progression by increasing tumor fibrosis and stiffness. Reducing NID2 in cancer-associated fibroblasts (CAFs) impairs invasion, reduces metastasis, and improves treatment response in preclinical models.

Area Of Science

Oncology
Cancer Biology
Biochemistry

Background

Pancreatic ductal adenocarcinoma (PDAC) is marked by significant fibrosis, which can drive tumor progression and metastasis.
The tumor microenvironment, particularly the extracellular matrix (ECM), plays a crucial role in PDAC.
Understanding the temporal changes in the ECM (matrisome) is vital for identifying therapeutic targets.

Purpose Of The Study

To conduct an unbiased temporal assessment of the matrisome in distinct pancreatic cancer mouse models.
To identify key ECM components contributing to PDAC metastasis and progression.
To evaluate the therapeutic potential of targeting identified ECM components.

Main Methods

Utilized mass spectrometry proteomics for unbiased temporal matrisome assessment in KPC and KPflC mouse models.
Employed biomechanical assessments, second harmonic generation imaging, and birefringence analysis to evaluate matrix properties.
Used CRISPR interference (CRISPRi) for NID2 knockdown in cancer-associated fibroblasts (CAFs).
Performed intravital imaging and orthotopic implantation in mouse models to assess tumor progression and metastasis.

Main Results

Identified increased abundance of nidogen-2 (NID2) in the highly metastatic KPC model compared to the poorly metastatic KPflC model.
Demonstrated that NID2 is primarily expressed by CAFs within the tumor microenvironment.
Showed that NID2 reduction in CAFs decreased tumor stiffness and matrix remodeling, impairing cancer cell invasion.
Observed improved vascular patency and enhanced response to gemcitabine/Abraxane in NID2-depleted tumors.
Found reduced liver metastasis and increased survival in orthotopic models with NID2-depleted tumors.

Conclusions

Nidogen-2 (NID2) is a key contributor to pancreatic ductal adenocarcinoma (PDAC) progression and metastasis.
Targeting NID2 in cancer-associated fibroblasts (CAFs) represents a promising therapeutic strategy for PDAC.
NID2 inhibition can reduce tumor stiffness, enhance drug delivery, and decrease metastatic spread, highlighting its potential as a PDAC cotarget.

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