Tumour DDR1 promotes collagen fibre alignment to instigate immune exclusion

Sun, Xiujie; Wu, Bogang; Chiang, Huai-Chin; Deng, Hui; Zhang, Xiaowen; Xiong, Wei; Liu, Junquan; Rozeboom, Aaron M.; Harris, Brent T.; Blommaert, Eline; Gómez, Antonio; Espín, Roderic; Zhou, Yufan; Mitra, Payal; Prevost, M.; Zhang, Deyi; Banik, Debarati; Isaacs, Claudine; Berry, Deborah L.; Lai, Catherine; Chaldekas, Krysta; Latham, Patricia S.; Brantner, Christine A.; Popratiloff, Anastas; Jin, Victor X.; Zhang, Ningyan; Hu, Yanfen; Pujana, Miguel Ángel; Curiel, Tyler J.; An, Zhiqiang; Li, Rong

doi:10.1038/s41586-021-04057-2

Cited by 213 publications

(162 citation statements)

References 37 publications

Supporting

Mentioning

153

Contrasting

Order By: Relevance

“…Upon knock‐out and capture by monoclonal antibodies specific to DDR1‐ECD, T cell invasion was restored, resulting in triple‐negative breast cancer remission for 10 out of 18 mice. [ 35 ] This potential new strategy to alter the ECM is promising and together with optimizing T cell infiltration through the restrictive ECM could provide a potential cure. T cells therefore must break free from the ECM confinement and move forward, drastically altering, that is, deform, their cell bodies through actin cytoskeletal dynamics (cell deformability).…”

Section: Ecm Microarchitecture and Stiffness Influence Tumor Infiltra...mentioning

confidence: 99%

The solid tumor microenvironment—Breaking the barrier for T cells

Simsek

Klotzsch

2022

BioEssays

View full text Add to dashboard Cite

The tumor microenvironment (TME) plays a pivotal role in the behavior and development of solid tumors as well as shaping the immune response against them. As the tumor cells proliferate, the space they occupy and their physical interactions with the surrounding tissue increases. The growing tumor tissue becomes a complex dynamic structure, containing connective tissue, vascular structures, and extracellular matrix (ECM) that facilitates stimulation, oxygenation, and nutrition, necessary for its fast growth. Mechanical cues such as stiffness, solid stress, interstitial fluid pressure (IFP), matrix density, and microarchitecture influence cellular functions and ultimately tumor progression and metastasis. In this fight, our body is equipped with T cells as its spearhead against tumors. However, the altered biochemical and mechanical environment of the tumor niche affects T cell efficacy and leads to their exhaustion. Understanding the mechanobiological properties of the TME and their effects on T cells is key for developing novel adoptive tumor immunotherapies.

show abstract

Section: Ecm Microarchitecture and Stiffness Influence Tumor Infiltra...mentioning

confidence: 99%

The solid tumor microenvironment—Breaking the barrier for T cells

Simsek

Klotzsch

2022

BioEssays

View full text Add to dashboard Cite

show abstract

“…In TNBC, DDR1 supports progression by aligning collagen fibers to elicit immune exclusion 28 . Using second harmonic generation (SHG) measurements, we observed no change in collagen fiber alignment between tumors from Col I WT and Col I r/r pancreata or parental and DDR1 KD tumors (Extended Data Fig.…”

Section: Therapeutic Targeting Of the Ddr1-nf-κb-nrf2-tumor Metabolis...mentioning

confidence: 99%

Collagen remodeling dictates pancreatic cancer bioenergetics and outcome through DDR1 activation or degradation

Yang

et al. 2022

Preprint

View full text Add to dashboard Cite

Pancreatic ductal adenocarcinoma (PDAC) is a highly desmoplastic, aggressive cancer that frequently progresses by liver metastasis1. Cancer-associated fibroblasts (CAF), extracellular matrix (ECM), and type I collagen (Col I) support2–5 or restrain PDAC progression and may impede blood supply and nutrient availability6–8. The dichotomous role of the stroma in PDAC, and the mechanisms through which it influences patient survival and enables desmoplastic cancers escape nutrient limitation remain poorly understood. Here we show that matrix metalloprotease (MMP)-cleaved or intact Col I (cCol I and iCol I, respectively) exert opposing effects on PDAC bioenergetics, macropinocytosis (MP), tumor growth and liver metastasis. While cCol I activates DDR1 (discoidin domain receptor-1)-NF-κB-p62-NRF2 signaling to promote PDAC growth, iCol I triggers DDR1 degradation and restrains PDAC growth. Patients whose tumors are enriched in iCol I and low in DDR1 and NRF2 have improved median survival compared to those enriched in cCol I, DDR1 and NRF2. Inhibition of DDR1-stimulated NF-κB or mitochondrial biogenesis blocked tumorigenesis in wildtype mice but not in mice expressing MMP-resistant Col I. In summary, the diverse effects of tumor stroma on PDAC growth, metastasis, and patient survival are mediated through the Col I-DDR1-NF-κB-NRF2-mitochondrial biogenesis pathway, presenting multiple new opportunities for PDAC therapy.

show abstract

“…Upon knock-out and capture by monoclonal antibodies specific to DDR1-ECD, T cell invasion was restored, resulting in triple-negative breast cancer remission for 10 out of 18 mice. [35] This potential new strategy to alter the ECM is promising and together with optimizing T cell infiltration through the restrictive ECM could provide a potential cure. T cells therefore must break free from the ECM confinement and move forward, drastically altering, ie deform, their cell bodies through actin cytoskeletal dynamics (cell deformability).…”

Section: Ecm Microarchitecture and Stiffness Influence Tumor Infiltrationmentioning

confidence: 99%

The Solid Tumor Microenvironment - Breaking The Barrier For T Cells<strong> </strong>

Simsek¹,

Klotzsch²

2021

Preprint

View full text Add to dashboard Cite

The tumor microenvironment plays a pivotal role in the behavior and development of solid tumors as well as shaping the immune response against them. As the tumor cells proliferate, the space they occupy and their physical interactions with the surrounding tissue increases. The growing tumor tissue becomes a complex dynamic structure, containing connective tissue, vascular structures, and extracellular matrix that facilitates stimulation, oxygenation, and nutrition, necessary for its fast growth. Mechanical cues such as stiffness, solid stress, interstitial fluid pressure, matrix density, and microarchitecture influence cellular functions and ultimately tumor progression and metastasis. In this fight, our body is equipped with T cells as its spearhead against tumors. However, the altered biochemical and mechanical environment of the tumor niche affects T cell efficacy and leads to their exhaustion. Understanding the mechanobiological properties of the tumor microenvironment and their effects on T cells is key for developing novel adoptive tumor immunotherapies.

show abstract

Tumour DDR1 promotes collagen fibre alignment to instigate immune exclusion

Cited by 213 publications

References 37 publications

The solid tumor microenvironment—Breaking the barrier for T cells

The solid tumor microenvironment—Breaking the barrier for T cells

Collagen remodeling dictates pancreatic cancer bioenergetics and outcome through DDR1 activation or degradation

The Solid Tumor Microenvironment - Breaking The Barrier For T Cells<strong> </strong>

Contact Info

Product

Resources

About