Extracellular matrix internalization links nutrient signalling to invasive migration

Rainero, Elena

doi:10.1111/iep.12265

Cited by 15 publications

(10 citation statements)

References 28 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…The mechanism of cellular uptake of PL1-NPs remains to be determined in detail. Integrins, along with their ECM ligands, are internalized through a variety of endocytic mechanisms, including macropinocytosis [45]. Proteolytic processing of the fibronectin-containing ECM has been shown to facilitate FN endocytosis [46].…”

Section: Discussionmentioning

confidence: 99%

PL1 Peptide Engages Acidic Surfaces on Tumor-Associated Fibronectin and Tenascin Isoforms to Trigger Cellular Uptake

Lingasamy

Põšnograjeva

Kopanchuk

et al. 2021

Preprint

View full text Add to dashboard Cite

Tumor extracellular matrix (ECM) is a high-capacity and genetically stable target for the precision delivery of affinity ligand-guided drugs and imaging agents. Recently, we developed a PL1 peptide (sequence: PPRRGLIKLKTS) for systemic targeting of malignant ECM. Here we map the dynamics of PL1 binding to its receptors Fibronectin Extra Domain B (FN-EDB) and Tenascin C C-isoform (TNC-C) by computational modeling and cell-free binding studies on mutated receptor proteins, and study cellular binding and internalization of PL1 nanoparticles in cultured cells. Molecular dynamics simulation and docking analysis suggested that the engagement of PL1 peptide with both receptors is primarily driven by electrostatic interactions. Substituting acidic amino acid residues with neutral amino acids at predicted PL1 binding sites in FN-EDB (D52N-D49N-D12N) and TNC-C (D39N-D45N) resulted in the loss of binding of PL1 nanoparticles. Remarkably, PL1-functionalized nanoparticles (NPs) were not only deposited on the target ECM but bound the cells and initiated a robust cellular uptake via a pathway resembling macropinocytosis. Our studies establish the mode of engagement of the PL1 peptide with its receptors and suggest applications for intracellular delivery of nanoscale payloads. The outcomes of this work can be used for the development of PL1-derived peptides with improved stability, affinity and specificity for precision targeting of the tumor ECM and malignant cells.

show abstract

Section: Discussionmentioning

confidence: 99%

PL1 Peptide Engages Acidic Surfaces on Tumor-Associated Fibronectin and Tenascin Isoforms to Trigger Cellular Uptake

Lingasamy

Põšnograjeva

Kopanchuk

et al. 2021

Preprint

View full text Add to dashboard Cite

show abstract

“…Recent evidence sheds further light on the critical role played by integrin and ECM stiffness in shaping metabolic behaviors of cancer cells 57 , 58 . Mammalian target of rapamycin (mTOR) and PI3K signaling allow tumor cells to grow in a nutrient-deprived environment and to overcome anoikis in anchorage-independent conditions 59 .…”

Section: Regulation Of Integrin Function and Signaling In Cancer Cellsmentioning

confidence: 99%

The roles of integrins in cancer

Valdembri¹,

Serini²

2021

Fac Rev

View full text Add to dashboard Cite

Integrin-mediated adhesion of cells to the extracellular matrix (ECM) is crucial for the physiological development and functioning of tissues but is pathologically disrupted in cancer. Indeed, abnormal regulation of integrin receptors and ECM ligands allows cancer cells to break down tissue borders, breach into blood and lymphatic vessels, and survive traveling in suspension through body fluids or residing in metabolically or pharmacologically hostile environments. Different molecular and cellular mechanisms responsible for the modulation of integrin adhesive function or mechanochemical signaling are altered and participate in cancer. Cancer development and progression are also bolstered by dysfunctionalities of integrin-mediated ECM adhesion occurring both in tumor cells and in elements of the surrounding tumor microenvironment, such as vascular cells, cancer-associated fibroblasts, and immune cells. Mounting evidence suggests that integrin inhibitors may be effectively exploited to overcome resistance to standard-of-care anti-cancer therapies.

show abstract

“…Expanding evidence links integrin trafficking to the normal execution of cellular processes such as cell adhesion 4,15 , migration 14,20,69 , matrix remodelling 70–72 and differentiation 73,74 . The concept that these pathways can be hijacked by cancer cells has been reviewed elsewhere 4,75–77 .…”

Section: Integrin Traffic In Developing Tissuesmentioning

confidence: 99%

“…A cell’s metabolic state is intimately associated with integrin traffic and matrix remodelling 72 . In high-nutrient conditions, tensin expression is suppressed by the cellular metabolic sensor AMPK 89 .…”

Section: Integrin Traffic In Developing Tissuesmentioning

confidence: 99%

Integrin trafficking in cells and tissues

et al. 2019

View full text Add to dashboard Cite

Cell adhesion to the extracellular matrix (ECM) is fundamental to metazoan multicellularity and is accomplished primarily through the integrin family of cell-surface receptors. Integrins are internalised and enter the endo/exocytic pathway before being recycled back to the plasma membrane. The trafficking of this extensive protein family is regulated in multiple context-dependent ways to modulate integrin function in the cell. Here we discuss recent advances in understanding the mechanisms and cellular roles of integrin endocytic trafficking.

show abstract

Extracellular matrix internalization links nutrient signalling to invasive migration

Cited by 15 publications

References 28 publications

PL1 Peptide Engages Acidic Surfaces on Tumor-Associated Fibronectin and Tenascin Isoforms to Trigger Cellular Uptake

PL1 Peptide Engages Acidic Surfaces on Tumor-Associated Fibronectin and Tenascin Isoforms to Trigger Cellular Uptake

The roles of integrins in cancer

Integrin trafficking in cells and tissues

Contact Info

Product

Resources

About