Ectodomain Shedding Mechanisms in Cancer Biology

Ectodomain shedding is the proteolytic cleavage of membrane‐anchored proteins that liberates their extracellular domains into the tumour microenvironment, thereby modulating cell–cell communication, growth factor availability and immune surveillance. Central to this process are the ‘molecular scissors’ of the ADAM (a disintegrin and metalloprotease) family, notably ADAM10, ADAM17 and ADAM8, which govern the release of key ligands and receptors such as epidermal growth factor family members, tumour necrosis factor-α and adhesion molecules. Dysregulated sheddase activity is implicated in oncogenic signalling, angiogenesis, invasion and evasion of immune cytotoxicity. The sheddases themselves are subject to multilayered control by membrane lipids (for example phosphatidylserine exposure), by rhomboid-like pseudoproteases (iRhom1 and iRhom2) that dictate ADAM17 trafficking and maturation, and by tetraspanin microdomains that influence ADAM10 substrate selectivity. Therapeutic strategies under investigation include small-molecule or biologic inhibitors of sheddases, as well as targeted delivery systems such as nanocarriers for gene silencing of regulatory cofactors. Together, these advances underscore the global significance of ectodomain shedding as both a fundamental regulatory mechanism and a promising axis for anti‐cancer intervention.

Research from Nature Portfolio

Recent studies have developed a biodegradable nanocarrier that co-delivers siRNA against the pseudoprotease iRhom1 together with chemotherapeutic agents to tumour and endothelial cells. By targeting CD44 and exploiting enhanced permeability and retention, this system not only inhibits iRhom1-mediated suppression of antigen presentation and chemoresistance but also further impedes CD44 ectodomain cleavage, resulting in improved antitumour immunity and chemotherapy efficacy in multiple preclinical models. In another seminal work, the dependence of ADAM17 sheddase activity on externalised phosphatidylserine has been elucidated. A cationic phosphatidylserine-binding motif within the membrane-proximal domain of ADAM17 was shown to mediate direct lipid interaction, ensuring precise substrate engagement and cleavage. Loss of this motif abolishes proteolysis of physiological substrates, highlighting a lipid-driven mechanism of sheddase regulation. Foundational investigations of ADAM8 in pancreatic ductal adenocarcinoma have further validated it as a therapeutic target: a peptidomimetic inhibitor that prevents ADAM8 multimerisation reduces tumour invasiveness, metastasis and improves survival in genetically engineered mouse models.

Ectodomain Shedding Mechanisms in Cancer Biology publication trend

The graph below shows the total number of articles in ectodomain shedding mechanisms in cancer biology across all publications each year (not limited to Nature Index journals).

Technical terms

Ectodomain shedding: Proteolytic cleavage of the extracellular portion of a transmembrane protein, releasing a soluble fragment that can act as a signalling molecule.

ADAM proteases: A family of transmembrane metalloproteases with disintegrin and catalytic domains responsible for ectodomain shedding of growth factors, cytokines and receptors.

iRhoms: Inactive rhomboid-like pseudoproteases (iRhom1 and iRhom2) that regulate ADAM17 trafficking, maturation and substrate specificity.

Phosphatidylserine: A negatively charged phospholipid that, upon externalisation to the outer leaflet of the plasma membrane, facilitates ADAM17 binding and activation.

Nanocarrier: A biodegradable delivery system engineered to transport nucleic acids or drugs selectively to tumour cells or the tumour microenvironment, enhancing therapeutic index.

References

1. Combined proteomics and CRISPR‒Cas9 screens in PDX identify ADAM10 as essential for leukemia in vivo. Molecular Cancer (2023).
2. Inhibition of iRhom1 by CD44-targeting nanocarrier for improved cancer immunochemotherapy. Nature Communications (2024).
3. Cryo-EM reveals that iRhom2 restrains ADAM17 protease activity to control the release of growth factor and inflammatory signals. Molecular Cell (2024).
4. Regulation of A disintegrin and metalloproteinase (ADAM) family sheddases ADAM10 and ADAM17: The emerging role of tetraspanins and rhomboids. Platelets (2016).
5. Phosphatidylserine exposure is required for ADAM17 sheddase function. Nature Communications (2016).
6. ADAM8 as a drug target in pancreatic cancer. Nature Communications (2015).