Biophysical regulation of EGFR signalling in tumour cells

Lead Research Organisation: King's College London
Department Name: Immunology Infection and Inflam Diseases


Extracellular matrix (ECM) stiffening is a common phenomenon during tumour development, often associating with more
aggressive metastatic disease and a poorer prognosis. This protein scaffold comprises an extensive network of fibrotic proteins,
including collagen, fibronectin, proteoglycans and laminins. Its stiffening involves the deposition, crosslinking, and alignment of
ECM proteins, in addition to the secretion of growth factors and enzymes. Cells sense changes in ECM stiffness through
heterodimeric cell surface mechano-receptors called integrins. Integrins bind to ECM proteins, form focal adhesions, and activate
focal adhesion kinase (FAK), leading to the activation of multiple signalling pathways. In malignant cells, ECM stiffening and
increased formation of focal adhesions promotes cellular invasion and metastasis through the aberrant activation of these
pathways. Epidermal growth factor receptor (EGFR) is frequently mutated in cancers, particularly in non-small-cell lung cancer
(NSCLC). Canonically, EGFR dimerizes on the plasma membrane upon binding EGF, leading to the autophosphorylation of
intracellular tyrosine kinase domains. EGFR activation triggers signalling via the MAPK, PI3K and PLCY1 pathways to promote
cellular proliferation, migration, and survival. In cells with EGFR mutations, aberrant activation of these pathways can drive
oncogenesis. Some studies have previously suggested that EGFR plays a role in integrin-mediated mechano-sensing of ECM
stiffness. EGFR associates with integrins and other focal adhesion proteins on the plasma membrane, and EGFR phosphorylation
can occur in an integrin-dependent manner- via Src-family kinase (SFK) activity in absence of EGF. EGFR activation also plays a
role in adhesion-dependent MAPK/ERK and PI3K/Akt signalling, inducing Rac GTPase activity and formation of F-actin protrusions
that contribute to invasion. In human small cell carcinoma biopsy cells, stiffer ECM environments also appear to promote
invasion in an EGFR-dependent manner, and EGFR is overexpressed at the cell-ECM interface. However, whether EGFR plays a
clinically relevant role in tumour-mechano-sensing remains unknown.


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