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Matrix Fibulin-1 protein can regulate epidermal growth factor receptor: Implications in cellular function and cancer

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Adding to our understanding of molecular interactions in cancer is a recent paper from Dr. Nagaraj Balasubramanian’s group at IISER Pune. Here, the team showed that Fibulin-1 protein from the extracellular matrix can interact with and regulate the activity of the epidermal growth factor receptor (EGFR) in lung cancer cells. The expression and activity of EGFR is often found to be altered in many cancers.


The human body is made up of millions of cells. A framework of proteins called the extracellular matrix (ECM) holds the cells together, providing physical support and keeping them together within the tissues of the human body.


Matrix proteins can control how cells function by communicating signals from external microenvironment to the cell. They do so through receptors on the cell surface that bind the matrix called integrins. When they bind the extracellular matrix, integrins sense both the biophysical and biochemical cues, which they communicate through signaling pathways inside the cells. The ECM also communicates with growth factor receptors (like EGFR) regulating their organization and function, playing a vital role in mediating cell growth and migration.


“The composition of the ECM has a major role in regulating cellular function. In diseases like cancer, changes in matrix composition and organization can affect tumor progression and metastasis,” says Dr. Balasubramanian whose research group works on cell adhesion, the phenomenon of cells sticking to each other or to their surrounding microenvironment. Among the differences in cancer cells when compared to normal cells, includes the ability of cancer cells to poorly bind and be regulated by adhesion.


In the present work, the team worked with Fibulin-1, a major ECM protein which is highly expressed by the lung and is known to regulate airway remodeling during pathogenesis of chronic lung diseases.


Panel A shows the cell shape and active EGF receptor (green) localization in re-adherent Calu-1 cells. Panels B and C show Fibulin1C and Fibulin1D knockdown cells, respectively, with increased spreading and an altered distribution of the active EGF receptor (pEGFR). (Image: Dr. Balasubramanian's Group)


“First, we looked at the expression levels of Fibulin-1 non-small cell lung cancer and found them to be much lower than in normal cells. We then found that Fibulin-1 binds EGFR, making EGFR the first known receptor for Fibulin-1,” says Dr. Keerthi Harikrishnan, an independent scientist working with Dr. Balasubramanian and a co-corresponding author on this paper. This discovery meant that the team now could assess what Fibulin-1 binding or lack thereof with EGFR meant in terms of cellular signaling.


Using molecular approaches, the team knocked down (reduced) the expression of Fibulin-1 gene splice variants, FBLN1C and FBLN1D and found an increase in EGFR activation. This led to promoting the migration of lung cancer Calu1 cells, vital to their metastatic potential. In a converse confirmation, when they overexpressed Fibulin-1, they found reduced activation of EGFR. The team also discovered that cell derived matrix (CDM) Fibulin-1, but not cellular Fibulin-1, binds EGFR and regulates its function.


“This study establishes Fibulin-1 as a novel matrix regulator of EGFR function. As EGFR is a key receptor involved in cell growth, we believe our findings have implications beyond understanding lung cancer—in regulating cellular functions,” says Dr. Balasubramanian.


This work received funding from Wellcome Trust-DBT India Alliance grant, IISER Pune Postdoctoral Fellowship Program, and Department of Science and Technology, India – Women Scientist Program.


Article Citation: Cell derived matrix Fibulin-1 associates with epidermal growth factor receptor to inhibit its activation, localization and function in lung cancerCalu-1 cells. Keerthi Harikrishnan, Omkar Joshi, Saili Madangirikar and Nagaraj Balasubramanian. Front. Cell Dev. Biol. 03 July 2020 | (This is part of a series on The Impact of Tumor Extracellular Matrix Cross-Talk on Cancer Hallmarks)


- With inputs from Dr. Balasubramanian and Dr. Keerthi Harikrishnan; Edited by Dr. Shanti Kalipatnapu