Innovative Treatments Based on Emerging Mechano-Biology of Cancer and Fibrosis
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Mechano-Biology: Tissue Stiffness as a Driving Force of Human Diseases
Mechano-biology studies the relationship between cells and their physical microenvironment, and how cells can detect and respond to changes in the rigidity of their surrounding extracellular matrix (ECM). Changes in the biophysical cues of the ECM (i.e. tissue stiffness, viscoelasticity) directly control cellular behavior during tissue repair and regeneration, inflammation and diseases such as cancer and fibrotic diseases. Tissue stiffness activates mechanical signaling pathways and change gene expression programs in cells via specific ECM receptors known as via “Mechano-Sensors”.
Tissue Stiffness-Cell Interactions are Regulated by Mechano-Sensors and Drive Cellular Responses Including Cell Plasticity, Migration and Division
The Extracellular Matrix Supplies the 3D Physical Structure in Which Cells Live
The Mechanical Tumor Microenvironment in Aggressive, Untreatable Cancers
Aggressive tumors such as pancreatic adenocarcinoma (PDAC) and hepatocellular carcinoma (HCC) are associated with alterations to the extracellular matrix (ECM) and creation of a dense fibrotic tumor environment. Cancers with a high degree of ECM deposition and stiffening have poor prognosis and are highly progressive and metastatic. The stiff fibrotic niche associated with the primary cancer cells can promote tumor progression, metastatic escape, and formation of a metastatic niche at distant sites. Experimental evidence shows that targeting tumor mechanics, either through targeting the matrix directly, the fibroblasts that deposit the ECM, or the interaction between tumor cells and their stiff fibrotic matrix can mitigate tumor development, progression and/or metastasis.
PANCREATIC ADENOCARCINOMA (PDAC)
Tumors with Excessive Extracellular Matrix Deposition and Stiffening are Highly Progressive
Extracellular Matrix (80-90%)
Cancer Cells (10-20%)
Mechano-Biology of Fibrotic Diseases
Extracellular matrix (ECM) stiffening and remodeling is a hallmark of fibrotic diseases in which excessive ECM deposition and crosslinking distort tissue architecture and impair organ function. Progressive and irreversible fibrosis (scarring) is a primary or contributing factor in human diseases including idiopathic pulmonary fibrosis (IPF), scleroderma (SSc), chronic kidney disease (CKD), and non-alcoholic steatohepatitis (NASH). Pulmonary fibrosis after severe COVID-19 infection is also emerging as a complication of COVID-19. Changes in the mechanical properties of ECM, such as stiffness, activate fibrogenic cells such as myofibroblasts, deregulate inflammation and prevent stem cells pro-regenerative responses, ultimately tipping the balance from tissue repair to fibrosis in response to tissue injury.
LUNG FIBROSIS
Excessive Extracellular Matrix Deposition Distorts Lung Architecture and Impairs Function in Idiopathic Pulmonary Fibrosis (IPF)
Extracellular Matrix Deposition (Fibrosis)
Mechano-Sensors as Targets in Human Disease and the Development of Zenon’s Innovative Mechano-Therapeutics
In the era of “-omics” sciences, genetic abnormalities and pathologic cellular communication through soluble biochemical signaling dominate the way we think about the development and treatment of human diseases. However, recent discoveries demonstrated that cellular behavior is largely controlled by biophysical cues such as tissue stiffness. Research in the Lagares Lab has identified mechanisms in which increased tissue stiffness alters cell behavior and drives disease progression. Zenon is targeting “mechano-sensors” selectivety upregulated in pathologic cells in cancer and fibrosis, which drive unique cellular disease mechanisms currently untreatable by existing treatments.
The Stiff Fibrotic Tumor Microenvironment is Recognized as a Major Driver of Tumor Cell Proliferation and Migration During Tumorigenesis and Metastasis
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