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CURATOR
A pinboard by
Hadi Nia

Postdoctoral Fellow, Harvard Medical School/Massachusetts General Hospital

PINBOARD SUMMARY

I investigate the role of physical forces in tumors to propose new targets in fight against cancer

A solid tumor is composed of cancer cells and stromal cells (normal cells recruited by cancer cells) that collectively gives rise to the abnormal biology of the tumor including uncontrolled growth. The abnormalities of tumor microenvironment, however, are not limited to the biology of the tumor. The solid tumors are also mechanically abnormal. For example most solid tumors are stiffer than normal tissues. Our lab recently discovered that solid tumors, unlike normal tissues, bear internal forces that compress blood vessels inside the tumors, and consequently impede drug delivery to the cancer cells. These forces also promote the growth and invasiveness of the cancer cells directly or indirectly by giving rise to a low-oxygen environment, known as hypoxia. We have shown that strategies to target these mechanopathologies and normalize the mechanical microenvironment of solid tumors lead to potential therapeutic approaches for improving the efficiency of conventional anti-cancer treatments, and are currently being tested in clinical trials. My research includes the development of methods to detect and quantify these internal forces in mouse and human tumors, unveil the consequences of these forces on the biology of the tumor, and eventually propose new approaches to target and normalize these forces.

4 ITEMS PINNED

Laser Speckle Rheology for evaluating the viscoelastic properties of hydrogel scaffolds.

Abstract: Natural and synthetic hydrogel scaffolds exhibit distinct viscoelastic properties at various length scales and deformation rates. Laser Speckle Rheology (LSR) offers a novel, non-contact optical approach for evaluating the frequency-dependent viscoelastic properties of hydrogels. In LSR, a coherent laser beam illuminates the specimen and a high-speed camera acquires the time-varying speckle images. Cross-correlation analysis of frames returns the speckle intensity autocorrelation function, g2(t), from which the frequency-dependent viscoelastic modulus, G*(ω), is deduced. Here, we establish the capability of LSR for evaluating the viscoelastic properties of hydrogels over a large range of moduli, using conventional mechanical rheometry and atomic force microscopy (AFM)-based indentation as reference-standards. Results demonstrate a strong correlation between |G*(ω)| values measured by LSR and mechanical rheometry (r = 0.95, p < 10(-9)), and z-test analysis reports that moduli values measured by the two methods are identical (p > 0.08) over a large range (47 Pa - 36 kPa). In addition, |G*(ω)| values measured by LSR correlate well with indentation moduli, E, reported by AFM (r = 0.92, p < 10(-7)). Further, spatially-resolved moduli measurements in micro-patterned substrates demonstrate that LSR combines the strengths of conventional rheology and micro-indentation in assessing hydrogel viscoelastic properties at multiple frequencies and small length-scales.

Pub.: 03 Dec '16, Pinned: 20 Aug '17

Anti-VEGF therapy induces ECM remodeling and mechanical barriers to therapy in colorectal cancer liver metastases.

Abstract: The survival benefit of anti-vascular endothelial growth factor (VEGF) therapy in metastatic colorectal cancer (mCRC) patients is limited to a few months because of acquired resistance. We show that anti-VEGF therapy induced remodeling of the extracellular matrix with subsequent alteration of the physical properties of colorectal liver metastases. Preoperative treatment with bevacizumab in patients with colorectal liver metastases increased hyaluronic acid (HA) deposition within the tumors. Moreover, in two syngeneic mouse models of CRC metastasis in the liver, we show that anti-VEGF therapy markedly increased the expression of HA and sulfated glycosaminoglycans (sGAGs), without significantly changing collagen deposition. The density of these matrix components correlated with increased tumor stiffness after anti-VEGF therapy. Treatment-induced tumor hypoxia appeared to be the driving force for the remodeling of the extracellular matrix. In preclinical models, we show that enzymatic depletion of HA partially rescued the compromised perfusion in liver mCRCs after anti-VEGF therapy and prolonged survival in combination with anti-VEGF therapy and chemotherapy. These findings suggest that extracellular matrix components such as HA could be a potential therapeutic target for reducing physical barriers to systemic treatments in patients with mCRC who receive anti-VEGF therapy.

Pub.: 14 Oct '16, Pinned: 20 Aug '17