van Laarhoven, H. | Search bioRxiv

bioRxiv2018

Targeting integrin alpha5 receptor in pancreatic stellate cells to diminish tumor-promoting effects in pancreatic cancer

Pancreatic stellate cells (PSCs) are the main precursors of cancer-associated fibroblasts (CAFs) in pancreatic ductal adenocarcinoma (PDAC), known to induce cancer aggressiveness. Integrin alpha5 (ITGA5), a fibronectin receptor, was found to be overexpressed by CAFs in stroma and linked to poor overall survival (log-rank p=0.022, n=137) of patients with PDAC. In vitro, knockdown of ITGA5 in human PSCs (hPSCs) inhibited their adhesion, migration, and proliferation and also inhibited TGF-{beta}-mediated differentiation. In vivo, co-injection of PANC-1 tumor cells and hPSCs (sh-ITGA5) developed tumors with reduced fibrosis and slower growth rate compared to those composed of PANC-1 and hPSC (sh-Ctrl). Furthermore, we developed a ITGA5-antagonizing peptidomimetic (AV3) which inhibited TGF{beta}-mediated hPSC differentiation by blocking ITGA5/FAK pathway. In vivo, treatment with AV3 intraperitoneally attenuated tumor fibrosis and thereby enhanced the efficacy of gemcitabine in patient-derived xenografts in mice. Altogether, this study reports the therapeutic importance of ITGA5 in PDAC and provides novel therapeutic peptidomimetic to enhance the effect of chemotherapy.

cancer biology↗

bioRxiv2018

Improved localizers and anatomical images to enable phosphorus magnetic resonance spectroscopy of liver metastasis at 7T

Phosphorus spectroscopy (31P) at 7T (300 MHz) enables clinically-relevant spatial resolutions and time scales with high potential for monitoring response to cancer treatment. However, at 7T collecting a radiological-grade anatomical image of the liver--which is required for performing localized 31P spectroscopy--presents a challenge. Unlike lower field-strength scanners, there is no body coil in the bore of the 7T and despite inadequate penetration depth (<10 cm), surface coils are the current state-of-the-art for acquiring anatomical (1H) images. Therefore, thus far, high field 31P spectroscopy has been limited to diffuse liver disease. However, the use of antennas enable improved penetration depths at 300 MHz, and when combined with parallel transmit, can enable body imaging at 7T. We have developed a protocol for imaging liver metastases of patients using parallel transmit and 31P spectroscopy at 7T. We used a custom-made liver coil consisting of eight 30-cm dipole antennas tuned to the proton (300 MHz) frequency, and two partially overlapping 20-cm-diameter loops tuned for 31P (120 MHz). The field of view afforded by the two antennas underneath the 31P loops is not sufficient to image the complete boundaries of the liver for chemical shift imaging (CSI) planning and region-of-interest-based B0 shimming. The liver and full axial slice of the abdomen was imaged with eight transmit/receive antennas using parallel transmit B1-shimming to overcome image voids. Through the use of antennas we overcome the challenges for multi-parametric body imaging, and can begin to explore the possibility of monitoring the response of patients with liver metastasis to cancer treatments.\n\nABBREVIATIONS

bioengineering↗