Abstract 3753: Patient derived xenograft colorectal cancer in a micro-vascularized tumor on a microfluidic chip

Abstract

Abstract Colorectal cancer (CRC) is the third leading cause of cancer-related deaths in the United States. Cellular and biochemical cues from the tumor microenvironment (TME) modulate tumor aggressiveness including metastasis and treatment failure with cancer therapeutics. Conventional tumor models exhibit several shortcomings including lack of cell heterogeneity which limits their potential to examine more complex phenomena associated with drug testing applications. Patient-derived xenografts (PDX) represent an alternative model which maintains tumor heterogeneity. Physiological correlation of current preclinical models is limited by the degree of endothelial vascularization of tumor and incorporation of the tumor cell heterogeneity with an appropriate extracellular matrix to form a three-dimensional (3D) tumor. Herein, we have developed a micro-vascularized tumor on a chip model to examine the dynamics of tumor cell metastasis using CRC PDX lines. PDX tumors established from stage II, III-B, IV adenocarcinomas were propagated subcutaneously in SCID-NOD mice. Two days prior to tumor dissociation, the tumor chip containing an intricate vascular network for the growth of endothelial cells was primed and coated with 200 µg/ml fibronectin. EA.hy926 endothelial cells were seeded in the vascular channel and were allowed to form a lumen over 48 hours. The excised PDX tumor was dissociated and the cells (20 x 106 cells/ml) were mixed with a polymer precursor containing Poly(ethylene glycol)-fibrinogen and the photoinitiator eosin Y, then seeded into the primary tumor chamber and crosslinked under visible light. Serum containing media was perfused through the vascular channel at a constant flow rate of 1µl/minute. Metastasis was observed by maintaining the chip long-term. Significant differences (p = 0.034) in tumor cell migration in the chip (intravasation, tumor cell circulation through the vascular channel, invasion and extravasation) over time were observed between the PDX CRC stages. Stage II tumor cells intravasated to the vascular channel by day 8 followed by circulation and adhered to the endothelium as single circular cells or clusters by day 15. Stage III-B tumor cells were observed to intravasate, circulate, and adhere to the vascular channel by day 8, and the endothelium was overtaken by the cancer cells by day 8. Stage IV tumor cells began intravasation from the primary chamber to the vascular channel and circulated through the endothelium by day 8, while invasion to the secondary chamber adjacent to the primary chamber was observed by day 15. The Stage IV tumor cells also formed clusters in the vascular channel at a distant site and extravasated to the secondary chamber which is consistent with the staging of the tumor. Finally, this chip can be used for screening anti-cancer drugs for CRC patients. Citation Format: Benjamin Anbiah, Iman Hassani, Bulbul Ahmed, Nicole Habbit, Michael Greene, Balabhaskar Prabhakarpandian, Elizabeth Lipke. Patient derived xenograft colorectal cancer in a micro-vascularized tumor on a microfluidic chip [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2019; 2019 Mar 29-Apr 3; Atlanta, GA. Philadelphia (PA): AACR; Cancer Res 2019;79(13 Suppl):Abstract nr 3753.