Circulating Tumor Cell-Derived Organoid On-A-Chip: Applications for Colorectal Cancer Drug Discovery

Colorectal cancer (CRC) is the third common cancer and the second leading cause of cancer death in the world. Uncontrolled metastatic disease contributes to the majority of CRC death, and liquid biopsy with circulating tumor cells (CTC) is a novel approach to tackle metastatic CRC. Currently phase 3 drug trials for metastatic CRC has unsatisfactory success rate. One of the major limits lie in the preclinical screening models, which usually lack both diversity to mimic clinical diseases and tumor microenvironment (TME) related information. Having patient derived primary tumor culture to be applied in a TME-mimicry microfluidic chip may advance towards a more efficient preclinical lead screening system. Currently the team has developed DS-SACA (dynamic staining on selfassembled cell array) and TAH (transwell alginate hydrogel) chips that are capable of analyzing circulating tumor cell phenotypes as well as their homing potential to premetastatic TME. Also we have established CTC-derived organoid culture and drug sensitivity profiling from patients with CRC. Recently, we found that extracellular matrix in the CRC organoid contributes to drug resistance and is a novel druggable target. With these findings, we propose this research to develop CTC-organoid on-a-chip as a novel drug screening approach and test the principle on leads targeting WNT pathway for CRC. Three specific aims are designed. In this study, we construct a novel biomimetic microenvironment chip platform with incorporation of hydrogel. This platform will utilize external circulatory loop simulating blood flow to observe the physical cues that lead to tumor metastasis. Together the work may lead to a new drug screening platform that considers patient diversity and TME in the model and supplement the current workflow to increase lead hit rate for CRC drug discovery.