3D Engineered Model of Microscopic Colorectal Cancer Liver Metastasis for Adjuvant Chemotherapy Screens

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PROJECT SUMMARY 50% of colorectal cancer (CRC) patients develop liver metastasis (CRLM). Despite adjuvant chemotherapy and surgery, 75% of CRLM recurs due to microscopic residual disease (~1-3mm) that escapes radiographic detection. The objective of this proposal is to engineer and utilize an adjuvant chemotherapy screening platform specific to microscopic CRLM, to identify therapeutics that can eradicate microscopic residual disease. Preclinical models like spheroids and patient-derived xenograft models lack the architecture and extracellular matrix (ECM) composition of the liver metastatic microenvironment. We hypothesize that by engineering the liver metastatic microenvironment, we can produce reproducible instances of microscopic CRLM that can be used for therapeutic screening. Engineered microscopic CRLM models will include: i) decellularized porcine liver biomatrix scaffolds that contain both liver ECM composition and 3D architecture; ii) microscopic spheroids from cells established from patient-derived xenografts of stage IV CRLM. Our methods offer advantages over other decellularized models by: i) using patient-derived cells; and ii) using optical imaging to quantitatively benchmark the establishment of microscopic CRLM; iii) using orthogonal validation including clinical patient-response benchmarking of engineered models to therapeutics; iv) being medium- and high-throughput amenable. The project will build on the PI's (Raghavan) expertise in cancer tissue engineering, but represent significant changes in research directions: The PI's expertise is in studying ovarian cancer initiation and chemoresistance, and this proposal focuses on CRC metastasis and CRLM. To support these research pivots, the PI has assembled an investigative team with expertise in clinical treatment and management of CRC (Kopetz), high-throughput drug screening (Stephan) and microscopy (Walsh). Specific Aims proposed include: (1) : Establish and characterize a bioengineered model of microscopic CRLM from human stage IV CRC; (2) Therapeutic screening of microscopic CRLM using an NCI-approved library; (3) Validation of therapeutic targeting of microscopic CRLM in orthotopic metastasis models. This will be the first instance of a bioengineered in vitro model of microscopic CRLM. Immediate outcomes using the engineered microscopic CRLM model include: i) screening a library of NCI-approved compounds; ii) identifying efficacious strategies to treat microscopic CRLM. Long-term outcomes envisioned include: i) predict the aggressiveness of microscopic residual disease, stratifying patients who are at high-risk of recurrence; ii) testing compounds that can translate into phase I clinical trials in patients with microscopic CRLM identified with circulating tumor DNA biomarkers.