Abstract B057: An organoids-on-a-chip model to recapitulate and dissect the tumor microenvironment of PDAC

Abstract

Abstract Abstract Body: Characteristics of the PDAC tumor microenvironment (TME) such as desmoplasia and an immunosuppressive landscape contribute to its resistance to chemotherapy and immunotherapy approaches. To recapitulate and dissect the in vivo PDAC TME, we bioengineered a PDAC organoid-on-a-chip model by integrating patient-derived PDAC organoids on a microfluidic-based organ-on-a-chip. While the patient-derived organoids (PDOs) maintain the characteristics of the in vivo counterparts with high fidelity, the organ-on-a-chip provides a controllable and reproducible environment with stromal and immune niche cells, creating an in vitro model that may providing insights into PDAC drug resistance and allow testing for new therapies. The multicellular organoid-on-a-chip model is composed of 1) a central PDAC niche including patient-derived PDAC organoids, patient-derived cancer-associated macrophages (CAFs), tumor-associated macrophages (TAMs) and blood vessels, and 2) surrounding vascular networks for nutrient transport and drug delivery. We reproduced the hypovasculariy of PDAC stromal niche on the chip and found a lower level of CD31 expression in the PDAC organoid niche than in the normal pancreatic organoid niche (p<0.0001). Comparing with the niche without PDOs, the PDAC niche on chip demonstrated a higher expression level of α-smooth muscle actin (α-SMA) on CAFs (fold-change=2.32, p<0.0001) and a more extensive deposition of ECM components (e.g., collagen I, collagen III, collagen IV and hyaluronic acid, fold-change>=2.25, p⇐0.0002), indicating the existence of desmoplasia on chip. Profiling of cytokine levels in the media revealed that, compared to models used with normal pancreatic epithelial cells with the other cellular components, the PDAC organoid TME induced the upregulation of a series of pro-tumor cytokines including MIP-3α, IL-8, CXCL5, IL-13 (fold-change>=5.02), the inflammation-related cytokines MIF, IL-5, MCP-1 (fold-change>=1.82), and CAF-derived cytokines like CXCL10, HGF, CXCL1, CXCL12 (fold-change>=1.82). The immunosuppressive cytokine TGF-β was increased after PDOs were loaded on the chip (762.3 pg/mL vs. 222.6 pg/mL in conditioned medium), as was the proinflammatory cytokine IL-6 (1089.5 pg/mL vs. 81.3 pg/mL), was maintained at a higher level than that in the niche with normal organoids (380.5 pg/mL vs. 60.4 pg/mL at day 13). We also found that PDOs induced TAMs inclined to be M2-like (CD68+CD163+) phenotype on chip. In turn niche cells (TAMs and CAFs) contributed to the immunosuppression in PDAC TME: the secretion of cytokines like IL-6, IL-13, MIP-1β and HGF were downregulated without niche cells (fold-change⇐0.646). In conclusion, we have developed a PDAC organoid-on-a-chip recapitulates the PDAC TME and is promising to serving as a platform to study mechanisms of drug resistance in PDAC as well as test novel therapies. Citation Format: Lunan Liu, Diane M. Simeone, Weiqiang Chen. An organoids-on-a-chip model to recapitulate and dissect the tumor microenvironment of PDAC [abstract]. In: Proceedings of the AACR Special Conference in Cancer Research: Pancreatic Cancer; 2023 Sep 27-30; Boston, Massachusetts. Philadelphia (PA): AACR; Cancer Res 2024;84(2 Suppl):Abstract nr B057.