Microvascularized tumor assembloids model for drug delivery evaluation in colorectal cancer-derived peritoneal metastasis.

Abstract

Peritoneal metastasis (PM) is a fatal state of colorectal cancer, and only a few patients may benefit from systemic chemotherapy. Although hyperthermic intraperitoneal chemotherapy (HIPEC) brings hope for affected patients, the drug development and preclinical evaluation of HIPEC are seriously lagging behind, mainly due to the lack of an ideal in vitro PM model that makes drug development over-reliant on expensive and inefficient animal experiments. This study developed an in vitro colorectal cancer PM model [microvascularized tumor assembloids (vTA)] based on an assembly strategy of endothelialized microvessels and tumor spheroids. Our data showed that the in vitro perfusion cultured vTA could maintain a similar gene expression pattern to their parental xenografts. Also, the drug penetration pattern of the in vitro HIPEC in vTA could mimic the drug delivery behavior in tumor nodules during in vivo HIPEC. More importantly, we further confirmed the feasibility of constructing a tumor burden-controlled PM animal model using vTA. In conclusion, we propose a simple and effective strategy to construct physiologically simulated PM models in vitro, thus providing a basis for PM-related drug development and preclinical evaluation of locoregional therapies. STATEMENT OF SIGNIFICANCE: This study developed an in vitro colorectal cancer peritoneal metastasis (PM) model based on microvascularized tumor assembloids (vTA) for drug evaluation. With perfusion culture, vTA could maintain a similar gene expression pattern and tumor heterogeneity to their parental xenografts. And the drug penetration pattern in vTA was similar to the drug delivery behavior in tumor nodules under in vivo treatment. Moreover, vTA was more conducive to construct PM animal models with controllable tumor burden. In conclusion, the construction of vTA could provide a new strategy for the PM-related drug development and preclinical evaluation of locoregional therapies.