Multifocal organoids reveal clonal associations between synchronous intestinal tumors with pervasive heterogeneous drug responses

Abstract

Multifocal colorectal cancer (CRC) comprises both clonally independent primary tumors caused by inherited predisposition and clonally related tumors mainly due to intraluminal spreading along an intact basement membrane. The distinction between these multifocal CRCs is essential because therapeutic strategies vary according to the clonal association of multiple tumor masses. Here, we report one unique case of synchronous intestinal cancer (SIC) with tumors occurring along the entire bowel tract, including the small intestine. We established six patient-derived organoids (PDOs), and patient-derived cell lines (PDCs) from each site of the SIC, which were subjected to extensive genomic, transcriptomic, and epigenomic sequencing. We also estimated the drug responses of each multifocal SIC to 25 clinically relevant therapeutic compounds to validate how the clinically actionable alternations between SICs were associated with drug sensitivity. Our data demonstrated distinct clonal associations across different organs, which were consistently supported by multi-omics analysis, as well as the accordant responses to various therapeutic compounds. Our results indicated the imminent drawback of a single tumor-based diagnosis of multifocal CRC and suggested the necessity of an in-depth molecular analysis of all tumor regions to avoid unexpected resistance to the currently available targeted therapies.

Spheroids and organoids derived from colorectal cancer as tools for in vitro drug screening

“…Notably, the use of PDO has been exclusively designed to represent diverse genomic and proteomic characteristics from different patients, unleashing the possibility in tailoring personalized therapy. The whole-exome sequencing on multifocal CRC organoids was performed which demonstrated intertumoral heterogeneity between patients [ 147 ]. The significant similarity and stability of organoids genetic and epigenetic to tumor derived from patient has led to the establishment of living biobank of CRC organoids [ 16 , 148 ].…”

Tumor organoid model of colorectal cancer (Review)

“…They tested 24 drugs and found that tumors with high intratumor heterogeneity showed elevated expression of oncogenic features, thereby reducing their susceptibility to related inhibitors ( 77 ). Jeong et al ( 78 ) constructed organoid models for different sites of multifocal CRC, performed whole-exome sequencing, evaluated 25 medications to capture patients' intertumoral heterogeneity and identified clonal relationships between multifocal CRCs in terms of biological processes and therapeutic responses. After constructing primary and metastatic CRC organoids, transcriptomics and single-cell sequencing analysis revealed differences in cell composition between primary and metastatic foci ( 79 ).…”