Open AccessMultifocal Organoid Capturing of Colon Cancer Reveals Pervasive Intratumoral Heterogenous Drug Responses
Author(s) -
Kim SoonChan,
Park Ji Won,
Seo HaYoung,
Kim Minjung,
Park JaeHyeon,
Kim GaHye,
Lee Ja Oh,
Shin YoungKyoung,
Bae Jeong Mo,
Koo BonKyoung,
Jeong SeungYong,
Ku JaLok
Publication year - 2022
Publication title -
advanced science
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 5.388
H-Index - 100
ISSN - 2198-3844
DOI - 10.1002/advs.202103360
Subject(s) - transcriptome , exome sequencing , genetic heterogeneity , tumor heterogeneity , colorectal cancer , organoid , cancer , exome , cancer research , biology , deep sequencing , precision medicine , digital polymerase chain reaction , drug , computational biology , biopsy , medicine , gene , genetics , mutation , phenotype , pathology , genome , gene expression , pharmacology , polymerase chain reaction
Intratumor heterogeneity (ITH) stands as one of the main difficulties in the treatment of colorectal cancer (CRC) as it causes the development of resistant clones and leads to heterogeneous drug responses. Here, 12 sets of patient‐derived organoids (PDOs) and cell lines (PDCs) isolated from multiple regions of single tumors from 12 patients, capturing ITH by multiregion sampling of individual tumors, are presented. Whole‐exome sequencing and RNA sequencing of the 12 sets are performed. The PDOs and PDCs of the 12 sets are also analyzed with a clinically relevant 24‐compound library to assess their drug responses. The results reveal unexpectedly widespread subregional heterogeneity among PDOs and PDCs isolated from a single tumor, which is manifested by genetic and transcriptional heterogeneity and strong variance in drug responses, while each PDO still recapitulates the major histologic, genomic, and transcriptomic characteristics of the primary tumor. The data suggest an imminent drawback of single biopsy‐originated PDO‐based clinical diagnosis in evaluating CRC patient responses. Instead, the results indicate the importance of targeting common somatic driver mutations positioned in the trunk of all tumor subregional clones in parallel with a comprehensive understanding of the molecular ITH of each tumor.