Abstract
In Rspondin-based 3D cultures, Lgr5 stem cells from multiple organs form ever-expanding epithelial organoids that retain their tissue identity. We report the establishment of tumor organoid cultures from 20 consecutive colorectal carcinoma (CRC) patients. For most, organoids were also generated from adjacent normal tissue. Organoids closely recapitulate several properties of the original tumor. The spectrum of genetic changes within the "living biobank" agrees well with previous large-scale mutational analyses of CRC. Gene expression analysis indicates that the major CRC molecular subtypes are represented. Tumor organoids are amenable to high-throughput drug screens allowing detection of gene-drug associations. As an example, a single organoid culture was exquisitely sensitive to Wnt secretion (porcupine) inhibitors and carried a mutation in the negative Wnt feedback regulator RNF43, rather than in APC. Organoid technology may fill the gap between cancer genetics and patient trials, complement cell-line- and xenograft-based drug studies, and allow personalized therapy design. PAPERCLIP.
Highlights
Colorectal carcinoma (CRC) represents one of the major forms of cancer
Seminal studies have revealed a series of molecular pathways that are critical to the pathogenesis of CRC, including WNT, RAS-MAPK, PI3K, P53, TGF-b, and DNA mismatch repair (Fearon, 2011; Fearon and Vogelstein, 1990)
Over 90% of CRC cases harbor mutations that aberrantly activate the Wnt signaling pathway (Cancer Genome Atlas Network, 2012), so we exploited the Wnt-dependency of normal colonic stem cells to selectively expand tumor organoids
Summary
Colorectal carcinoma (CRC) represents one of the major forms of cancer. Seminal studies have revealed a series of molecular pathways that are critical to the pathogenesis of CRC, including WNT, RAS-MAPK, PI3K, P53, TGF-b, and DNA mismatch repair (Fearon, 2011; Fearon and Vogelstein, 1990). Large-scale sequencing analyses have dramatically extended the list of recurrently mutated genes and chromosomal translocations (Garraway and Lander, 2013; Vogelstein et al, 2013). CRC cases are characterized by either microsatellite instability (MSI) (associated with a hyper-mutator phenotype), or as microsatellite-stable (MSS) but chromosomally unstable (CIN) (Lengauer et al, 1997). The absolute number and combination of genetic alterations in CRC confounds our ability to unravel the functional contribution of each of these potential cancer genes. While genome changes in tumors of individual patients can be assessed in great detail and at low cost, these data are difficult to interpret in terms of prognosis, drug response, or patient outcome, necessitating model systems for analysis of genotype-to-phenotype correlations
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