Unknown,Transcriptomics,Genomics,Proteomics

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Transient activation of the WNT pathway after disruption/remodeling of colorectal cancer cell clusters promotes a malignant phenotype

ABSTRACT: Cancer progression and wound healing share some characteristics. Most colorectal cancers are differentiated adenocarcinomas that maintain three-dimensional structures to some extent. Hence, disruption of the architecture can provoke remodeling similar to the remodeling of normal intestinal epithelium. We used our recently developed three-dimensional culture system to investigate the response of cancer cell spheroids to mechanical disruption. Specifically, we developed a protocol for homogenous disruption of the spheroids that maintained the cell-cell contacts. After disruption, 9 spheroids from 9 patient samples reformed within a few hours, and 2 showed accelerated spheroid growth. Stemness increased after spheroid disruption, as assessed by marker expression, spheroid forming capacity, radiation sensitivity, and tumorigenesis. The spheroid-forming capacity increased in 6 of 11 spheroids. The disruption signature, as determined by gene expression profiling, supported the incidence of remodeling and predicted the prognosis of the colorectal cancer patients. WNT and HER3 signaling was increased in the reformed spheroids, and suppression of these signaling pathways attenuated the increases in growth and stemness after disruption. Thus, disorganized architecture in patient tumors might reflect the processes of disruption and subsequent remodeling and represent a cause rather than simply a consequence of malignancy progression. Gene expression in cancer tissue-originated spheroids (CTOSs) was measured at pre, 6 hr, 24 hr, and 4 days after mechanical disruption. One experiment was performed at each time point.

ORGANISM(S): Homo sapiens

SUBMITTER: masahiro inoue

PROVIDER: E-GEOD-75867 | biostudies-arrayexpress |

REPOSITORIES: biostudies-arrayexpress

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Project description:Full title: Comprehensive Characterization of Three-Dimensional Models for Prostate Cancer Growth and Invasion in Laminin-rich Extracellular Matrix Prostate Cancer (PrCa) cells undergo acinar morphogenesis and spheroid formation in three-dimensional (3D) culture, supported by laminin-rich extracellular matrix (lrECM, Matrigel). We developed miniaturized 3D model systems that facilitate investigation of morphogenesis and invasion of normal and PrCa cell lines in lrECM. Primary and non-transformed cell lines formed round structures with strong cell-cell contacts and epithelial polarization, lumen and a complete basal lamina (BL). In contrast, most PrCa cell lines formed either defective, “mass” spheroids with incomplete BL, or invasive “stellate” structures. The bioinformatic analyses of genome-wide mRNA expression data revealed massive alteration of key functional and signaling pathways in 3D cultures, with lipid and steroid metabolism, epigenetic reprogramming, and differentiation-related transcription factors induced across all cell lines by lrECM. In invasive cells, AKT, PI3Kinase, mTOR, and hedgehog signaling pathways were most highly activated, validated by small molecule inhibitors compounds specifically targeting key regulatory molecules. Compounds against AKT and PI3kinase pathways were significantly more effective in invasive cells, compared to mass or round/normal phenotype spheroids, and monolayer culture. A severe morphologic conversion was observed in PC-3 and PC-3M cells, transforming initially round, normal-appearing epithelial spheroids into rapidly invading cell masses. Markers for EMT (epithelial-mesenchymal transition) were highly expressed already in early stage, round spheroids prior to invasive conversion, and were not further increased in invasive cells. This indicates that PrCa cells can display extraordinary plasticity. EMT may be involved in providing a metastable genotype that allows morphological transformation, but is not be required for invasive processes themselves. Total RNA was obtained from non-transformed prostate epithelial cells and prostate cancer cells cultured in monolayer and three-dimensional laminin-rich extracellular matrix (growth factor-reduced Matrigel).

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Transient activation of the WNT pathway after disruption/remodeling of colorectal cancer cell clusters promotes a malignant phenotype

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