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TGF-β signaling activated by cancer-associated fibroblasts determines the histological signature of lung adenocarcinoma

ABSTRACT: Invasive lung adenocarcinoma (LADC) is classified histologically as lepidic, acinar, papillary, micropapillary, or solid. We found that A549 human LADC cells formed tumors with distinct histological features—solid-type or acinar-type tumors—depending on the site of development in immunodeficient mice and that a solid-to-acinar transition (SAT) could be induced by cancer-associated fibroblasts (CAFs) in 3D cocultures with A549. To clarify the molecular mechanisms contributing to SAT induction, we performed RNA-seq analysis of four A549 tumor cell samples derived from solid- or acinar-type tumor tissue formed in vivo or from 3D tumor colonies formed in the presence or absence of CAFs in vitro.

ORGANISM(S): Homo sapiens

PROVIDER: GSE169029 | GEO | 2022/03/15

REPOSITORIES: GEO

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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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TGF-β signaling activated by cancer-associated fibroblasts determines the histological signature of lung adenocarcinoma

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