3D modeling of cancer stem cell niche

He, Jun; Li, Xiong; Li, Qinglong; Lin, Liangwu; Miao, Xiangshui; Yan, Shichao; Hong, Zhangyong; Li, Yang; Wen, Yu; Deng, Xiyun

doi:10.18632/oncotarget.19847

Cited by 49 publications

(41 citation statements)

References 184 publications

(199 reference statements)

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“…When cultured as single cells into matrigel [30][31][32] the L1 low cells generated more organoid-like structures than L1 high cells ( Fig. 2c) and retained low expression of L1 even after 7 days of culture (Org) ( Supplementary Fig.…”

Section: Lack Of L1cam Expression Features Factors Associated With Stmentioning

confidence: 99%

TGF-β1 secreted by pancreatic stellate cells promotes stemness and tumourigenicity in pancreatic cancer cells through L1CAM downregulation

et al. 2020

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Pancreatic stellate cells (PSCs) secrete high levels of transforming growth factor-β1 (TGF-β1) that contributes to the development of pancreatic ductal adenocarcinoma (PDAC). TGF-β1 modulates the expression of L1 cell adhesion molecule (L1CAM), but its role in tumour progression still remains controversial. To clarify L1 function in PDAC and cellular phenotypes, we performed L1CAM cell sorting, silencing and overexpression in several primary pancreatic cancer cells. PSCs silenced for TGF-β1 were used for crosstalk experiments. We found that TGF-β1 secreted by PSCs negatively regulates L1CAM expression, through canonical TGF-β-Smad2/3 signalling, leading to a more aggressive PDAC phenotype. Cells with reduced expression of L1CAM harboured enhanced stemness potential and tumourigenicity. Inactivation of TGF-β1 signalling in PSCs strongly reduced the aggressiveness of PDAC cells. Our data provide functional proof and mechanistic insights for the tumour-suppressive function of L1CAM via reducing stemness. Rescuing L1CAM expression in cancer cells through targeting of TGF-β1 reverses stemness and bears the potential to improve the still miserable prognosis of PDAC patients.

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Section: Lack Of L1cam Expression Features Factors Associated With Stmentioning

confidence: 99%

TGF-β1 secreted by pancreatic stellate cells promotes stemness and tumourigenicity in pancreatic cancer cells through L1CAM downregulation

et al. 2020

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“…To this end, we used as an experimental model the generation and maintenance of oncospheres starting from breast cancer cells. These structures can be generated with multiple cancer cell lines and are known to be enriched in CSCs, on the basis of the expression of CSC genes, including ALDH1 , SOX2 , CD44+/CD24− [14,15]. They are also enriched in markers of EMT, including CTNNB1 , EGR1 , ERBB2 and MUC1 [16,17].…”

Section: Introductionmentioning

confidence: 99%

Expression of Oncogenic Drivers in 3D Cell Culture Depends on Nuclear ATP Synthesis by NUDT5

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Pardow

Carbonell-Caballero

et al. 2019

Cancers

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The growth of cancer cells as oncospheres in three-dimensional (3D) culture provides a robust cell model for understanding cancer progression, as well as for early drug discovery and validation. We have previously described a novel pathway in breast cancer cells, whereby ADP (Adenosine diphosphate)-ribose derived from hydrolysis of poly (ADP-Ribose) and pyrophosphate (PPi) are converted to ATP, catalysed by the enzyme NUDT5 (nucleotide diphosphate hydrolase type 5). Overexpression of the NUDT5 gene in breast and other cancer types is associated with poor prognosis, increased risk of recurrence and metastasis. In order to understand the role of NUDT5 in cancer cell growth, we performed phenotypic and global expression analysis in breast cancer cells grown as oncospheres. Comparison of two-dimensional (2D) versus 3D cancer cell cultures from different tissues of origin suggest that NUDT5 increases the aggressiveness of the disease via the modulation of several key driver genes, including ubiquitin specific peptidase 22 (USP22), RAB35B, focadhesin (FOCAD) and prostagladin E synthase (PTGES). NUDT5 functions as a master regulator of key oncogenic pathways and of genes involved in cell adhesion, cancer stem cell (CSC) maintenance and epithelial to mesenchyme transition (EMT). Inhibiting the enzymatic activities of NUDT5 prevents oncosphere formation and precludes the activation of cancer driver genes. These findings highlight NUDT5 as an upstream regulator of tumour drivers and may provide a biomarker for cancer stratification, as well as a novel target for drug discovery for combinatorial drug regimens for the treatment of aggressive cancer types and metastasis.

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“…Interestingly though, EGF is also a known epithelial differentiation factor; however, this effect seems to be successfully counteracted by other components of the stem medium as evident by the expression profiles of the SCESM spheroids [ 55 ]. The SCESM spheroids exceeded 450 µm already at day 3 and 800 µm at day four (these diameters enabling the development of hypoxia and necrotic core, respectively) [ 28 , 56 , 57 ], both stimulating the dedifferentiation process and CSC enrichment [ 30 , 58 , 59 , 60 ]. Additionally, analyses of the proliferation marker Ki-67 and the 7-AAD nuclear stain suggested that only the outermost rim of cells is fast proliferating, while the cells deeper in are poorly/not proliferating.…”

Section: Discussionmentioning

confidence: 99%

Head and Neck Cancer Stem Cell-Enriched Spheroid Model for Anticancer Compound Screening

Goričan

Gole

Potočnik

2020

Cells

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Cancer stem cells (CSCs), a rare cell population in tumors, are resistant to conventional chemotherapy and thus responsible for tumor recurrence. To screen for active compounds targeting CSCs, a good CSC-enriched model compatible with high-throughput screening (HTS) is needed. Here, we describe a new head and neck cancer stem cell-enriched spheroid model (SCESM) suitable for HTS analyses of anti-CSC compounds. We used FaDu cells, round-bottom ultra-low adherent (ULA) microplates, and stem medium. The formed spheroids displayed increased expression of all stem markers tested (qRT-PCR and protein analysis) in comparison to the FaDu cells grown in a standard adherent culture or in a well-known HTS-compatible multi-cellular tumor spheroid model (MCTS). Consistent with increased stemness of the cells in the spheroid, confocal microscopy detected fast proliferating cells only at the outer rim of the SCESM spheroids, with poorly/non-proliferating cells deeper in. To confirm the sensitivity of our model, we used ATRA treatment, which strongly reduced the expression of selected stem markers. Altogether, we developed a CSC-enriched spheroid model with a simple protocol, a microplate format compatible with multimodal detection systems, and a high detection signal, making it suitable for anti-CSC compounds’ HTS.

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3D modeling of cancer stem cell niche

Cited by 49 publications

References 184 publications

TGF-β1 secreted by pancreatic stellate cells promotes stemness and tumourigenicity in pancreatic cancer cells through L1CAM downregulation

TGF-β1 secreted by pancreatic stellate cells promotes stemness and tumourigenicity in pancreatic cancer cells through L1CAM downregulation

Expression of Oncogenic Drivers in 3D Cell Culture Depends on Nuclear ATP Synthesis by NUDT5

Head and Neck Cancer Stem Cell-Enriched Spheroid Model for Anticancer Compound Screening

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