Single-cell transcriptomics reveals the landscape of intra-tumoral heterogeneity and stemness-related subpopulations in liver cancer

Ho, Daniel Wai‐Hung; Tsui, Yu Man; Sze, Karen Man Fong; Chan, Lap Ki; Cheung, Tan To; Lee, Eva; Sham, Pak C.; Tsui, Stephen Kwok Wing; Lee, Terence; Ng, Irene Oi Lin

doi:10.1016/j.canlet.2019.06.002

Cited by 128 publications

(122 citation statements)

References 44 publications

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“…Differentiated capacity was assessed via culturing sphere cells in medium supplemented with 10% FBS according to our previous study and expression of stemnessassociated genes were determined by RT-PCR [27]. EpCAM was set as an internal control reflecting CSC traits due to its universal expression pattern in HCC stem cells [29]. For self-renewal capacity evaluation, serial sphere formation was conducted in continuous 6 passages according to previous studies [27,30].…”

Section: Evaluations Of Self-renewal and Differentiated Capacitiesmentioning

confidence: 99%

“…1h). Three rounds of serial passaging were performed to investigate dynamic changes in CD73 mRNA expression, and the expression of EpCAM as a universal CSC marker was measured as an internal control to reflect CSC traits [29]. CD73 mRNA expression in Hep3B and HCCLM3 cells was significantly upregulated in sphere cells and showed a notable decrease following 10% FBS-induced differentiation (Additional file 4: Figure S2A).…”

Section: Cd73 Expression Conferred Csc Traits To Hcc Cellsmentioning

confidence: 99%

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CD73 sustained cancer-stem-cell traits by promoting SOX9 expression and stability in hepatocellular carcinoma

Lü

Tang

et al. 2020

J Hematol Oncol

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Background: Aberrant AKT activation contributes to cancer stem cell (CSC) traits in hepatocellular carcinoma (HCC). We previously reported that CD73 activated AKT signaling via the Rap1/P110β cascade. Here, we further explored the roles of CD73 in regulating CSC characteristics of HCC. Methods: CD73 expression modulations were conducted by lentiviral transfections. CD73+ fractions were purified by magnetic-based sorting, and fluorescent-activated cell sorting was used to assess differentiation potentials. A sphere-forming assay was performed to evaluate CSC traits in vitro, subcutaneous NOD/SCID mice models were generated to assess in vivo CSC features, and colony formation assays assessed drug resistance capacities. Stemness-associated gene expression was also determined, and underlying mechanisms were investigated by evaluating immunoprecipitation and ubiquitylation. Results: We found CD73 expression was positively associated with sphere-forming capacity and elevated in HCC spheroids. CD73 knockdown hindered sphere formation, Lenvatinib resistance, and stemness-associated gene expression, while CD73 overexpression achieved the opposite effects. Moreover, CD73 knockdown significantly inhibited the in vivo tumor propagation capacity. Notably, we found that CD73+ cells exhibited substantially stronger CSC traits than their CD73-counterparts. Mechanistically, CD73 exerted its pro-stemness activity through dual AKT-dependent mechanisms: activating SOX9 transcription via c-Myc, and preventing SOX9 degradation by inhibiting glycogen synthase kinase 3β. Clinically, the combined analysis of CD73 and SOX9 achieved a more accurate prediction of prognosis. Conclusions: Collectively, CD73 plays a critical role in sustaining CSCs traits by upregulating SOX9 expression and enhancing its protein stability. Targeting CD73 might be a promising strategy to eradicate CSCs and reverse Lenvatinib resistance in HCC.

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Section: Evaluations Of Self-renewal and Differentiated Capacitiesmentioning

confidence: 99%

Section: Cd73 Expression Conferred Csc Traits To Hcc Cellsmentioning

confidence: 99%

CD73 sustained cancer-stem-cell traits by promoting SOX9 expression and stability in hepatocellular carcinoma

Lü

Tang

et al. 2020

J Hematol Oncol

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“…[ 30 ] Unfortunately, such a situation in HCC is still uncommon and patient heterogeneity, much less tumor heterogeneity, makes this prospect more difficult. [ 31 ]…”

Section: Successes and Challenges In Liver Disease And Transplantationmentioning

confidence: 99%

Phenotypic Response and Personalized Medicine in Liver Cancer and Transplantation: Approaches to Complex Systems

Zarrinpar

Kim

Boominathan

2020

Advanced Therapeutics

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Rapid improvements in medical technology, big data analysis, and molecular medicine come with promises of revolutionizing medical care. They span the spectrum from diagnostics to genome-based drug selection to multi-biomarker analysis to deciphering large amounts of data. Below, recent developments in personalized and precision medicine are reviewed, focusing specifically on the liver, ranging from fatty liver disease to liver cancer treatment and liver transplantation. Furthermore, current technologies and their advantages and limitations are discussed, in addition to ways in which these disadvantages can be overcome, using phenotypic personalized medicine.

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“…5 Similarly, human and mouse parenchymal, nonparenchymal and myeloid immune cells comprise astonishingly heterogeneous subpopulations in HCC and premalignant fibrotic conditions. 6,7 We, therefore, hope that our principal observation of a role of the chemokine receptor CXCR6 in antitumor immune surveillance during hepatocarcinogenesis will trigger more research in this direction that will allow translating these fundamental findings into new prognostic and/or therapeutic approaches for patients with chronic liver diseases and HCC. Our work should also raise caution that interfering with seemingly harmful "inflammatory" chemokine pathways in liver fibrosis 8 always needs to be evaluated for potential consequences of immune surveillance mechanisms.…”

Section: Most Current Articlementioning

confidence: 99%

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Mossanen

Tacke

2019

Gastroenterology

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Single-cell transcriptomics reveals the landscape of intra-tumoral heterogeneity and stemness-related subpopulations in liver cancer

Cited by 128 publications

References 44 publications

CD73 sustained cancer-stem-cell traits by promoting SOX9 expression and stability in hepatocellular carcinoma

CD73 sustained cancer-stem-cell traits by promoting SOX9 expression and stability in hepatocellular carcinoma

Phenotypic Response and Personalized Medicine in Liver Cancer and Transplantation: Approaches to Complex Systems

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