Single-cell analysis of hepatoblastoma identifies tumor signatures that predict chemotherapy susceptibility using patient-specific tumor spheroids

Song, Hanbing; Bucher, Simon; Rosenberg, Katherine; Tsui, Margaret; Burhan, Deviana; Hoffman, Daniel; Cho, Soo‐Jin; Rangaswami, Arun; Breese, Marcus R.; Leung, Stanley G.; Ventura, María V. Pons; Sweet-Cordero, E. Alejandro; Huang, Franklin W.; Nijagal, Amar; Wang, Bruce

doi:10.1038/s41467-022-32473-z

Cited by 24 publications

(32 citation statements)

References 46 publications

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“…Using scRNA-seq, other groups have also postulated that HB consists of multiple genomically unique cell populations. 10,[51][52][53] Therefore, isolation and characterization of these cell subclusters will become important to understand tumor development, evolution, self-renewal, and metastasis, to target the HB patients most in need of novel therapies. Indeed, in a clinical study, elevated serum EZH2 may be related to more aggressive disease.…”

Section: Discussionmentioning

confidence: 99%

“…Although this finding may be explained by clinical sampling variability, it may also be consistent with our previous finding that EZH2 expression is mostly limited to the Tr2 cell subcluster. Using scRNA‐seq, other groups have also postulated that HB consists of multiple genomically unique cell populations 10,51–53 . Therefore, isolation and characterization of these cell subclusters will become important to understand tumor development, evolution, self‐renewal, and metastasis, to target the HB patients most in need of novel therapies.…”

Section: Discussionmentioning

confidence: 99%

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EZH2 is a key component of hepatoblastoma tumor cell growth

Glaser,

Schepers,

Zwolshen

et al. 2023

Pediatric Blood & Cancer

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BackgroundEnhancer of zeste homolog 2 (EZH2) catalyzes the trimethylation of histone H3 at lysine 27 via the polycomb recessive complex 2 (PRC2) and plays a time‐specific role in normal fetal liver development. EZH2 is overexpressed in hepatoblastoma (HB), an embryonal tumor. EZH2 can also promote tumorigenesis via a noncanonical, PRC2‐independent mechanism via proto‐oncogenic, direct protein interaction, including β‐catenin. We hypothesize that the pathological activation of EZH2 contributes to HB propagation in a PRC2‐independent manner.Methods and resultsWe demonstrate that EZH2 promotes proliferation in HB tumor‐derived cell lines through interaction with β‐catenin. Although aberrant EZH2 expression occurs, we determine that both canonical and noncanonical EZH2 signaling occurs based on specific gene‐expression patterns and interaction with SUZ12, a PRC2 component, and β‐catenin. Silencing and inhibition of EZH2 reduce primary HB cell proliferation.ConclusionsEZH2 overexpression promotes HB cell proliferation, with both canonical and noncanonical function detected. However, because EZH2 directly interacts with β‐catenin in human tumors and EZH2 overexpression is not equal to SUZ12, it seems that a noncanonical mechanism is contributing to HB pathogenesis. Further mechanistic studies are necessary to elucidate potential pathogenic downstream mechanisms and translational potential of EZH2 inhibitors for the treatment of HB.

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Section: Discussionmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

EZH2 is a key component of hepatoblastoma tumor cell growth

Glaser,

Schepers,

Zwolshen

et al. 2023

Pediatric Blood & Cancer

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“…Informed consent was obtained from the parents of all patients from whom fresh specimens were collected. All patient-derived tissues and cells described in this study were obtained at Stanford/Lucile Packard Children's Hospital except for HB7, which was a gift from Bruce Wang (UCSF) 57 .…”

Section: Resource Availabilitymentioning

confidence: 99%

Cholangiocytic differentiation drives cell proliferation in hepatoblastoma through Wnt-dependent FGF19 signaling

Wu¹,

Fish²,

Hazard³

et al. 2023

Preprint

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Cancers evolve not only through the acquisition and clonal transmission of somatic mutations but also by non-genetic mechanisms that modify cell phenotype. Here, we describe how transcriptional heterogeneity arises within human hepatoblastoma, one of the cancers with the lowest mutational burden, characterized by activating mutations in the Wnt pathway. Histology-guided RNA sequencing and evaluation of spatial gene expression in primary hepatoblastomas identified foci of tumor cells within the highly proliferative embryonal histology that express the growth factor FGF19, colocalizing with markedly increased expression of Wnt target genes and cholangiocyte markers. In patient-derived tumoroids, FGF19 provided a required growth signal for FGF19-negative cells, and its expression depended on both Wnt/β-catenin and the biliary transcription factor SOX4. Our results reveal that a biliary lineage program induces FGF19 as a paracrine signal for tumor growth, thereby modulating the transcriptional outcome of constitutive Wnt activation and tumor cell proliferation.

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“…Some studies indicate that there are differences in the transcriptomic signature and epigenetic machinery of HB with varied treatment responses. These findings contribute to a deeper understanding of HB development and therapeutic responses, offering potential predictive biomarkers for personalized therapy (Song et al 2022 ; Clavería-Cabello et al 2023 ). However, the development of a simple and practical predictive model for chemotherapy response in HB is still a challenge.…”

Section: Introductionmentioning

confidence: 97%

Predicting response of hepatoblastoma primary lesions to neoadjuvant chemotherapy through contrast-enhanced computed tomography radiomics

Yang,

Wang,

et al. 2024

J Cancer Res Clin Oncol

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Objective To investigate the clinical value of contrast-enhanced computed tomography (CECT) radiomics for predicting the response of primary lesions to neoadjuvant chemotherapy in hepatoblastoma. Methods Clinical and CECT imaging data were retrospectively collected from 116 children with hepatoblastoma who received neoadjuvant chemotherapy. Tumor response was assessed according to the Response Evaluation Criteria in Solid Tumors (RECIST). Subsequently, they were randomly stratified into a training cohort and a test cohort in a 7:3 ratio. The clinical model was constructed using univariate and multivariate logistic regression, while the radiomics model was developed based on selected radiomics features employing the support vector machine algorithm. The combined clinical–radiomics model incorporated both clinical and radiomics features. Results The area under the curve (AUC) for the clinical, radiomics, and combined models was 0.704 (95% CI: 0.563–0.845), 0.830 (95% CI: 0.704–0.959), and 0.874 (95% CI: 0.768–0.981) in the training cohort, respectively. In the validation cohort, the combined model achieved the highest mean AUC of 0.830 (95% CI 0.616–0.999), with a sensitivity, specificity, accuracy, precision, and f1 score of 72.0%, 81.1%, 78.5%, 57.2%, and 63.5%, respectively. Conclusion CECT radiomics has the potential to predict primary lesion response to neoadjuvant chemotherapy in hepatoblastoma.

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Single-cell analysis of hepatoblastoma identifies tumor signatures that predict chemotherapy susceptibility using patient-specific tumor spheroids

Cited by 24 publications

References 46 publications

EZH2 is a key component of hepatoblastoma tumor cell growth

EZH2 is a key component of hepatoblastoma tumor cell growth

Cholangiocytic differentiation drives cell proliferation in hepatoblastoma through Wnt-dependent FGF19 signaling

Predicting response of hepatoblastoma primary lesions to neoadjuvant chemotherapy through contrast-enhanced computed tomography radiomics

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