Biology subjects

de Krijger, R. R.

Publications and source records attributed to de Krijger, R. R..

3 recordsLinked to original sources

bioRxiv2023

An engineered tumor organoid model reveals cellular identity and signaling trajectories underlying translocation RCC.

Translocation renal cell carcinoma (tRCC) is a rare, aggressive type of kidney cancer primarily occurring in children. They are genetically defined by translocations involving MiT/TFE gene family members, TFE3 or, in rare cases, TFEB. The biology underlying tRCC development remains poorly understood, partly due to the lack of representative experimental models. Here, we utilized human kidney organoids, or tubuloids, to engineer a tRCC model by expression of one of the most common MiT/TFE fusions, SFPQ-TFE3. Fusion expressing tubuloids adopt a tRCC-like phenotype and gene expression signature in vitro and grow as clear cell RCC upon xenotransplantation in mice. Genome-wide binding analysis reveals that SFPQ-TFE3 reprograms gene expression signatures by aberrant, gain-of-function genome-wide DNA binding. Combining these analyses with single-cell mRNA readouts reveals an epithelium-to-mesenchymal differentiation trajectory underlying tRCC transformation, potentially caused by deregulated Wnt signaling. Our study demonstrates that SFPQ-TFE3 expression is sufficient to transform kidney epithelial cells into tRCC and defines the trajectories underlying malignant transformation, thereby facilitating the development of new therapeutic interventions.

cancer biology↗

bioRxiv2023

Multi-dimensional profiling of hepatoblastomas and patient-derived tumor organoids uncovers tumor subpopulations with divergent WNT activation profiles and identifies pan-hepatoblastoma drug sensitivities

Hepatoblastoma, the most prevalent pediatric liver cancer, almost always carries a WNT-activating CTNNB1 mutation, yet exhibits notable molecular heterogeneity. To characterize this heterogeneity and identify novel targeted therapies, we performed comprehensive analysis of hepatoblastomas and tumor-derived organoids using single-cell RNA-seq, spatial transcriptomics, single-cell ATAC-seq and high throughput drug profiling. We identified two distinct tumor epithelial signatures: hepatic fetal-like and WNT-high embryonal-like signatures, displaying divergent WNT signaling patterns. The liver-specific WNT targets were enriched in the fetal-like group, while the embryonal-like group was enriched in canonical WNT target genes. Gene regulatory network analysis revealed enrichment of regulons related to hepatic function such as bile acid, lipid and xenobiotic metabolism in the fetal-like subgroup but not in the embryonal-like subgroup. In addition, the dichotomous expression pattern of the transcription factors HNF4A and LEF1 allowed for a clear distinction between the fetal- and embryonal-like tumors. We also performed high-throughput drug screening using patient-derived tumor organoids and identified sensitivity to multiple inhibitor classes, most notably HDAC inhibitors. Intriguingly, embryonal-like tumor organoids, but not fetal-like tumor organoids, were sensitive to FGFR inhibitor treatments, suggesting a dependency on FGFR signaling. In summary, our data uncover the molecular and drug sensitivity landscapes of hepatoblastoma and pave the way for the development of targeted therapies.

cancer biology↗

bioRxiv2020

Tumor to normal single cell mRNA comparisons reveal a pan-neuroblastoma cancer cell

Neuroblastoma is an embryonal childhood cancer that arises from aberrant development of the neural crest, mostly within the fetal adrenal medulla. It is not established what developmental processes neuroblastoma cancer cells represent. Here, we sought to reveal the phenotype of neuroblastoma cancer cells by comparing cancer (n=16,591) with fetal adrenal single cell transcriptomes (n=57,972). Our principal finding was that the neuroblastoma cancer cell resembled fetal sympathoblasts, but no other fetal adrenal cell type. The sympathoblastic state was a universal feature of neuroblastoma cells, transcending cell cluster diversity, individual patients and clinical phenotypes. We substantiated our findings in 652 neuroblastoma bulk transcriptomes and by integrating canonical features of the neuroblastoma genome with transcriptional signals. Overall, our observations indicate that there exists a pan-neuroblastoma cancer cell state which may be an attractive target for novel therapeutic avenues.

cancer biology↗