PI: Weng Chuan Peng
Understanding childhood liver cancer
Pediatric liver cancer is a rare cancer that affects approximately 1 in a million children. In the Netherlands, about 8 – 10 children are diagnosed with liver cancer every year. The most common malignant liver tumors in children are hepatoblastoma (HB) and hepatocelullar carcinoma (HCC). Histologically, hepatoblastoma can generally be classified into various subtypes such as pure fetal (well differentiated, crowded), embryonal (less differentiated, more aggressive), small-cell undifferentiated (very aggressive), while HCCs oberved in children and adolescents are pathologically and biologically distinct from HCC in adults. Due to the limited number of patients, childhood liver cancer is poorly studied.
We will investigate the biology underlying liver cancer, based on NGS data (WGS/WES, single cell RNA-seq, spatially-resolved transcriptomics etc), in vitro organoid model derived from tumor cells (gene editing, advanced imaging, high throughput screening), and in vivo mouse model (tumor cells, organoid transplantion in the liver). The overall aim is to unravel the genetic basis of tumor variants, identify key signaling pathways, the role of tumor microenviroment, and characterization of the immune profile. One of our immediate goal is to establish a patient-derived tumor organoid biobank. These ‘tumoroids’ will be the basis for personalized medicines, for e.g., genomic analysis, drug screening, and predicting responses to chemotherapy, among others. With the knowledge gained from basic research, we aim to answer clinically relevant questions; for instance, why are some tumor subtypes more aggresive than others and respond poorly to chemotherapy. In addition, we hope to find novel biomarkers for tracking tumor responses to chemotherapy and identify potential therapeutics (e.g., antibodies, engineered ligands) targeting tumor subtypes that are difficult to treat.
At the Maxima, we will be working closely with the clinicians (i.e., pediatric oncologist, pathologist, surgeon) to understand childhood liver cancer. Through the understanding of tumor biology, we hope to find novel strategies to treat liver cancer, expose fewer children to chemotherapy, and ultimately cure more children without compromising their quality of life.
Adult stem cell 3D culture and cell replacement therapy
Establishing engraftable hepatocyte organoids (‘mini liver on a dish’):
A long-standing challenge in the stem cell field is the ability to expand primary cell type indefinitely in vitro, while maintaining its physiological properties. This is exacerbated by the fact that many tissues are slow cycling, for example, the liver, lung, kidney, pancreas, heart, showing little-to-no proliferation in vivo.
Our lab utilizes the liver as our model organ due to its immense regenerative capacity following injury. Recently, we demonstrated that murine hepatocytes can be propagated indefinitely in 3D culture, by incorporating factors that are typically observed during tissue repair. Of particular significance is that these in vitro- expanded progenitor cells could engraft efficiently in the injured livers of FAH mice and expressed the appropriate markers related to liver function (Peng et al., Cell, 2018).
The ability to generate large number of healthy cells is the first essential step towards making cell replacement therapy (to treat liver diseases) possible. It is estimated that 5 – 10% of engraftment is sufficient to maintain normal liver function. We are currently focusing on expanding functional adult human hepatocytes indefinitely in vitro, and develop strategies to (i) achieve significant engraftment, and more importantly (ii) maintain their long-term engraftment in mouse model; Our long-term goal is that cell transplantation may one day address the issue of organ donor shortage.
We are always looking for students from diverse backgrounds (molecular biology, engineering, computational etc), who are passionate in science and problem-solving to join our lab.
Organoid culture and transplantation:
Peng WC*, Logan CY, Fish M, Anbarchian T, Aguisanda F, Alvarez A, Wu P, Jin Y, Zhu J, Li B, Grompe M, Wang B, Nusse R*. 2018) Inflammatory cytokine TNFa promotes the long-term expansion of primary hepatocytes in 3D culture. Cell 175, 607–1619.e1615. (* corresponding authors, Featured in F1000 Faculty Recommendation).
Tabula Muris Consortium et al. (2018) Single-cell transcriptomics of 20 mouse organs creates a Tabula Muris. Nature 562, 367–372.
Tabula Muris Consortium, Pisco, A.O., Schaum, N., McGeever, A., Karkanias, J., Neff, N.F., Darmanis, S., Wyss-Coray, T., Quake, S.R. (2019) A Single Cell Transcriptomic Atlas Characterizes Aging Tissues in the Mouse. bioRxiv 661728. https://doi.org/10.1101/661728
Structural studies of WNT signaling complexes in adult stem cells:
de Lau W, Peng WC, Gros P, Clevers H (2014) The R-spondin/Lgr5/Rnf43 module: regulator of Wnt signal strength. Genes & development 28(4): 305–16.
Peng WC*, de Lau W*, Forneris F, Granneman JCM, Huch M, Clevers H, Gros P (2013) Structure of Stem Cell Growth Factor R-spondin 1 in Complex with the Ectodomain of Its Receptor LGR5. Cell Reports 3(6): 1885–1892. * co-first authors
Peng WC, de Lau W, Madoori PK, Forneris F, Granneman JCM, Clevers H, Gros P (2013) Structures of Wnt-antagonist ZNRF3 and its complex with R-spondin 1 and implications for signaling. PLoS ONE 8(12): e83110.
Structural studies of transmembrane domain in lipid bilayers:
Peng WC, Lin X, Torres J (2009) The strong dimerization of the transmembrane domain of the fibroblast growth factor receptor 3 (FGFR3) is modulated by C-terminal juxtamembrane residues. Protein Science 18: 450–459.
Priya R, Tadwal, VS, Roessle MW, Gayen S, Hunke C, Peng WC, Torres J, Grüber G (2008) Low resolution structure of subunit b (b (22-156)) of Escherichia coli F(1)F(O) ATP synthase in solution and the b-delta assembly. Journal of Bioenergetics and Biomembranes 40: 245–255.