PI: Dr. Claudia Janda
Dissecting the molecular mechanisms underlaying osteosarcoma
Osteosarcoma (OS) is the most common type of primary malignant bone tumor. OS predominantly affects children and young adults, accounting for 5% of all pediatric tumors, and most frequently develops around the metaphysis of long bones, coinciding with the adolescent growth spurt. While patients with localized OS have improved outcome, treatment options remain limited and harsh, and there is an ongoing need for more selective and effective therapeutics.
In collaboration with various groups at the Princess Maxima Center for Pediatric Oncology, we take a multidisciplinary approach and integrate organoid technology, single cell transcriptomics, single cell genomics and 3D imaging of primary bone tissue and tumor biopsies, and transgenic mouse models. We aim to dissect the molecular mechanisms of OS initiation and progression, development of intratumor heterogeneity, and the importance of signaling cross-talk between tumor sub-population and micro-environment for tumor growth, metastatic transformation, and evasion of differentiation, apoptosis and immune recognition.
Patient-derived organoids as model of OS to develop personalized treatment strategies
While our current models of OS are limited, tumor organoids, which recapitulate the patient-characteristic molecular and cellular tumor properties, have emerged as robust preclinical models. My laboratory aims to develop bone and OS organoid cultures, and to interrogate molecular mechanisms of tumorigenesis (e.g. tumor evolution and development of drug resistance). Ultimately, we would also like to develop co-cultures that mimic tumor interaction with its microenvironment. Furthermore, our laboratory aims to establish patient-derived OS organoids cultures of primary, secondary, relapsed and metastatic OS tumors, which recapitulate the mutational, transcriptional and morphological diversity of primary OS tumors and to leverage the ‘living biobank’ for drug screening and biomarker identification with the ultimate goal of developing personalized OS therapy.
Dissecting the role of pleiotropic developmental signaling pathways in bone formation and cancer evolution
Wnt, BMP/TGFb and Notch signaling are activated by promiscuous interactions between multiple ligand and receptor variants allowing them to elicit highly pleiotropic functions. Deregulation of these signaling pathways has been associated with a wide range of cancers. While it is clear that Wnt, BMP and Notch signaling play important roles in bone and cartilage formation, the promiscuity, poor stability and/or low affinity of the natural ligands have complicated functional studies to dissect their activity during normal and tumor development in bone tissue. My laboratory uses protein engineering approaches, including protein crystallography and directed evolution of ligands and antibodies, to develop new Wnt, BMP/TGFb and Notch signaling modulators with drug-like properties to overcome these limitations. We will interrogate their activity and potential therapeutic efficacy in various in vitro and in vivo bone formation and OS models. We are in particular interested in identifying modulators that interfere with the ability of OS to evade differentiation, apoptosis and immune recognition.
Developing new strategies for the treatment of side effects of cancer therapy
New chemotherapeutic agents and improved treatment regiments have led to an increased survival rate, however pediatric cancer therapy is frequently accompanied by significant side effects that worsen the quality of life during and after treatment. The management of side effects of cancer treatment has gained increased attention, however efficient therapeutic intervention strategies are often lacking. Our lab is interested in developing new therapeutic strategies for the treatment of side effects, with the primary focus on mucositis and skeletal health issues, common immediate and late effects of cancer treatment, respectively.
Yan KS, Janda CY, Chang J, Zheng GXY, Larkin KA, Luca VC, Chia LA, Mah AT, Han A1, Terry JM, Ootani A, Roelf K, Lee M, Yuan J, Li X, Bolen CR, Wilhelmy J, Davies PS, Ueno H, von Furstenberg RJ, Belgrader P, Ziraldo SB, Ordonez H, Henning SJ, Wong MH, Snyder MP, Weissman IL, Hsueh AJ, Mikkelsen TS, Garcia KC, Kuo CJ. Non-equivalence of Wnt and R-spondin ligands during Lgr5+ intestinal stem-cell self-renewal. 9 (2017) Nature 545:238-242 PubMed PMID:28467820
Janda CY, Dang LT, You C, Chang J, de Lau W, Zhong ZA, Yan KS, Marecic O, Siepe D, Li X, Moody JD, Williams BO, Clevers H, Piehler J, Baker D, Kuo CJ, Garcia KC. Surrogate Wnt agonists that phenocopy canonical Wnt and β-catenin signalling. (2017) Nature 545:234-237 PubMed PMID:28467818
Keupp K, Beleggia F, Kayserili H, Barnes AM, Steiner M, Semler O, Fischer B, Yigit G, Janda CY, Becker J, Breer S, Altunoglu U, Grünhagen J, Krawitz P, Hecht J, Schinke T, Makareeva E, Lausch E, Cankaya T, Caparrós-Martín JA, Lapunzina P, Temtamy S, Aglan M, Zabel B, Eysel P, Koerber F, Leikin S, Garcia KC, Netzer C, Schönau E, Ruiz- Perez VL, Mundlos S, Amling M, Kornak U, Marini J, Wollnik B. Mutations in WNT1 Cause Different Forms of Bone Fragility.(2013) American Society of Human Genetics 92: 565-574 PubMed PMID:23499309
Bazan JF, Janda CY, Garcia KC. Structural architecture and functional evolution of Wnts. (2012) Developmental Cell 23: 227-232 PubMed PMID:22898770
Janda CY, Waghray D, Levin AM, Thomas C & Garcia KC. (2012) Structural basis of Wnt recognition by Frizzled. (2012) Science 337: 59-64 PubMed PMID:22653731