Role of cilia in oncogenic signaling and drug resistance
Primary cilia are microtubule-based antennae that detect mechanical and chemical stimuli. Although cilia house a number of oncogenic molecules (including Smoothened, KRAS, EGFR, and PDGFR), their precise role in cancer remains unclear. We recently found that cilia mediate acquired and de novo resistance to a variety of kinase inhibitors in cancer, and found that, in several examples, resistant cells are distinctly characterized by an increase in the number and/or length of cilia with altered structural features. Changes in ciliation seem to be linked to differences in the molecular composition of cilia and result in enhanced Hedgehog pathway activation.
The aim of this project is to elucidate the nature of the oncogenic pathways controlled by cilia and how do they change in resistant versus sensitive cells. This project will use biochemical approaches, microscopy, cell biology, molecular biology and cancer biology techniques.
Barbara E. Tanos, Hui-Ju Yang, Rajesh Soni, Won-Jing Wang, Frank P. Macaluso, John M. Asara and Meng-Fu Bryan Tsou.Centriole distal appendages promote membrane docking, leading to cilia initiation. 2013. Genes Dev 27: 163-168.
T. Tony Yang, Weng Man Chong, Won-Jing Wang, Gregory Mazo, Barbara Tanos, Zhengmin Chen, Thi Minh Nguyet Tran, Yi-De Chen, Rueyhung Roc Weng, Chia-En Huang, Wann-Neng Jane, Meng-Fu Bryan Tsou, Jung-Chi Liao. Architecture of mammalian centriole distal appendages supports a matrix that gates the primary cilium. 2018. Nature Communications. 2018 May 22;9(1):2023. doi: 10.1038/s41467-018-04469-1. doi: https://doi.org/10.1101/193474
Andrew D. Jenks, Simon Vyse, Jocelyn P. Wong, Deborah Keller, Tom Burgoyne, Amelia Shoemark, Maike de la Roche, Martin Michaelis, Jindrich Cinatl, Paul H. Huang and Barbara E. Tanos. Primary cilia mediate diverse kinase inhibitor resistance mechanisms in cancer. 2018. 2018. Cell Reports. 2018 Jun 5;23(10):3042-3055. doi: 10.1016/j.celrep.2018.05.016.
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