Memory of stochastic single-cell apoptotic signaling promotes chemoresistance in neuroblastoma
Jordan F. Hastings, Sharissa L. Latham, Alvin Kamili, Madeleine S. Wheatley, Jeremy Z. R. Han, Marie Wong, Monica Phimmachanh, Max Nobis, Chiara Pantarelli, Antonia L. Cadell, Yolande E. I. O’Donnell, King Ho Leong, Sophie A Lynn, Fan‐Suo Geng, Lujing Cui, Sabrina Yan, Joanna Achinger-Kawecka, Clare Stirzaker, Murray D. Norris, Michelle Haber, Toby N. Trahair, Frank Speleman, Katleen De Preter, Mark J. Cowley, Ozren Bogdanović, Paul Timpson, Thomas R. Cox, Walter Kölch, Jamie I. Fletcher, Dirk Fey, David R. Croucher
Abstract
Gene expression noise is known to promote stochastic drug resistance through the elevated expression of individual genes in rare cancer cells. However, we now demonstrate that chemoresistant neuroblastoma cells emerge at a much higher frequency when the influence of noise is integrated across multiple components of an apoptotic signaling network. Using a JNK activity biosensor with longitudinal high-content and in vivo intravital imaging, we identify a population of stochastic, JNK-impaired, chemoresistant cells that exist because of noise within this signaling network. Furthermore, we reveal that the memory of this initially random state is retained following chemotherapy treatment across a series of in vitro, in vivo, and patient models. Using matched PDX models established at diagnosis and relapse from individual patients, we show that HDAC inhibitor priming cannot erase the memory of this resistant state within relapsed neuroblastomas but improves response in the first-line setting by restoring drug-induced JNK activity within the chemoresistant population of treatment-naïve tumors.