Memory of stochastic single-cell apoptotic signaling promotes chemoresistance in neuroblastoma

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.

Stochastic Gene Expression in Proliferating Cells: Differing Noise Intensity in Single-Cell and Population Perspectives

“…These include, but are not limited to, driving genetically-identical cells to different fates [26][27][28][29][30][31][32][33] and facilitating population adaptation to environmental fluctuations [34][35][36][37][38]. The latter scenario is exemplified by rare populations of clonal cells that survive lethal stresses, as seen in antibiotic treatment of bacteria [39][40][41][42][43][44], or cancer cells undergoing chemotherapy [45][46][47][48][49]. The non-genetic basis of heterogeneous single-cell responses to stress is a topic of current research, and several publications have implicated preexisting drug-tolerant expression states arising as result of noise in gene regulatory networks [50,51].…”