Memory of stochastic single-cell apoptotic signaling promotes chemoresistance in neuroblastoma.
Jordan F HastingsSharissa L LathamAlvin KamiliMadeleine S WheatleyJeremy Z R HanMarie WongMonica PhimmachanhMax NobisChiara PantarelliAntonia L CadellYolande E I O'DonnellKing Ho LeongSophie LynnFan-Suo GengLujing CuiSabrina YanJoanna Achinger-KaweckaClare StirzakerMurray D NorrisMichelle HaberToby N TrahairFrank SpelemanKatleen De PreterMark J CowleyOzren BogdanovicPaul TimpsonThomas R CoxWalter KolchJamie I FletcherDirk FeyDavid R CroucherPublished in: Science advances (2023)
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.
Keyphrases
- induced apoptosis
- cell death
- cell cycle arrest
- drug induced
- gene expression
- signaling pathway
- single cell
- endoplasmic reticulum stress
- liver injury
- air pollution
- oxidative stress
- working memory
- end stage renal disease
- ejection fraction
- poor prognosis
- newly diagnosed
- dna methylation
- squamous cell carcinoma
- chronic kidney disease
- acute myeloid leukemia
- diffuse large b cell lymphoma
- cell proliferation
- sensitive detection
- mass spectrometry
- multiple myeloma
- combination therapy
- transcription factor
- pi k akt
- fluorescence imaging
- label free