RESUMEN
Cancer cells enter a reversible drug-tolerant persister (DTP) state to evade death from chemotherapy and targeted agents. It is increasingly appreciated that DTPs are important drivers of therapy failure and tumor relapse. We combined cellular barcoding and mathematical modeling in patient-derived colorectal cancer models to identify and characterize DTPs in response to chemotherapy. Barcode analysis revealed no loss of clonal complexity of tumors that entered the DTP state and recurred following treatment cessation. Our data fit a mathematical model where all cancer cells, and not a small subpopulation, possess an equipotent capacity to become DTPs. Mechanistically, we determined that DTPs display remarkable transcriptional and functional similarities to diapause, a reversible state of suspended embryonic development triggered by unfavorable environmental conditions. Our study provides insight into how cancer cells use a developmentally conserved mechanism to drive the DTP state, pointing to novel therapeutic opportunities to target DTPs.
Asunto(s)
Antineoplásicos/uso terapéutico , Neoplasias Colorrectales/tratamiento farmacológico , Diapausa , Resistencia a Antineoplásicos , Animales , Antineoplásicos/farmacología , Autofagia/efectos de los fármacos , Autofagia/genética , Línea Celular Tumoral , Células Clonales , Neoplasias Colorrectales/genética , Neoplasias Colorrectales/patología , Resistencia a Antineoplásicos/efectos de los fármacos , Embrión de Mamíferos/efectos de los fármacos , Embrión de Mamíferos/metabolismo , Perfilación de la Expresión Génica , Regulación Neoplásica de la Expresión Génica/efectos de los fármacos , Heterogeneidad Genética/efectos de los fármacos , Humanos , Irinotecán/farmacología , Irinotecán/uso terapéutico , Ratones Endogámicos NOD , Ratones SCID , Modelos Biológicos , Transducción de Señal/efectos de los fármacos , Regulación hacia Arriba/efectos de los fármacos , Regulación hacia Arriba/genética , Ensayos Antitumor por Modelo de XenoinjertoRESUMEN
PURPOSE: Sleep, both overnight and daytime naps, can facilitate the consolidation of declarative memories in healthy humans. However, it is unclear whether such beneficial effects of sleep occur in special populations, such as individuals with elevated neuropsychiatric symptoms, and if they apply to clinically relevant material that may have personal significance to those populations. METHODS: We examined memory retention over a 60-minute interval of wakefulness or nap opportunity in participants with low or elevated scores (≤13 and ≥21, respectively) on the Beck Depression Inventory-II (BDI-II). Memory for depression-related information was assessed by (a) free-recall of a video depicting a personal experience narrative of the impact of depression on cognition and workplace performance; and (b) a paired-associates task linking depression-related cognitive symptoms to appropriate coping strategies. RESULTS: The results showed no overall difference in recall between the nap and waking condition. However, across the full sample of participants, there were significant positive correlations between total sleep time and paired associates recall, and slow wave sleep (SWS) percentage and story free recall performance. Unexpectedly, participants with elevated BDI-II scores exhibited better free-recall performance compared to those with low scores. CONCLUSION: These results suggest that sleep, specifically SWS, may stabilize memories for clinically relevant information in populations with low and elevated depressive symptoms. The superior recall in participants with elevated-BDI scores may be related to the personal significance and stronger encoding of depression-related information. These observations raise the possibility that mnemonic deficits in depressed patients may be, at least in part, related to the type of information used to assess memory performance.