DNMT and EZH2 inhibitors synergize to activate therapeutic targets in hepatocellular carcinoma.

A major challenge in cancer therapy is drug resistance, which is typically attributed to acquired mutations and tumor heterogeneity. However, emerging evidence suggests that dynamic cellular interactions and group behavior also contribute to drug resistance, although, the details of such mechanisms are poorly understood. Here, by combining real time cellular growth data with mathematical modeling, we showed that the cisplatin- sensitive and tolerant lung cancer cells when co-cultured in cisplatin-free and cisplatin- treated environments, exhibit drastically different group strategies in response to environmental changes. While tolerant cells exhibited a persister-like behaviour and were attenuated by sensitive cells, sensitive cells learned to evade chemotherapy from tolerant cells when co-cultured. Further, tolerant cells could switch phenotypes to become sensitive, although high cisplatin concentrations suppressed this switching. Finally, switching cisplatin administration from continuous to intermittent suppressed the emergence of tolerant cells, suggesting that intermittent rather than continuous chemotherapy may result in better outcomes in lung cancer.

/pdf/suppressing-chemoresistance-in-lung-cancer-via-dynamic-4hg1gwi7si.pdf

Suppressing chemoresistance in lung cancer via dynamic phenotypic switching and intermittent therapy

Background: Muscle-invasive bladder cancer (MIBC) accounts for approximately 20% of all urothelial bladder carcinomas (UBC) at time of diagnosis, and up to 30% of patients with non-muscle invasive UBC will progress to MIBC over time. Increasing body of evidence has revealed a strong correlation between aberrant DNA methylation and tumorigenesis in MIBC. Results: Using The Cancer Genome Atlas (TCGA) molecular data, we described a DNA methylation-based signature as a prognostic factor for overall survival (OS) in patients with MIBC. By using a least absolute shrinkage and selection operator (LASSO) model, differentially methylated regions were first identified using multiple criteria followed by survival and LASSO analyses to identify DNA methylation probes related to OS and build a classifier to stratify patients with MIBC. The prognostic value of the classifier, referred to as risk score (RS), was validated in held-out testing set from the TCGA MIBC cohort. Finally, receiver operating characteristic (ROC) analysis was used to compare the prognostic accuracy of the models built with RS alone, RS plus clinicopathologic features, and clinicopathologic features alone. A DNA methylation signature was generated using a DNA methylation array from 413 MIBC patients. We found that our seven-probe classifier-based RS, stratifies patients into high- and low-risk groups with higher predictive value for overall survival (OS) in the training (n=276) (AUC at 3 years, 0.73; AUC at 5 years, 0.75) and testing (n=137) (AUC at 3 years, 0.65; AUC at 5 years, 0.65) sets compared to a model composed of only clinicopathologic features. In addition, RS significantly improved the prognostic model when it was combined with clinical information including age, smoking status, Tumor (T) stage and Lymph node metastasis (N) stage. Conclusions: The DNA methylation-based RS can be a useful tool to improve the predictive accuracy of preoperative and/or post-cystectomy models of OS in MIBC patients.

/pdf/a-novel-dna-methylation-signature-as-an-independent-2kviotzinn.pdf

A Novel DNA Methylation Signature as an Independent Prognostic Factor in Muscle-Invasive Bladder Cancer.

The impact of group behaviour on drug resistance in cancer remains poorly understood. We used fluorescently-tagged cisplatin-sensitive and tolerant lung cancer cells grown as monotypic or heterotypic cultures in the absence or presence of cisplatin, and monitored their behaviour and growth in real time. Competition and cooperation were modeled by estimating the parameters through the best fit of observed measurements. The two populations adopted different cooperative and competitive strategies and dynamic phenotypic switching in response to changes in their environment. Interestingly, while tolerant cells were attenuated by sensitive cells and exhibited a persister-like behaviour, the sensitive cells learned to evade chemotherapy from the tolerant cells after prolonged co-culture. Furthermore, treating tolerant cells with the epigenetic regulator SAHA, rendered them sensitive but had no effect on truly resistant cells. Finally, switching the treatment regimen from continuous to intermittent therapy delayed the emergence of the tolerant cells in the population.

https://biorxiv.org/content/10.1101/2020.04.06.028472v1.full.pdf

Phenotypic switching and adaptive strategies of cancer cells in response to stress: insights from live cell imaging and mathematical modeling

During induced differentiation, the process often involves a commitment event, after which induced cells, when returned to noninducing conditions, continue to differentiate. The commitment event is rarely identified. Candida albicans differentiates from the white to opaque phenotype, a prerequisite for mating and a process accompanying colonization of the lower gastrointestinal tract and skin. In analyses of white cell populations induced to synchronously differentiate from the white to opaque phenotype, opaque commitment occurs at approximately the same time as evagination and chitin ring formation in the process of daughter cell formation, several hours after the master switch gene WOR1 is upregulated. Mutational analyses of transcription factor binding regions P1, P2, P3, P4, and P6 of the WOR1 promoter reveal that individual deletion of any of the five transcription factor binding regions does not eliminate morphological differentiation to the opaque cell phenotype under opaque-inducing conditions, but individual deletion of P2, P3, or P4, blocks opaque commitment and maintenance of the opaque phenotype after transition to noninducing conditions. These results suggest that commitment occurs at the level of the WOR1 promoter and that morphological differentiation can be dissociated from phenotypic commitment. IMPORTANCE Candida albicans, the most pervasive fungal pathogen colonizing humans, undergoes a phenotypic transition between a white and opaque phenotype. The unique opaque phenotype is necessary for mating and colonization of the lower gastrointestinal tract. Wor1, a transcription factor (TF), plays a central role in activating this transition. Under physiological conditions that induce mass conversion from white to opaque in vitro, cells commit to the opaque phenotype at the time of evagination to form a daughter cell, but several hours after upregulation of WOR1 expression. By analyzing deletion derivatives of the WOR1 promoter, we demonstrate that three of five regulatory regions of WOR1 that bind TFs involved with the regulation of the phenotypic switch are individually required for commitment to the opaque phenotype, but are not necessary for expressing the opaque phenotype. These results demonstrate that morphological differentiation can be dissociated from phenotypic commitment and that commitment occurs at the level of the WOR1 promoter.

Role of the WOR1 Promoter of Candida albicans in Opaque Commitment.

Highly tumorigenic, drug-resistant cancer stem-like cells drive cancer progression. These aggressive cells can arise repeatedly from bulk tumor cells independently of mutational events, suggesting an epigenetic mechanism. To test this possibility, we studied bladder cancer cells as they cyclically shifted to and from a cancer stem-like phenotype, and we discovered that these two states exhibit distinct DNA methylation and chromatin accessibility. Most differential chromatin accessibility was independent of methylation and affected the expression of driver genes such as E2F3, a cell cycle regulator associated with aggressive bladder cancer. Cancer stem-like cells exhibited increased E2F3 promoter accessibility and increased E2F3 expression that drove cell migration, invasiveness and drug resistance. Epigenetic interference using a DNA methylation inhibitor blocked the transition to a cancer stem-like state and reduced E2F3 expression. Our findings indicate that epigenetic plasticity plays a key role in the transition to and from an aggressive, drug-resistant phenotype.

https://onlinelibrary.wiley.com/doi/epdf/10.1002/ijc.32904

Epigenetic plasticity potentiates a rapid cyclical shift to and from an aggressive cancer phenotype.

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Epigenetic plasticity potentiates a rapid cyclical shift to and from an aggressive cancer phenotype.