Chromosomal translocations encode oncogenic fusion proteins that have been proven to be causally involved in tumorigenesis. Our understanding of whether such genomic alterations also affect ...non-coding RNAs is limited, and their impact on circular RNAs (circRNAs) has not been explored. Here, we show that well-established cancer-associated chromosomal translocations give rise to fusion circRNAs (f-circRNA) that are produced from transcribed exons of distinct genes affected by the translocations. F-circRNAs contribute to cellular transformation, promote cell viability and resistance upon therapy, and have tumor-promoting properties in in vivo models. Our work expands the current knowledge regarding molecular mechanisms involved in cancer onset and progression, with potential diagnostic and therapeutic implications.
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•F-circRNAs are generated from cancer-associated chromosomal translocations•F-circRNAs promote transformation and cell survival upon treatment•F-circRNAs confer resistance to treatment in tumor cells
Chromosomal translocations associated with cancer give rise to fusion circRNAs which contribute to cellular transformation, affect cell viability, and have tumor-promoting properties in in vivo models.
Stromal cells within the tumor microenvironment are essential for tumor progression and metastasis. Surprisingly little is known about the factors that drive the transcriptional reprogramming of ...stromal cells within tumors. We report that the transcriptional regulator heat shock factor 1 (HSF1) is frequently activated in cancer-associated fibroblasts (CAFs), where it is a potent enabler of malignancy. HSF1 drives a transcriptional program in CAFs that complements, yet is completely different from, the program it drives in adjacent cancer cells. This CAF program is uniquely structured to support malignancy in a non-cell-autonomous way. Two central stromal signaling molecules—TGF-β and SDF1—play a critical role. In early-stage breast and lung cancer, high stromal HSF1 activation is strongly associated with poor patient outcome. Thus, tumors co-opt the ancient survival functions of HSF1 to orchestrate malignancy in both cell-autonomous and non-cell-autonomous ways, with far-reaching therapeutic implications.
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•Reprogramming of cancer-associated fibroblasts by HSF1 enables malignant progression•Distinct transcriptional programs are driven by HSF1 in stromal versus malignant cells•HSF1 activation in tumor stroma is strongly associated with poor patient outcome•Dual roles in both tumor cells and stroma make HSF1 an attractive anticancer target
HSF1 drives a transcriptional program in stromal cells that potentiates tumor cell malignancy and is associated with poor patient outcomes.
The ERG gene is fused to TMPRSS2 in approximately 50% of prostate cancers (PrCa), resulting in its overexpression. However, whether this is the sole mechanism underlying ERG elevation in PrCa is ...currently unclear. Here we report that ERG ubiquitination and degradation are governed by the Cullin 3-based ubiquitin ligase SPOP and that deficiency in this pathway leads to aberrant elevation of the ERG oncoprotein. Specifically, we find that truncated ERG (ΔERG), encoded by the ERG fusion gene, is stabilized by evading SPOP-mediated destruction, whereas prostate cancer-associated SPOP mutants are also deficient in promoting ERG ubiquitination. Furthermore, we show that the SPOP/ERG interaction is modulated by CKI-mediated phosphorylation. Importantly, we demonstrate that DNA damage drugs, topoisomerase inhibitors, can trigger CKI activation to restore the SPOP/ΔERG interaction and its consequent degradation. Therefore, SPOP functions as a tumor suppressor to negatively regulate the stability of the ERG oncoprotein in prostate cancer.
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•The E3 ubiquitin ligase SPOP promotes ERG degradation in a CKI-dependent manner•Prostate cancer-associated SPOP mutants fail to promote ERG destruction•ERG fusion proteins evade SPOP-mediated degradation and could be restored by CKI•Etoposide-induced ERG fusion protein degradation depends on SPOP and CKI
Gan et al. report that the Cullin 3SPOP E3 ubiquitin ligase plays a critical tumor-suppressive role in prostate cancer by negatively controlling ERG stability. Therefore, either SPOP mutation or ERG fusion can lead to elevated ERG protein levels by evading the SPOP-mediated degradation pathway to promote prostate cancer progression.
The categorization of intraductal proliferative lesions of the breast based on routine light microscopic examination of histopathologic sections is in many cases challenging, even for experienced ...pathologists. The development of computational tools to aid pathologists in the characterization of these lesions would have great diagnostic and clinical value. As a first step to address this issue, we evaluated the ability of computational image analysis to accurately classify DCIS and UDH and to stratify nuclear grade within DCIS. Using 116 breast biopsies diagnosed as DCIS or UDH from the Massachusetts General Hospital (MGH), we developed a computational method to extract 392 features corresponding to the mean and standard deviation in nuclear size and shape, intensity, and texture across 8 color channels. We used L1-regularized logistic regression to build classification models to discriminate DCIS from UDH. The top-performing model contained 22 active features and achieved an AUC of 0.95 in cross-validation on the MGH data-set. We applied this model to an external validation set of 51 breast biopsies diagnosed as DCIS or UDH from the Beth Israel Deaconess Medical Center, and the model achieved an AUC of 0.86. The top-performing model contained active features from all color-spaces and from the three classes of features (morphology, intensity, and texture), suggesting the value of each for prediction. We built models to stratify grade within DCIS and obtained strong performance for stratifying low nuclear grade vs. high nuclear grade DCIS (AUC = 0.98 in cross-validation) with only moderate performance for discriminating low nuclear grade vs. intermediate nuclear grade and intermediate nuclear grade vs. high nuclear grade DCIS (AUC = 0.83 and 0.69, respectively). These data show that computational pathology models can robustly discriminate benign from malignant intraductal proliferative lesions of the breast and may aid pathologists in the diagnosis and classification of these lesions.
Two large-scale pharmacogenomic studies were published recently in this journal. Genomic data are well correlated between studies; however, the measured drug response data are highly discordant. ...Although the source of inconsistencies remains uncertain, it has potential implications for using these outcome measures to assess gene-drug associations or select potential anticancer drugs on the basis of their reported results.
Disparities in health service use have been described across a range of sociodemographic factors. Patterns of PICU use have not been thoroughly assessed.
This was a population-level, retrospective ...analysis of admissions to the Cincinnati Children's Hospital Medical Center PICU between 2011 and 2016. Residential addresses of patients were geocoded and spatially joined to census tracts. Pediatric patients were eligible for inclusion if they resided within Hamilton County, Ohio. PICU admission and bed-day rates were calculated by using numerators of admissions and bed days, respectively, over a denominator of tract child population. Relationships between tract-level PICU use and child poverty were assessed by using Spearman's ρ and analysis of variance. Analyses were event based; children admitted multiple times were counted as discrete admissions.
There were 4071 included admissions involving 3129 unique children contributing a total of 12 297 PICU bed days. Child poverty was positively associated with PICU admission rates (
= 0.59;
< .001) and bed-day rates (
= 0.47;
< .001). When tracts were grouped into quintiles based on child poverty rates, the PICU bed-day rate ranged from 23.4 days per 1000 children in the lowest poverty quintile to 81.9 days in the highest poverty quintile (
< .001).
The association between poverty and poor health outcomes includes pediatric intensive care use. This association exists for children who grow up in poverty and around poverty. Future efforts should characterize the interplay between patient- and neighborhood-level risk factors and explore neighborhood-level interventions to improve child health.
Racism, segregation, and inequality contribute to health outcomes and drive health disparities across the life course, including for newborn infants and their families. In this review, we address ...their effects on the health and well-being of newborn infants and their families with a focus on preterm birth. We discuss three causal pathways: increased risk; lower-quality care; and socioeconomic disadvantages that persist into infancy, childhood, and beyond. For each pathway, we propose specific interventions and research priorities that may remedy the adverse effects of racism, segregation, and inequality. Infants and their families will not realize the full benefit of advances in perinatal and neonatal care until we, collectively, accept our responsibility for addressing the range of determinants that shape long-term outcomes.
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