Oncogenic fatty acid oxidation senses circadian disruption in sleep-deficiency-enhanced tumorigenesis.

Circadian disruption predicts poor cancer prognosis, yet how circadian disruption is sensed in sleep-deficiency (SD)-enhanced tumorigenesis remains obscure. Here, we show fatty acid oxidation (FAO) as a circadian sensor relaying from clock disruption to oncogenic metabolic signal in SD-enhanced lung tumorigenesis. Both unbiased transcriptomic and metabolomic analyses reveal that FAO senses SD-induced circadian disruption, as illustrated by continuously increased palmitoyl-coenzyme A (PA-CoA) catalyzed by long-chain fatty acyl-CoA synthetase 1 (ACSL1). Mechanistically, SD-dysregulated CLOCK hypertransactivates ACSL1 to produce PA-CoA, which facilitates CLOCK-Cys194 S-palmitoylation in a ZDHHC5-dependent manner. This positive transcription-palmitoylation feedback loop prevents ubiquitin-proteasomal degradation of CLOCK, causing FAO-sensed circadian disruption to maintain SD-enhanced cancer stemness. Intriguingly, timed ß-endorphin resets rhythmic Clock and Acsl1 expression to alleviate SD-enhanced tumorigenesis. Sleep quality and serum ß-endorphin are negatively associated with both cancer development and CLOCK/ACSL1 expression in patients with cancer, suggesting dawn-supplemented ß-endorphin as a potential chronotherapeutic strategy for SD-related cancer.

Transcriptome profiling of patient-derived tumor xenografts suggests novel extracellular matrix-related signatures for gastric cancer prognosis prediction.

BACKGROUND: A major obstacle to the development of personalized therapies for gastric cancer (GC) is the prevalent heterogeneity at the intra-tumor, intra-patient, and inter-patient levels. Although the pathological stage and histological subtype diagnosis can approximately predict prognosis, GC heterogeneity is rarely considered. The extracellular matrix (ECM), a major component of the tumor microenvironment (TME), extensively interacts with tumor and immune cells, providing a possible proxy to investigate GC heterogeneity. However, ECM consists of numerous protein components, and there are no suitable models to screen ECM-related genes contributing to tumor growth and prognosis. We constructed patient-derived tumor xenograft (PDTX) models to obtain robust ECM-related transcriptomic signatures to improve GC prognosis prediction and therapy design. METHODS: One hundred twenty two primary GC tumor tissues were collected to construct PDTX models. The tumorigenesis rate and its relationship with GC prognosis were investigated. Transcriptome profiling was performed for PDTX-originating tumors, and least absolute shrinkage and selection operator (LASSO) Cox regression analysis was applied to extract prognostic ECM signatures and establish PDTX tumorigenicity-related gene (PTG) scores. The predictive ability of the PTG score was validated using two independent cohorts. Finally, we combined PTG score, age, and pathological stage information to establish a robust nomogram for GC prognosis prediction. RESULTS: We found that PDTX tumorigenicity indicated a poor prognosis in patients with GC, even at the same pathological stage. Transcriptome profiling of PDTX-originating GC tissues and corresponding normal controls identified 383 differentially expressed genes, with enrichment of ECM-related genes. A robust prognosis prediction model using the PTG score showed robust performance in two validation cohorts. A high PTG score was associated with elevated M2 polarized macrophage and cancer-associated fibroblast infiltration. Finally, combining the PTG score with age and TNM stage resulted in a more effective prognostic model than age or TNM stage alone. CONCLUSIONS: We found that ECM-related signatures may contribute to PDTX tumorigenesis and indicate a poor prognosis in GC. A feasible survival prediction model was built based on the PTG score, which was associated with immune cell infiltration. Together with patient ages and pathological TNM stages, PTG score could be a new approach for GC prognosis prediction.

A liquid biopsy signature of circulating exosome-derived mRNAs, miRNAs and lncRNAs predict therapeutic efficacy to neoadjuvant chemotherapy in patients with advanced gastric cancer.

At present, there is no validated marker to identify the subpopulation of patients with advanced gastric cancer (AGC) who might benefit from neoadjuvant chemotherapy (NACT). In view of this clinical challenge, the identification of non-invasive biomarkers for efficacy prediction of NACT in patients with AGC is imperative. Herein, we aimed to develop a non-invasive, liquid-biopsy-based assay by using an exosome-derived RNAs model based on multi-omics characteristics of RNAs. We firstly used a multi-omics strategy to characterize the mRNAs, microRNAs (miRNAs) and long non-coding RNAs (lncRNAs) profiles of circulating exosome enriched fractions in responders to NACT paired with non-responders, using RNA sequencing. Finally, numerous miRNAs, mRNAs and lncRNAs were identified to be associated with the response to NACT in patients with AGC, and it was validated in an independent cohort with promising AUC values. Furthermore, we established a 6-exosome-RNA panel that could robustly identified responders from non-responders treated with fluorouracil-based neoadjuvant chemotherapy.

Nuclear Aurora kinase A switches m6A reader YTHDC1 to enhance an oncogenic RNA splicing of tumor suppressor RBM4.

Aberrant RNA splicing produces alternative isoforms of genes to facilitate tumor progression, yet how this process is regulated by oncogenic signal remains largely unknown. Here, we unveil that non-canonical activation of nuclear AURKA promotes an oncogenic RNA splicing of tumor suppressor RBM4 directed by m6A reader YTHDC1 in lung cancer. Nuclear translocation of AURKA is a prerequisite for RNA aberrant splicing, specifically triggering RBM4 splicing from the full isoform (RBM4-FL) to the short isoform (RBM4-S) in a kinase-independent manner. RBM4-S functions as a tumor promoter by abolishing RBM4-FL-mediated inhibition of the activity of the SRSF1-mTORC1 signaling pathway. Mechanistically, AURKA disrupts the binding of SRSF3 to YTHDC1, resulting in the inhibition of RBM4-FL production induced by the m6A-YTHDC1-SRSF3 complex. In turn, AURKA recruits hnRNP K to YTHDC1, leading to an m6A-YTHDC1-hnRNP K-dependent exon skipping to produce RBM4-S. Importantly, the small molecules that block AURKA nuclear translocation, reverse the oncogenic splicing of RBM4 and significantly suppress lung tumor progression. Together, our study unveils a previously unappreciated role of nuclear AURKA in m6A reader YTHDC1-dependent oncogenic RNA splicing switch, providing a novel therapeutic route to target nuclear oncogenic events.

Adaptations to the One-Child Policy: Chinese Young Adults' Attitudes Toward Elder Care and Living Arrangement After Marriage.

After four decades of China's family planning policy, the shrinking family size and increasing life expectancy pose special challenges for the one-child generation in terms of providing care for aging parents. The current study explored young adults' responses to such pressure by examining their concerns about elder care, attitudes toward nursing homes, and living arrangement after marriage in a sample of 473 Chinese working young adults from six cities in China (46.9% males, Mage = 25.1 years, 47.8% only children). Results showed that although most of the young adults reported to have thought about the issue of parents' elder care, the majority did not worry a lot about it. Only children expressed similar levels of worrying as those with siblings did. However, educational level, rather than sibling status, was systematically related to concerns about parents' elder care and attitudes toward nursing homes. People with higher education tended to worry less about elder care, and were less likely to consider placing parents in nursing homes as a violation of filial piety. Analyses of the married sub-sample (n = 140) revealed that only children were more likely to co-reside with parents after marriage than those with siblings. And the main reason for co-residence was that the younger generation needed their parents' help for childcare, rather than to better take care of their parents. Implications for parents' elder care among Chinese only children were discussed.

Cancer and stress: NextGen strategies.

Chronic stress is well-known to cause physiological distress that leads to body balance perturbations by altering signaling pathways in the neuroendocrine and sympathetic nervous systems. This increases allostatic load, which is the cost of physiological fluctuations that are required to cope with psychological challenges as well as changes in the physical environment. Recent studies have enriched our knowledge about the role of chronic stress in disease development, especially carcinogenesis. Stress stimulates the hypothalamic-pituitaryadrenal (HPA) axis and the sympathetic nervous system (SNS), resulting in an abnormal release of hormones. These activate signaling pathways that elevate expression of downstream oncogenes. This occurs by activation of specific receptors that promote numerous cancer biological processes, including proliferation, genomic instability, angiogenesis, metastasis, immune evasion and metabolic disorders. Moreover, accumulating evidence has revealed that ß-adrenergic receptor (ADRB) antagonists and downstream target inhibitors exhibit remarkable anti-tumor effects. Psychosomatic behavioral interventions (PBI) and traditional Chinese medicine (TCM) also effectively relieve the impact of stress in cancer patients. In this review, we discuss recent advances in the underlying mechanisms that are responsible for stress in promoting malignancies. Collectively, these data provide approaches for NextGen pharmacological therapies, PBI and TCM to reduce the burden of tumorigenesis.

The prognostic landscape of interactive biological processes presents treatment responses in cancer.

BACKGROUND: Differential gene expression patterns are commonly used as biomarkers to predict treatment responses among heterogeneous tumors. However, the link between response biomarkers and treatment-targeting biological processes remain poorly understood. Here, we develop a prognosis-guided approach to establish the determinants of treatment response. METHODS: The prognoses of biological processes were evaluated by integrating the transcriptomes and clinical outcomes of ~26,000 cases across 39 malignancies. Gene-prognosis scores of 39 malignancies (GEO datasets) were used for examining the prognoses, and TCGA datasets were selected for validation. The Oncomine and GEO datasets were used to establish and validate transcriptional signatures for treatment responses. FINDINGS: The prognostic landscape of biological processes was established across 39 malignancies. Notably, the prognoses of biological processes varied among cancer types, and transcriptional features underlying these prognostic patterns distinguished response to treatment targeting specific biological process. Applying this metric, we found that low tumor proliferation rates predicted favorable prognosis, whereas elevated cellular stress response signatures signified resistance to anti-proliferation treatment. Moreover, while high immune activities were associated with favorable prognosis, enhanced lipid metabolism signatures distinguished immunotherapy resistant patients. INTERPRETATION: These findings between prognosis and treatment response provide further insights into patient stratification for precision treatments, providing opportunities for further experimental and clinical validations. FUND: National Natural Science Foundation, Innovative Research Team in University of Ministry of Education of China, National Key Research and Development Program, Natural Science Foundation of Guangdong, Science and Technology Planning Project of Guangzhou, MRC, CRUK, Breast Cancer Now, Imperial ECMC, NIHR Imperial BRC and NIH.

Estrogen receptor ß upregulated by lncRNA-H19 to promote cancer stem-like properties in papillary thyroid carcinoma.

Estrogen receptor ß (ERß) plays critical roles in thyroid cancer progression. However, its role in thyroid cancer stem cell maintenance remains elusive. Here, we report that ERß is overexpressed in papillary thyroid cancer stem cells (PTCSCs), whereas ablation of ERß decreases stemness-related factors expression, diminishes ALDH+ cell populations, and suppresses sphere formation ability and tumor growth. Screening estrogen-responsive lncRNAs in PTC spheroid cells, we find that lncRNA-H19 is highly expressed in PTCSCs and PTC tissue specimens, which is correlated with poor overall survival. Mechanistically, estradiol (E2) significantly promotes H19 transcription via ERß and elevates H19 expression. Silencing of H19 inhibits E2-induced sphere formation ability. Furthermore, H19 acting as a competitive endogenous RNA sequesters miRNA-3126-5p to reciprocally release ERß expression. ERß depletion reverses H19-induced stem-like properties upon E2 treatment. Appropriately, ERß is upregulated in PTC tissue specimens. Notably, aspirin attenuates E2-induced cancer stem-like traits through decreasing both H19 and ERß expression. Collectively, our findings reveal that ERß-H19 positive feedback loop has a compelling role in PTCSC maintenance under E2 treatment and provides a potential therapeutic targeting strategy for PTC.

Transcriptomic but not genomic variability confers phenotype of breast cancer stem cells.

BACKGROUND: Breast cancer stem cells (BCSCs) are considered responsible for cancer relapse and drug resistance. Understanding the identity of BCSCs may open new avenues in breast cancer therapy. Although several discoveries have been made on BCSC characterization, the factors critical to the origination of BCSCs are largely unclear. This study aimed to determine whether genomic mutations contribute to the acquisition of cancer stem-like phenotype and to investigate the genetic and transcriptional features of BCSCs. METHODS: We detected potential BCSC phenotype-associated mutation hotspot regions by using whole-genome sequencing on parental cancer cells and derived serial-generation spheres in increasing order of BCSC frequency, and then performed target deep DNA sequencing at bulk-cell and single-cell levels. To identify the transcriptional program associated with BCSCs, bulk-cell and single-cell RNA sequencing was performed. RESULTS: By using whole-genome sequencing of bulk cells, potential BCSC phenotype-associated mutation hotspot regions were detected. Validation by target deep DNA sequencing, at both bulk-cell and single-cell levels, revealed no genetic changes specifically associated with BCSC phenotype. Moreover, single-cell RNA sequencing showed profound transcriptomic variability in cancer cells at the single-cell level that predicted BCSC features. Notably, this transcriptomic variability was enriched during the transcription of 74 genes, revealed as BCSC markers. Breast cancer patients with a high risk of relapse exhibited higher expression levels of these BCSC markers than those with a low risk of relapse, thereby highlighting the clinical significance of predicting breast cancer prognosis with these BCSC markers. CONCLUSIONS: Transcriptomic variability, not genetic mutations, distinguishes BCSCs from non-BCSCs. The identified 74 BCSC markers have the potential of becoming novel targets for breast cancer therapy.

New insights from the widening homogeneity perspective to target intratumor heterogeneity.

Precision medicine has shed new light on the treatment of heterogeneous cancer patients. However, intratumor heterogeneity strongly constrains the clinical benefit of precision medicine. Thus, rethinking therapeutic strategies from a different facet within the precision medicine framework will not only diversify clinical interventions, but also provide an avenue for precision medicine. Here, we explore the current approaches for targeting intratumor heterogeneity and their limitations. Furthermore, we propose a theoretical strategy with a "homogenization" feature based on iatrogenic evolutionary selection to target intratumor heterogeneity.