Human naive pluripotent stem cells have unrestricted lineage potential. Underpinning this property, naive cells are thought to lack chromatin-based lineage barriers. However, this assumption has not been tested. Here we define the chromatin-associated proteome, histone post-translational modifications and transcriptome of human naive and primed pluripotent stem cells. Our integrated analysis reveals differences in the relative abundance and activities of distinct chromatin modules. We identify a strong enrichment of polycomb repressive complex 2 (PRC2)-associated H3K27me3 in the chromatin of naive pluripotent stem cells and H3K27me3 enrichment at promoters of lineage-determining genes, including trophoblast regulators. PRC2 activity acts as a chromatin barrier restricting the differentiation of naive cells towards the trophoblast lineage, whereas inhibition of PRC2 promotes trophoblast-fate induction and cavity formation in human blastoids. Together, our results establish that human naive pluripotent stem cells are not epigenetically unrestricted, but instead possess chromatin mechanisms that oppose the induction of alternative cell fates.

Preparatory grief, psychological distress and hopelessness in advanced cancer patientsA study was undertaken to evaluate the preparatory grief process in advanced cancer patients and its relationship with hopelessness, depression and anxiety. In total, 94 advanced cancer patients treated in a Pain Relief and Palliative Care Unit completed the Preparatory Grief in Advanced Cancer Patients (PGAC) Scale, the Greek Hospital Anxiety and Depression (G-HAD) scales, and a measure of hopelessness the Beck Hopelessness Scale. The strongest correlation was found between grief and hopelessness (r = 0.63, P < 0.0005) and PGAC-1 'self-consciousness' (r = 0.54, P < 0.0005). Similarly, strong associations revealed between PGAC total with anxiety (HAD-D) and depression (HAD-D) (P < 0.0005). Significant associations were depicted between hopelessness, depression and anxiety with PGAC-total as well as with its components. Statistically significant associations were also obtained between grief, metastases (P = 0.073) and education (P = 0.043). In the multiple regression analysis (enter method), anxiety (P < 0.0005) was the strongest predictor of preparatory grief followed by hopelessness (P = 0.002), presence of metastases (P = 0.004) and depression (P = 0.033). Depression, hopelessness, anxiety and terminally ill patients' metastases contribute to the prediction of preparatory grief in this population.

Recent advances in cancer immunology revealed immune-related properties of cancer cells as novel promising therapeutic targets. The two TNF superfamily members, APRIL (TNFSF13), and BAFF (TNFSF13B), which are type II membrane proteins, released in active forms by proteolytic cleavage and are primarily involved in B-lymphocyte maturation, have also been associated with tumor growth and aggressiveness in several solid tumors, including breast cancer. In the present work we studied the effect of APRIL and BAFF on epithelial to mesenchymal transition, migration, and stemness of breast cancer cells. Our findings show that both molecules increase epithelial to mesenchymal transition and migratory capacity of breast cancer cells, as well as cancer stem cell numbers, by increasing the expression of pluripotency genes such as ALDH1A1, KLF4, and NANOG. These effects are mediated by their common receptor BCMA (TNFRSF17) and the JNK signaling pathway. Interestingly, transcriptional data analysis from breast cancer cells and patients revealed that androgens can increase APRIL transcription and subsequently, in an autocrine/paracrine manner, enhance its pluripotency effect. In conclusion, our data suggest a possible role of APRIL and BAFF in breast cancer disease progression and provide evidence for a new possible mechanism of therapy resistance, that could be particularly relevant in aromatase inhibitors-treated patients, were local androgen is increased.

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Triple-Negative Breast Cancer (TNBC) is the most aggressive breast cancer subtype, characterized by limited treatment options and higher relapse rates than hormone-receptor-positive breast cancers. Chemotherapy remains the mainstay treatment for TNBC, and platinum salts have been explored as a therapeutic alternative in neo-adjuvant and metastatic settings. However, primary and acquired resistance to chemotherapy in general and platinum-based regimens specifically strongly hampers TNBC management. In this study, we used carboplatin-resistant in vivo patient-derived xenograft and isogenic TNBC cell-line models and detected enhanced Wnt/β-catenin activity correlating with an induced expression of stem cell markers in both resistant models. In accordance, the activation of canonical Wnt signaling in parental TNBC cell lines increases stem cell markers’ expression, formation of tumorspheres and promotes carboplatin resistance. Finally, we prove that Wnt signaling inhibition resensitizes resistant models to carboplatin both in vitro and in vivo, suggesting the synergistic use of Wnt inhibitors and carboplatin as a therapeutic option in TNBC. Here we provide evidence for a prominent role of Wnt signaling in mediating resistance to carboplatin, and we establish that combinatorial targeting of Wnt signaling overcomes carboplatin resistance enhancing chemotherapeutic drug efficacy.