Single-cell transcriptional profiling informs efficient reprogramming of human somatic cells to cross-presenting dendritic cells.

Type 1 conventional dendritic cells (cDC1s) are rare immune cells critical for the induction of antigen-specific cytotoxic CD8+ T cells, although the genetic program driving human cDC1 specification remains largely unexplored. We previously identified PU.1, IRF8, and BATF3 transcription factors as sufficient to induce cDC1 fate in mouse fibroblasts, but reprogramming of human somatic cells was limited by low efficiency. Here, we investigated single-cell transcriptional dynamics during human cDC1 reprogramming. Human induced cDC1s (hiDC1s) generated from embryonic fibroblasts gradually acquired a global cDC1 transcriptional profile and expressed antigen presentation signatures, whereas other DC subsets were not induced at the single-cell level during the reprogramming process. We extracted gene modules associated with successful reprogramming and identified inflammatory signaling and the cDC1-inducing transcription factor network as key drivers of the process. Combining IFN-γ, IFN-ß, and TNF-α with constitutive expression of cDC1-inducing transcription factors led to improvement of reprogramming efficiency by 190-fold. hiDC1s engulfed dead cells, secreted inflammatory cytokines, and performed antigen cross-presentation, key cDC1 functions. This approach allowed efficient hiDC1 generation from adult fibroblasts and mesenchymal stromal cells. Mechanistically, PU.1 showed dominant and independent chromatin targeting at early phases of reprogramming, recruiting IRF8 and BATF3 to shared binding sites. The cooperative binding at open enhancers and promoters led to silencing of fibroblast genes and activation of a cDC1 program. These findings provide mechanistic insights into human cDC1 specification and reprogramming and represent a platform for generating patient-tailored cDC1s, a long-sought DC subset for vaccination strategies in cancer immunotherapy.

In vivo the antioxidative extract of Averrhoa carambola Linn. leaves induced apoptosis in Ehrilch ascites carcinoma by modulating p53 expression.

This study was designed to evaluate the antioxidant activity of methanol extract of Averrhoa carambolla Linn. leaves (MELA) using DPPH· and ABTS·+ free radical scavenging assays whereas its antineoplastic effect against Ehrlich ascites carcinoma (EAC) was assed using viable cell count, life span, body weight gain and hematological parameters of experimental mice. Results showed that rich phenolic and flavonoid content of MELA had moderate dose dependent free radical scavenging activity (IC50: 62.0 µg/mL for DPPH· and 6.0 µg/mL for ABTS·+). In vivo antineoplastic assay, MELA significantly (P < 0.05) decreased viable cells and body weight gain, increased the survival time and restored altered hematological profiles of cancer cell bearing mice. Fluorescence microscopic view of EAC cells derived from MELA-treated group showed apoptotic characteristics and this observation was also supported by overexpression of pro-apoptotic genes coding p53 and Bax proteins in treated cancer cells. The anti-apoptotic genes coding Bcl-2 protein was also absent in treated EAC cells as compared with the control. Moreover, phytochemical profiles of MELA as identified by GC/MS analysis are also consistent with its activities.

Therapy Resistance in Cancers: Phenotypic, Metabolic, Epigenetic and Tumour Microenvironmental Perspectives.

BACKGROUND: Chemoresistance is a vital problem in cancer therapy where cancer cells develop mechanisms to encounter the effect of chemotherapeutics, resulting in cancer recurrence. In addition, chemotherapy- resistant leads to the formation of a more aggressive form of cancer cells, which, in turn, contributes to the poor survival of patients with cancer. OBJECTIVE: In this review, we aimed to provide an overview of how the therapy resistance property evolves in cancer cells, contributing factors and their role in cancer chemoresistance, and exemplified the problems of some available therapies. METHODS: The published literature on various electronic databases including, Pubmed, Scopus, Google scholar containing keywords cancer therapy resistance, phenotypic, metabolic and epigenetic factors, were vigorously searched, retrieved and analyzed. RESULTS: Cancer cells have developed a range of cellular processes, including uncontrolled activation of Epithelial- Mesenchymal Transition (EMT), metabolic reprogramming and epigenetic alterations. These cellular processes play significant roles in the generation of therapy resistance. Furthermore, the microenvironment where cancer cells evolve effectively contributes to the process of chemoresistance. In tumour microenvironment immune cells, Mesenchymal Stem Cells (MSCs), endothelial cells and cancer-associated fibroblasts (CAFs) contribute to the maintenance of therapy-resistant phenotype via the secretion of factors that promote resistance to chemotherapy. CONCLUSION: To conclude, as these factors hinder successful cancer therapies, therapeutic resistance property of cancer cells is a subject of intense research, which in turn could open a new horizon to aim for developing efficient therapies.

Natural Compounds Targeting Cancer Stem Cells: A Promising Resource for Chemotherapy.

BACKGROUND: Cancer Stem Cells (CSCs) are the subpopulation of cancer cells which are directly involved in drug resistance, metastases to distant organ and cancer recurrence. METHODS: A systematic literature search was conducted through various electronic databases including, Pubmed, Scopus, Google scholar using the keywords "cancer stem cells" and "natural compounds" in the present study. Articles published between 1999 and 2019 were reviewed. All the expositions concerning CSCs associated cancer pathogenesis and therapy resistance, as well as targeting these properties of CSCs by natural compounds were selected for the current study. RESULTS: Natural compounds have always been thought as a rich source of biologically active principles, which target aberrantly activated signaling pathways and other modalities of CSCs, while tethering painful side effects commonly involved in the first-line and second-line chemo-radiotherapies. In this review, we have described the key signaling pathways activated in CSCs to maintain their survival and highlighted how natural compounds interrupt these signaling pathways to minimize therapy resistance, pathogenesis and cancer recurrence properties of CSCs, thereby providing useful strategies to treat cancer or aid in cancer therapy improvement. Like normal stem cells, CSCs rely on different signaling pathways and other properties for their maintenance. Therefore, the success of cancer treatment depends on the development of proper anti-neoplastic drugs capable of intercepting those signaling pathways as well as other properties of CSCs in order to eradicate this evasive subpopulation of cancer cells. CONCLUSION: Compounds of natural origin might act as an outstanding source to design novel therapies against cancer stem cells.