Gliomas are a type of malignant central nervous system tumor with poor prognosis. Molecular biomarkers of gliomas can predict glioma patient's clinical outcome, but their limitations are also emerging. C-X-C motif chemokine ligand family plays a critical role in shaping tumor immune landscape and modulating tumor progression, but its role in gliomas is elusive. In this work, samples of TCGA were treated as the training cohort, and as for validation cohort, two CGGA datasets, four datasets from GEO database, and our own clinical samples were enrolled. Consensus clustering analysis was first introduced to classify samples based on CXCL expression profile, and the support vector machine was applied to construct the cluster model in validation cohort based on training cohort. Next, the elastic net analysis was applied to calculate the risk score of each sample based on CXCL expression. High-risk samples associated with more malignant clinical features, worse survival outcome, and more complicated immune landscape than low-risk samples. Besides, higher immune checkpoint gene expression was also noticed in high-risk samples, suggesting CXCL may participate in tumor evasion from immune surveillance. Notably, high-risk samples also manifested higher chemotherapy resistance than low-risk samples. Therefore, we predicted potential compounds that target high-risk samples. Two novel drugs, LCL-161 and ADZ5582, were firstly identified as gliomas' potential compounds, and five compounds from PubChem database were filtered out. Taken together, we constructed a prognostic model based on CXCL expression, and predicted that CXCL may affect tumor progression by modulating tumor immune landscape and tumor immune escape. Novel potential compounds were also proposed, which may improve malignant glioma prognosis.

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The CXCL Family Contributes to Immunosuppressive Microenvironment in Gliomas and Assists in Gliomas Chemotherapy.

Triple-negative breast cancer (TNBC) is a subtype of breast carcinoma characterized by poor prognosis and high rate of metastasis. Current treatment is based on chemo- and/or radiotherapy and surgery. TNBC is devoid of estrogen, progesterone and HER2 receptors. Although precision medicine has come a long way to ameliorate breast cancer disease management, targeted therapies for the treatment of TNBC patients are still limited. Mounting evidence has shown that non-coding RNAs (ncRNAs) drive many oncogenic processes at the basis of increased proliferation, invasion and angiogenesis in TNBC, strongly contributing to tumor progression and resistance to treatments. Many of these ncRNAs are secreted in the tumor microenvironment (TME) and impinge on the activity of the diverse immune and stromal cell types infiltrating the TME. Importantly, secreted ncRNAs may be detected as circulating molecules in serum/plasma from cancer patients and are emerging a promising diagnostic/therapeutic tools in TNBC. This review aims to discuss novel insights about the role of secreted circulating ncRNAs in the intercellular communication in the tumor microenvironment and their potential clinical use as diagnostic and prognostic non-invasive biomarkers in TNBC.

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Secreted Non-Coding RNAs: Functional Impact on the Tumor Microenvironment and Clinical Relevance in Triple-Negative Breast Cancer

Fungal secondary metabolites serve as a rich resource for exploring lead compounds with medicinal importance. Diorcinol N (DN), a fungal secondary metabolite isolated from an endophytic fungus, Arthrinium arundinis, exhibits robust anticancer activity. However, the anticancer mechanism of DN remains unclear. In this study, we examined the growth-inhibitory effect of DN on different human cancer cell lines. We found that DN decreased the viability of A3 T-cell leukemia cells in a time- and concentration-dependent manner. Transcriptome analysis indicated that DN modulated the transcriptome of A3 cells. In total, 9,340 differentially expressed genes were found, among which 4,378 downregulated genes and 4,962 upregulated genes were mainly involved in autophagy, cell cycle, and DNA replication. Furthermore, we demonstrated that DN induced autophagy, cell cycle arrest in the G1/S phase, and downregulated the expression of autophagy- and cell cycle-related genes in A3 cells. By labeling A3 cells with acridine orange/ethidium bromide, Hoechst 33,258, and monodansylcadaverine and via transmission electron microscopy, we found that DN increased plasma membrane permeability, structural disorganization, vacuolation, and autophagosome formation. Our study provides evidence for the mechanism of anticancer activity of DN in T-cell leukemia (A3) cells and demonstrates the promise of DN as a lead or even candidate molecule for the treatment of acute lymphoblastic leukemia.

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Transcriptome Profiling and Cytological Assessments for Identifying Regulatory Pathways Associated With Diorcinol N-Induced Autophagy in A3 Cells.

Identification of PIK3CA aberrations associated with telomere length in breast cancer

University of Chile		
Latin American Society of Pharmacogenomics and Personalized Medicine (SOLFAGEM)

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A New Insight for the Identification of Oncogenic Variants in Breast and Prostate Cancers in Diverse Human Populations, With a Focus on Latinos

Breast cancer is a heterogeneous disease with a complex microenvironment consisting of tumor cells, immune cells, fibroblasts and vascular cells. These cancer-associated cells shape the tumor microenvironment (TME) and influence the progression of breast cancer and the therapeutic responses in patients. The exact composition of the intra-tumoral cells is mixed as the highly heterogeneous and dynamic nature of the TME. Recent advances in single-cell technologies such as single-cell DNA sequencing (scDNA-seq), single-cell RNA sequencing (scRNA-seq) and mass cytometry have provided new insights into the phenotypic and functional diversity of tumor-infiltrating cells in breast cancer. In this review, we have outlined the recent progress in single-cell characterization of breast tumor ecosystems, and summarized the phenotypic diversity of intra-tumoral cells and their potential prognostic relevance.

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Comprehensive description of the current breast cancer microenvironment advancements via single-cell analysis

Background Previous case reports have shown the promising antitumor activity of everolimus in solid tumors containing molecular aberrations in PI3K/ATK/mTOR pathway, however, whether it is effective in patients with breast cancer remains unknown. Therefore, we conducted this retrospective cohort study to compare the efficacy of molecularly matched targeted therapy with everolimus to conventional therapy in refractory breast cancer patients harboring PI3K/ATK/mTOR pathway activating mutations. Methods Refractory metastatic breast cancer patients who have received molecular screening using next-generation sequencing (NGS) between September 8, 2015 and October 30, 2017 in two sites were screened for this study. The primary outcome was progression-free survival (PFS). The secondary outcomes were overall response rate (ORR), disease control rate (DCR), and safety profile. Results A total of 78 patients were screened for analysis, amongst all, 52 (66.7%) had at least one gene mutation in PI3K/AKT/mTOR pathway. The most common mutation fell in PIK3CA (76.9%, 40/52) with a mutational prevalence of 51.3%. Of the 32 patients who were eligible for efficacy analysis, patients in the everolimus group (n = 19) exhibited shorter PFS than those in the conventional group (n = 13) (median, 1.9 vs 6.1 months; HR, 3.6; 95% CI, 1.48-8.81; P = .0005). ORR was 15.4% (2/13) in the everolimus group and 23.1% (3/13) in the conventional group (P = 1.000), and DCR was 30.8% (4/13) and 100% (13/13) for each group, respectively (P = .000). The incidence of grade 3-5 adverse events was relatively higher in the conventional group (38.5%, 5/13) than that in the everolimus group (26.3%, 5/19). Conclusions Our findings suggested that everolimus might not be effective for cancer patients harboring mutations in PI3K/ATK/mTOR pathway and physicians should be cautious about its off-label use in clinical practice.

https://onlinelibrary.wiley.com/doi/pdf/10.1002/cam4.2460

Everolimus-containing therapy vs conventional therapy in the treatment of refractory breast cancer patients with PI3K/AKT/mTOR mutations: A retrospective study.

RAS family genes (HRAS, KRAS and NRAS) were frequently observed in several tumors The expression of constitutively active RAS proteins mediated by RAS variations promote the development of tumors KRAS is an important prognostic and drug resistance biomarker It would also be a promising drug target Several trials which evaluating the efficacy of RAS G12C inhibitor in solid tumors are initiated Herein, we analyzed the alterations status of KRAS/NRAS/HRAS across diverse solid tumors The sing nucleotide variants (SNV) and copy number variants (CNV) data of 17993 Chinese patients from 22 types of cancer were obtained in our database Genomic profiling of DNA was performed through a next-generation sequencing on tissue Only the pathogenic mutations and likely pathogenic mutations in clinical significance were rolled into our analysis Among 17993 pan-cancer patients, the total RAS variants frequency was 2258% KRAS was the most frequently altered, followed by NRAS and HRAS For the SNV, KRAS were most commonly found in pancreas cancer, intestine cancer and colorectal cancer Further analysis among KRAS SNV patients showed that the mutation frequency of KRAS G12C, G12D, G12R, and G12V was 181%, 681%, 069% and 425%, respectively A total of 21 in 22 types of solid tumors had KRAS G12C/D/R/V pathogenic or likely pathogenic mutation, which occurred most frequently in colorectal cancer, pancreas cancer and lung cancer Our results suggested that a variety of solid tumors may harbor KRAS G12C/D/R/V mutation These patients may benefit from KRAS inhibitors

Hao Wu

Papers

Comprehensive description of the current breast cancer microenvironment advancements via single-cell analysis

Everolimus-containing therapy vs conventional therapy in the treatment of refractory breast cancer patients with PI3K/AKT/mTOR mutations: A retrospective study.

Landscape of RAS Variations in 17,993 Pan-cancer Patients Identified by Next-generation Sequencing.