miR-15a targets the HSP90 co-chaperone Morgana in chronic myeloid leukemia.

Morgana is a ubiquitous HSP90 co-chaperone protein coded by the CHORDC1 gene. Morgana heterozygous mice develop with age a myeloid malignancy resembling human atypical myeloid leukemia (aCML), now renamed MDS/MPN with neutrophilia. Patients affected by this pathology exhibit low Morgana levels in the bone marrow (BM), suggesting that Morgana downregulation plays a causative role in the human malignancy.

RICTOR/mTORC2 downregulation in BRAF melanoma cells promotes resistance to BRAF/MEK inhibition.

Background: The main drawback of BRAF/MEK inhibitors (BRAF/MEKi)-based targeted therapy in the management of BRAF-mutated cutaneous metastatic melanoma (MM) is the development of therapeutic resistance. We aimed to assess in this context the role of mTORC2, a signaling complex defined by the presence of the essential RICTOR subunit, regarded as an oncogenic driver in several tumor types, including MM.

Methods: After analyzing The Cancer Genome Atlas MM patients' database to explore both overall survival and molecular signatures as a function of intra-tumor RICTOR levels, we investigated the effects of RICTOR downregulation in BRAF MM cell lines on their response to BRAF/MEKi.

p140Cap modulates the mevalonate pathway decreasing cell migration and enhancing drug sensitivity in breast cancer cells.

p140Cap is an adaptor protein involved in assembling multi-protein complexes regulating several cellular processes. p140Cap acts as a tumor suppressor in breast cancer (BC) and neuroblastoma patients, where its expression correlates with a better prognosis. The role of p140Cap in tumor metabolism remains largely unknown.

The role of tumor microenvironment in drug resistance: emerging technologies to unravel breast cancer heterogeneity.

Breast cancer is a highly heterogeneous disease, at both inter- and intra-tumor levels, and this heterogeneity is a crucial determinant of malignant progression and response to treatments. In addition to genetic diversity and plasticity of cancer cells, the tumor microenvironment contributes to tumor heterogeneity shaping the physical and biological surroundings of the tumor. The activity of certain types of immune, endothelial or mesenchymal cells in the microenvironment can change the effectiveness of cancer therapies via a plethora of different mechanisms.

p140Cap inhibits β-Catenin in the breast cancer stem cell compartment instructing a protective anti-tumor immune response.

The p140Cap adaptor protein is a tumor suppressor in breast cancer associated with a favorable prognosis. Here we highlight a function of p140Cap in orchestrating local and systemic tumor-extrinsic events that eventually result in inhibition of the polymorphonuclear myeloid-derived suppressor cell function in creating an immunosuppressive tumor-promoting environment in the primary tumor, and premetastatic niches at distant sites. Integrative transcriptomic and preclinical studies unravel that p140Cap controls an epistatic axis where, through the upstream inhibition of β-Catenin, it restricts tumorigenicity and self-renewal of tumor-initiating cells limiting the release of the inflammatory cytokine G-CSF, required for polymorphonuclear myeloid-derived suppressor cells to exert their local and systemic tumor conducive function.

Stroma-derived miR-214 coordinates tumor dissemination.

Background: Tumor progression is based on a close interaction between cancer cells and Tumor MicroEnvironment (TME). Here, we focus on the role that Cancer Associated Fibroblasts (CAFs), Mesenchymal Stem Cells (MSCs) and microRNAs (miRs) play in breast cancer and melanoma malignancy.

Methods: We used public databases to investigate miR-214 expression in the stroma compartment of primary human samples and evaluated tumor formation and dissemination following tumor cell injections in miR-214 overexpressing (miR-214) and knock out (miR-214) mice.

Dihydroorotate dehydrogenase inhibition reveals metabolic vulnerability in chronic myeloid leukemia.

The development of different generations of BCR-ABL1 tyrosine kinase inhibitors (TKIs) has led to the high overall survival of chronic myeloid leukemia (CML) patients. However, there are CML patients who show resistance to TKI therapy and are prone to progress to more advanced phases of the disease. So, implementing an alternative approach for targeting TKIs insensitive cells would be of the essence.

miRNA-guided reprogramming of glucose and glutamine metabolism and its impact on cell adhesion/migration during solid tumor progression.

MicroRNAs (miRNAs) are small, non-coding RNAs about 22 nucleotides in length that regulate the expression of target genes post-transcriptionally, and are highly involved in cancer progression. They are able to impact a variety of cell processes such as proliferation, apoptosis and differentiation and can consequently control tumor initiation, tumor progression and metastasis formation. miRNAs can regulate, at the same time, metabolic gene expression which, in turn, influences relevant traits of malignancy such as cell adhesion, migration and invasion.

Long-Term Effects of Alemtuzumab on CD4+ Lymphocytes in Multiple Sclerosis Patients: A 72-Month Follow-Up.

Introduction: Alemtuzumab is highly effective in the treatment of patients with relapsing multiple sclerosis (PwRMS) and selectively targets the CD52 antigen, with a consequent profound lymphopenia, particularly of CD4+ T lymphocytes. However, the immunological basis of its long-term efficacy has not been clearly elucidated.

Methods: We followed up 29 alemtuzumab-treated RMS patients over a period of 72 months and studied the immunological reconstitution of their CD4+ T cell subsets by means of phenotypic and functional analysis and through mRNA-related molecule expression, comparing them to healthy subject (HS) values (rate 2:1).

Tumors carrying BRAF-mutations over-express NAMPT that is genetically amplified and possesses oncogenic properties.

Background: Nicotinamide phosphoribosyltransferase (NAMPT), the rate-limiting enzyme in nicotinamide adenine dinucleotide (NAD) biosynthesis, is up-regulated in several cancers, including metastatic melanoma (MM). The BRAF oncogene is mutated in different cancer types, among which MM and thyroid carcinoma (THCA) are prominent. Drugs targeting mutant BRAF are effective, especially in MM patients, even though resistance rapidly develops.

Metabolic Interplay between the Immune System and Melanoma Cells: Therapeutic Implications.

Malignant melanoma represents the most fatal skin cancer due to its aggressive biological behavior and high metastatic potential. Treatment strategies for advanced disease have dramatically changed over the last years due to the introduction of BRAF/MEK inhibitors and immunotherapy. However, many patients either display primary (i.

Macrophage miR-210 induction and metabolic reprogramming in response to pathogen interaction boost life-threatening inflammation.

Unbalanced immune responses to pathogens can be life-threatening although the underlying regulatory mechanisms remain unknown. Here, we show a hypoxia-inducible factor 1α-dependent microRNA (miR)-210 up-regulation in monocytes and macrophages upon pathogen interaction. MiR-210 knockout in the hematopoietic lineage or in monocytes/macrophages mitigated the symptoms of endotoxemia, bacteremia, sepsis, and parasitosis, limiting the cytokine storm, organ damage/dysfunction, pathogen spreading, and lethality.

ESDN inhibits melanoma progression by blocking E-selectin expression in endothelial cells via STAT3.

An interactive crosstalk between tumor and stroma cells is essential for metastatic melanoma progression. We evidenced that ESDN/DCBLD2/CLCP1 plays a crucial role in endothelial cells during the spread of melanoma. Precisely, increased extravasation and metastasis formation were revealed in ESDN-null mice injected with melanoma cells, even if the primary tumor growth, vessel permeability, and angiogenesis were not enhanced.

MicroRNA-Mediated Metabolic Shaping of the Tumor Microenvironment.

The metabolism of cancer cells is generally very different from what is found in normal counterparts. However, in a tumor mass, the continuous crosstalk and competition for nutrients and oxygen among different cells lead to metabolic alterations, not only in cancer cells, but also in the different stromal and immune cells of the tumor microenvironment (TME), which are highly relevant for tumor progression. MicroRNAs (miRs) are small non-coding RNAs that silence their mRNA targets post-transcriptionally and are involved in numerous physiological cell functions as well as in the adaptation to stress situations.

The p140Cap adaptor protein as a molecular hub to block cancer aggressiveness.

The p140Cap adaptor protein is a scaffold molecule encoded by the SRCIN1 gene, which is physiologically expressed in several epithelial tissues and in the neurons. However, p140Cap is also strongly expressed in a significant subset of cancers including breast cancer and neuroblastoma. Notably, cancer patients with high p140Cap expression in their primary tumors have a lower probability of developing a distant event and ERBB2-positive breast cancer sufferers show better survival.

Axl-148b chimeric aptamers inhibit breast cancer and melanoma progression.

microRNAs (miRNAs) are small non-coding RNAs acting as negative regulators of gene expression and involved in tumor progression. We recently showed that inhibition of the pro-metastatic miR-214 and simultaneous overexpression of its downstream player, the anti-metastatic miR-148b, strongly reduced metastasis formation. To explore the therapeutic potential of miR-148b, we generated a conjugated molecule aimed to target miR-148b expression selectively to tumor cells.

The role of melatonin on miRNAs modulation in triple-negative breast cancer cells.

Melatonin, a hormone secreted by pineal gland, exerts antimetastatic effects by reducing tumor cell proliferation, migration and invasion. MicroRNAs (miRNAs) are small, non-coding RNAs that play a crucial role in regulation of gene expression and biological processes of the cells. Herein, we search for a link between the tumor/metastatic-suppressive actions of melatonin and miRNA expression in triple-negative breast cancer cells.

Investigating the epi-miRNome: identification of epi-miRNAs using transfection experiments.

Growing evidence shows a strong interplay between post-transcriptional regulation, mediated by miRNAs (miRs) and epigenetic regulation. Nevertheless, the number of experimentally validated miRs (called epi-miRs) involved in these regulatory circuitries is still very small. We propose a pipeline to prioritize candidate epi-miRs and to identify potential epigenetic interactors of any given miR starting from miR transfection experiment datasets.

Correction: By promoting cell differentiation, miR-100 sensitizes basal-like breast cancer stem cells to hormonal therapy.

[This corrects the article DOI: 10.18632/oncotarget.2962.

Role of miRNAs in tumor and endothelial cell interactions during tumor progression.

Cancer is a multistep disease based on crucial interactions between tumor cells and the microenvironment (extracellular matrix and stroma/immune cells). In fact, during dissemination, tumor cells have to escape from the primary tumor mass, cross the basal membrane, interact with endothelial cells to enter blood vessels (intravasation), survive in the bloodstream, get in contact with endothelial cells again to exit the bloodstream (extravasation) and seed in distant organs. Interactions between tumor and stroma cells are strongly coordinated by microRNAs (miRNAs), small non-coding RNAs able to silence protein coding genes by binding to specific recognition sites, mostly located at the 3' UTR of mature mRNAs.

Antitumoral effects of attenuated Listeria monocytogenes in a genetically engineered mouse model of melanoma.

Attenuated Listeria monocytogenes (Lm-LLO) represents a valuable anticancer vaccine and drug delivery platform. Here we show that in vitro Lm-LLO causes ROS production and, in turn, apoptotic killing of a wide variety of melanoma cells, irrespectively of their stage, mutational status, sensitivity to BRAF inhibitors or degree of stemness. We also show that, when administered in the therapeutic setting to Braf/Pten genetically engineered mice, Lm-LLO causes a strong decrease in the size and volume of primary melanoma tumors, as well as a reduction of the metastatic burden.

AGO2 promotes telomerase activity and interaction between the telomerase components TERT and TERC.

Telomerase reverse transcriptase (TERT) and telomerase RNA component (TERC) constitute the core telomerase enzyme that maintains the length of telomeres. Telomere maintenance is affected in a broad range of cancer and degenerative disorders. Taking advantage of gain- and loss-of-function approaches, we show that Argonaute 2 (AGO2) promotes telomerase activity and stimulates the association between TERT and TERC AGO2 depletion results in shorter telomeres as well as in lower proliferation rates and We also demonstrate that AGO2 interacts with TERC and with a newly identified sRNA (-sRNA), arising from the H/ACA box of TERC Notably, -sRNA is sufficient to enhance telomerase activity when overexpressed.

Therapeutic Silencing of miR-214 Inhibits Tumor Progression in Multiple Mouse Models.

We previously demonstrated that miR-214 is upregulated in malignant melanomas and triple-negative breast tumors and promotes metastatic dissemination by affecting a complex pathway including the anti-metastatic miR-148b. Importantly, tumor dissemination could be reduced by blocking miR-214 function or increasing miR-148b expression or by simultaneous interventions. Based on this evidence, with the intent to explore the role of miR-214 as a target for therapy, we evaluated the capability of new chemically modified anti-miR-214, R97/R98, to inhibit miR-214 coordinated metastatic traits.