Reconstituting immune surveillance in breast cancer: molecular pathophysiology and current immunotherapy strategies

Over the past 50 years, breast cancer immunotherapy has emerged as an active field of research, generating novel, targeted treatments for the disease. Immunotherapies carry enormous potential to improve survival in breast cancer, particularly for the subtypes carrying the poorest prognoses. Here, we review the mechanisms by which cancer evades immune destruction as well as the history of breast cancer immunotherapies and recent developments, including clinical trials that have shaped the treatment of the disease with a focus on cell therapies, vaccines, checkpoint inhibitors, and oncolytic viruses

Extracellular vesicles as mediators of therapy resistance in breast cancer microenvironment

Resistance to various therapies, including novel immunotherapies, poses a major challenge in the management of breast cancer and is the leading cause of treatment failure. Bidirectional communication between breast cancer cells and the tumour microenvironment is now known to be an important contributor to therapy resistance. Several studies have demonstrated that crosstalk with the tumour microenvironment through extracellular vesicles is an important mechanism employed by cancer cells that leads to drug resistance via changes in protein, lipid and nucleic acid cargoes. Moreover, the cargo content enables extracellular vesicles to be used as effective biomarkers for predicting response to treatments and as potential therapeutic targets. This review summarises the literature to date regarding the role of extracellular vesicles in promoting therapy resistance in breast cancer through communication with the tumour microenvironment

EGF and IGF1 affect Sunitinib activity in BP-NEN: new putative targets beyond VEGFR?

Broncho-Pulmonary Neuroendocrine Neoplasms (BP-NENs) are neoplasms orphan of an efficient therapy. Available medical treatments derived from clinical trials are not specific for the management of this malignancy. Sunitinib is a multi-receptor tyrosine-kinases (RTKs) inhibitor that has already shown its efficacy in NENs but there are not available data about its action in BP-NENs. Therefore, our aim was to understand the effects of RTKs inhibition promoted by Sunitinib in order to evaluate new putative targets useful in malignancy treatment. Since our results underlined a role for EGFR and IGF1R in modulating Sunitinib antiproliferative action, we investigated the effects of Erlotinib, an EGFR inhibitor, and Linsitinib, an IGF1R inhibitor, in order to understand their function in regulating cells behaviour. Cell viability and caspase activation were evaluated on two immortalized human BP-NEN cell lines and primary cultures. Our results showed that after treatment with Sunitinib and/or IGF1, EGF and VEGF, the antiproliferative effect of Sunitinib was counteracted by EGF and IGF1 but not by VEGF. Therefore, we evaluated with alpha-screen technology the phosphorylated EGFR and IGF1R levels in primary cultures treated with Sunitinib and/or EGF and IGF1. Results showed a decrease of p-IGF1R after treatment with Sunitinib and an increase after co-treatment with IGF1. Then, we assessed cell viability and caspase activation on BP-NEN cell lines after treatment with Linsitinib and/or Erlotinib. Results demonstrate that these two agents have a stronger antiproliferative effect compared to Sunitinib. In conclusion, our results suggest that IGF1R and EGF1R could represent putative molecular targets in BP-NENs treatment

Glioblastoma multiforme: a multidisciplinary approach to overcome chemoresistance and find new therapeutic strategies

Objectives: Glioblastoma multiforme is the most frequent malignant brain tumor. Patients die within 15 months after diagnosis. The failure of current therapies is ascribed to a subpopulation of cells with stem-like properties, called glioma stem cells (GSCs). The aim of this study is to develop new effective therapies. Moreover, we want to better characterize the orthotopic xenograft model established by GSCs injection into NOD/SCID mice. Materials and methods: We tested Temolomide and Valproic acid treatments, alone and in combination, on seven GSC lines by MTT assay and we sequenced p53. Moreover, we characterized our xenograft model investigating the expression of stemness and differentiation markers by immunohistochemistry on FFPE tissues and by immunofluorescence on the correspondent cell line. Finally, we performed aCGH on the DNA extracted from the cell line and from FFPE tissues. Results: GSCs were resistant to Temozolomide and slightly sensitive to Valproic acid. The two drugs exerted a synergistic effect when combined performing a pre-conditioning with Valproic acid. Furthermore, several cell lines carry p53 mutations. IF and IHC showed a perfect correspondence for stemness markers expression, but discordant data for the others. aCGH analysis evidenced numerous alterations specific for the ex vivo sample, suggesting the presence of an in vivo clonal selection. Discussion: This work shows the importance of murine microenvironment in GSCs phenotype in vivo and suggests the possibility to use our combined treatment for therapeutic purposes. Conclusions: Orthotopic models from GSCs and in vitro grown cell lines represent good models for the development of GSC-targeted therapies

LMTK3 inhibition affects microtubule stability

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Correction to: LMTK3 inhibition affects microtubule stability

Correction to: Mol Cancer 20, 53 (2021) https://doi.org/10.1186/s12943-021-01345-3 Following the publication of the original article [1], the authors noticed errors on the figures introduced during the production step. Below are the errors: Fig. 2a: The labels for the y- and x-axes have been translocated upwards and need to be realigned with the axes. The x-axis should read: -Log2 (fold change). Fig. 2d: the quantification values in the NUSAP1 blots, for T47D and MDA-MB-231 cells, are no longer visible. The original article has been corrected

Definition of an inflammatory biomarker signature in plasma-derived extracellular vesicles of glioblastoma patients

Glioblastoma (GB) is an aggressive type of tumour for which therapeutic options and biomarkers are limited. GB diagnosis mostly relies on symptomatic presentation of the tumour and, in turn, brain imaging and invasive biopsy that can delay its diagnosis. Description of easily accessible and effective biomarkers present in biofluids would thus prove invaluable in GB diagnosis. Extracellular vesicles (EVs) derived from both GB and stromal cells are essential to intercellular crosstalk in the tumour bulk, and circulating EVs have been described as a potential reservoir of GB biomarkers. Therefore, EV-based liquid biopsies have been suggested as a promising tool for GB diagnosis and follow up. To identify GB specific proteins, sEVs were isolated from plasma samples of GB patients as well as healthy volunteers using differential ultracentrifugation, and their content was characterised through mass spectrometry. Our data indicate the presence of an inflammatory biomarker signature comprising members of the complement and regulators of inflammation and coagulation including VWF, FCGBP, C3, PROS1, and SERPINA1. Overall, this study is a step forward in the development of a non-invasive liquid biopsy approach for the identification of valuable biomarkers that could significantly improve GB diagnosis and, consequently, patients’ prognosis and quality of life

PDGF-R inhibition induces glioblastoma cell differentiation via DUSP1/p38MAPK signalling

Glioblastoma (GBM) is the most common and fatal primary brain tumour in adults. Considering that resistance to current therapies leads to limited response in patients, new therapeutic options are urgently needed. In recent years, differentiation therapy has been proposed as an alternative for GBM treatment, with the aim of bringing cancer cells into a post-mitotic/differentiated state, ultimately limiting tumour growth. As an integral component of cancer development and regulation of differentiation processes, kinases are potential targets of differentiation therapies. The present study describes how the screening of a panel of kinase inhibitors (KIs) identified PDGF-Rα/β inhibitor CP-673451 as a potential differentiation agent in GBM. We show that targeting PDGF-Rα/β with CP-673451 in vitro triggers outgrowth of neurite-like processes in GBM cell lines and GBM stem cells (GSCs), suggesting differentiation into neural-like cells, while reducing proliferation and invasion in 3D hyaluronic acid hydrogels. In addition, we report that treatment with CP-673451 improves the anti-tumour effects of temozolomide in vivo using a subcutaneous xenograft mouse model. RNA sequencing and follow-up proteomic analysis revealed that upregulation of phosphatase DUSP1 and consecutive downregulation of phosphorylated-p38MAPK can underlie the pro-differentiation effect of CP-673451 on GBM cells. Overall, the present study identifies a potential novel therapeutic option that could benefit GBM patients in the future, through differentiation of residual GSCs post-surgery, with the aim to limit recurrence and improve quality of life

Genomic and epigenomic profile of uterine smooth muscle tumors of uncertain malignant potential (Stumps) revealed similarities and differences with leiomyomas and leiomyosarcomas

Uterine smooth muscle tumors of uncertain malignant potential (STUMPs) represent a heterogeneous group of tumors that cannot be histologically diagnosed as unequivocally benign or malignant. For this reason, many authors are working to obtain a better definition of diagnostic and prognostic criteria. In this work, we analyzed the genomic and epigenomic profile of uterine smooth muscle tumors (USMTs) in order to find similarities and differences between STUMPs, leiomyosarcomas (LMSs) and leiomyomas (LMs), and possibly identify prognostic factors in this group of tumors. Array-CGH data on 23 USMTs demonstrated the presence of a more similar genomic profile between STUMPs and LMSs. Some genes, such as PRKDC and PUM2, with a potential prognostic value, were never previously associated with STUMP. The methylation data appears to be very promising, especially with regards to the divergent profile found in the sample that relapsed, characterized by an overall CGI hypomethylation. Finally, the Gene Ontology analysis highlighted some cancer genes that could play a pivotal role in the unexpected aggressive behavior that can be found in some of these tumors. These genes could prove to be prognostic markers in the future

Tuneable synthetic reduced graphene oxide scaffolds elicit high levels of three-dimensional glioblastoma interconnectivity in vitro

Three-dimensional tissue scaffolds have utilised nanomaterials to great effect over the last decade. In particular, scaffold design has evolved to consider mechanical structure, morphology, chemistry, electrical properties, and of course biocompatibility - all vital to the performance of the scaffold and how successful they are in developing cell cultures. We have developed an entirely synthetic and tuneable three-dimensional scaffold of reduced graphene oxide (rGO) that shows good biocompatibility, and favourable mechanical properties as well as reasonable electrical conductivity. Importantly, the synthesis is scaleable and suitable for producing scaffolds of any desired geometry and size, and we observe a high level of biocompatibility and cell proliferation for multiple cell lines. In particular, one of the most devastating forms of malignant brain cancer, glioblastoma (GBM), grows especially well on our rGO scaffold in vitro, and without the addition of response-specific growth factors. We have observed that our scaffold elicits spontaneous formation of a high degree of intercellular connections across the GBM culture. This phenomenon is not well documented in vitro and nothing similar has been observed in synthetic scaffolds without the use of response-specific growth factors - which risk obscuring any potential phenotypic behaviour of the cells. The use of scaffolds like ours, which are not subject to the limitations of existing two-dimensional substrate technologies, provide an excellent system for further investigation into the mechanisms behind the rapid proliferation and success of cancers like GBM. These synthetic scaffolds can advance our understanding of these malignancies in the pursuit of improved theranostics against them