Biology subjects

Perez-Nunez, A.

Publications and source records attributed to Perez-Nunez, A..

3 recordsLinked to original sources

bioRxiv2020

A drug-screening platform based on organotypic cultures identifies vulnerabilities to prevent local relapse and treat established brain metastasis

Exclusion of brain metastases from clinical trials is a major cause of the limited therapeutic options for this growing population of cancer patients. Here, we report a medium-throughput drug-screening platform (METPlatform) based on organotypic cultures that allows to evaluate inhibitors against metastases growing in situ. By applying this approach to brain metastasis, we identified several hits from a library of FDA approved inhibitors and others being tested in clinical trials. A blood-brain barrier permeable HSP90 inhibitor showed high potency against mouse and human brain metastases at clinically relevant stages of the disease, including a novel model of local relapse after neurosurgery. Furthermore, in situ proteomic analysis applied to organotypic cultures with metastases treated with the chaperone inhibitor revealed novel biomarkers in human brain metastasis and actionable mechanisms of resistance. Our work validates METPlatform as a potent resource for metastasis research integrating drug-screening and unbiased omic approaches that is fully compatible with human samples. We envision that METPlatform could be established as a clinically relevant strategy to personalize the management of metastatic disease in the brain and elsewhere. SummarySystemic spread of cancer continues to be the key aspect associated with lethality. In this publication, Zhu et al. describes a drug-screening platform specifically designed to study vulnerabilities of metastasis when colonizing secondary organs and demonstrates its value in difficult-to-treat brain metastasis using new models and patient-derived samples.

cancer biology↗

bioRxiv2020

The genetic status of IDH1/2 and EGFR dictates the vascular landscape and the progression of gliomas

RationaleGlioma progression is driven by the induction of vascular alterations but how the tumor genotype influence these changes is still a pending issue. We propose to study the underlying mechanisms by which the genetic changes in isocitrate dehydrogenase 1/2 (IDH1/2) and epidermal growth factor receptor (EGFR) genes establish the different vascular profiles of gliomas. MethodsWe stratified gliomas based on the genetic status of IDH1/2 and EGFR genes. For that we used in silico data and a cohort of 93 glioma patients, where we analyzed the expression of several transcripts and proteins. For the in vitro and in vivo studies, we used a battery of primary glioblastoma cells derived from patients, as well as novel murine glioma cell lines expressing wild-type or mutant EGFR. In these models, the effect of the small molecule ibrutinib or the downregulation of CD248 and SOX9 was evaluated to establish a molecular mechanism. ResultsWe show that IDH1/2 mutations associate with a normalized vasculature. By contrast, EGFR mutations stimulate the plasticity of glioma cells and their capacity to function as pericytes in a bone-marrow and X-linked (BMX)/SOX9 dependent manner. The presence of tumor-derived pericytes stabilize the profuse vasculature and confers a growth advantage to these tumors, although they render them sensitive to pericyte-targeted molecules. Wild-type/amplified EGFR gliomas are enriched in blood vessels too, but they show a highly disrupted blood-brain-barrier due to a decreased BMX/SOX9 activation and pericyte coverage. This leads to poor nutrient supply, necrosis and hypoxia. ConclusionsThe function of tumor-derived pericytes delimitates two distinct and aggressive vascular phenotypes in IDH1/2 wild-type gliomas. Our results lay the foundations for a vascular dependent stratification of gliomas and suggest different therapeutic vulnerabilities depending on the genetic status of EGFR. O_FIG O_LINKSMALLFIG WIDTH=190 HEIGHT=200 SRC="FIGDIR/small/306134v1_ufig1.gif" ALT="Figure 1"> View larger version (55K): org.highwire.dtl.DTLVardef@64bff5org.highwire.dtl.DTLVardef@76711aorg.highwire.dtl.DTLVardef@1fb8306org.highwire.dtl.DTLVardef@1570f51_HPS_FORMAT_FIGEXP M_FIG Graphical Abstract. Schematic view of IDH and EGFR function in the regulation of glioma microenvironment. Mutant IDH gliomas express low levels of angiogenic molecules and have a vasculature reminiscent of normal tissue. EGFR mutations drive glioma growth by promoting tumor-to-pericyte transdifferentiation and vascular stabilization in a BMX-SOX9 dependent way. Leaky vessels with hypoxia and necrosis characterize tumors overexpressing the wild-type isoform of the receptor. These phenotypes determine the response to therapy of the different IDH wild-type gliomas. C_FIG

cancer biology↗

bioRxiv2020

Immune profiling of gliomas reveals a connection with Tau function and the tumor vasculature.

BackgroundGliomas remain refractory to all attempted treatments, including those using immune checkpoint inhibitors. The characterization of the tumor (immune) microenvironment has been recognized as an important challenge to get a mechanistic explanation for this lack of response and to improve the therapy of glial tumors. MethodsWe designed a prospective analysis of the immune cells of gliomas by flow cytometry. Tumors with or without isocytrate dehydrogenase 1/2 (IDH1/2) mutations were included in the study. The genetic profile and the presence of different molecular and cellular features of the gliomas were analyzed in parallel. The findings were validated in mouse glioma models. ResultsWe observed that few immune cells infiltrate mutant IDH1/2 gliomas and we distinguished two different profiles in their IDH1/2 wild-type counterparts. The first one has an important immune component, particularly enriched in myeloid cells with immunosuppressive features. The second group is more similar to mutant IDH1/2 gliomas, with few immune cells and a less immunosuppressive profile. Notably, we observed a direct correlation between the immune content and the presence of vascular alterations, which were associated with a reduced expression of Tau, a microtubule-binding-protein that controls the formation of tumor vessels in gliomas. Furthermore, overexpression of Tau was able to reduce the immune content in orthotopic mouse glioma models, delaying tumor growth. ConclusionsThere is a correlation between vascular alterations and the immune profile of gliomas, which could be exploited for the design of more successful clinical trials with immunomodulatory molecules. Key pointsO_LIMutant IDH1/2 gliomas harbor few immune cells in the tumor microenviroment. C_LIO_LIWe distinguished two different profiles in the IDH1/2 wild-type gliomas. C_LIO_LIThere is a correlation between Tau expression, vascular alterations and the immune profile. C_LI Importance of the StudyIn the present work we have confirmed that IDHmut gliomas are "cold" tumors and we have identified a subgroup of IDHwt GBMs that also contains a low immune infiltrate. By contrast, a large subgroup of IDHwt GBMs are characterized by an important immune component, particularly enriched in myeloid cells, and an elevated expression of the ligand of PD-L1 in the immune compartment. Notably, we have observed a direct correlation between the immune content and the presence of vascular alterations, as well as with the reduced expression of Tau, a microtubule-binding protein that we described as a negative regulator of angiogenesis. Here, we add that overexpression of Tau reduces the immune content in orthotopic glioma models, delaying tumor growth. This correlation between the vascular phenotype and the entrance and/or the function of the immune cells on gliomas, where Tau could play a central role, opens new venues to find synergistic treatments.

cancer biology↗