Biology subjects

Bocci, M.

Publications and source records attributed to Bocci, M..

4 recordsLinked to original sources

bioRxiv2024

Pericytes orchestrate a tumor-restraining microenvironment in glioblastoma

Glioblastoma (GBM) is characterized by fast progression, an infiltrative growth pattern, and a high rate of relapse. A defining feature of GBM is the existence of spatially and functionally distinct cellular niches, i.e. a hypoxic niche, a leading-edge niche, and a perivascular niche, in which malignant cells engage in paracrine crosstalk with cell types comprising the tumor microenvironment. Here, by analysis of single-cell transcriptomic data of human GBM and transgenic mouse models of GBM, we unexpectedly identified pericytes, mural cells intimately associated with the endothelium, as the most active paracrine signaling hub within the tumor parenchyma. Exclusive signaling axes emanating from pericytes were received by endothelial cells, malignant cells, astrocytes, and immune cells. Depletion of pericytes through genetic engineering in several different transgenic and orthotopic mouse models of GBM demonstrated accelerated tumor progression, a disrupted blood-brain-barrier, and premature death of pericyte-poor mice. Mechanistic studies revealed that pericyte deficiency altered the cellular composition of GBM, remodeled the endothelium, and impacted on the immune cell landscape, exacerbating tumor cell invasion and immune suppression. Specifically, endothelial cells deprived of pericyte association altered their signaling programs, which in turn attracted perivascular, tumor-associated macrophages polarized towards an immune-suppressive phenotype. The recruited macrophages expressed Hepatocyte Growth Factor (HGF), which reinforced activation of its receptor tyrosine kinase MET on GBM cells harboring an extreme mesenchymal subtype driven by the key phenotypic regulator Fosl1 within hypoxic regions. Indeed, orthotopic implantation of isolated, MET-expressing GBM cells corroborated their superior tumor-initiating capability and invasive phenotype. In patients, low expression of a pericyte core gene signature was reduced in recurrent GBM, compared to primary tumors. Consistently, gene signatures for transcriptional programs of Fosl1+Met+ GBM cells were indicative of poor survival in human tumors, and spatial transcriptomics corroborated their superior invasive capacity. Taken together, we infer that the pericyte represents a critical modulator of GBM development by orchestrating a tumor-suppressive microenvironment; our findings thus highlight the importance of pericyte preservation in the face of current and future GBM therapies. O_FIG O_LINKSMALLFIG WIDTH=200 HEIGHT=200 SRC="FIGDIR/small/609765v1_ufig1.gif" ALT="Figure 1"> View larger version (102K): org.highwire.dtl.DTLVardef@803a8eorg.highwire.dtl.DTLVardef@8441eaorg.highwire.dtl.DTLVardef@1038288org.highwire.dtl.DTLVardef@16eccfc_HPS_FORMAT_FIGEXP M_FIG C_FIG

cancer biology↗

bioRxiv2024

An ALK1-governed monocytic lineage shapes an immunosuppressive landscape inbreast cancer metastases

The biology centered around the TGF-{beta} type I receptor ALK1 (encoded by ACVRL1) has been almost exclusively based on its reported endothelial expression pattern since its first functional characterization more than two decades ago. Here, in efforts to better define the therapeutic context in which to use ALK1 inhibitors, we uncover a population of tumor-associated macrophages (TAMs) that, by virtue of their unanticipated Acvrl1 expression, are effector targets for adjuvant anti-angiogenic immunotherapy in mouse models of metastatic breast cancer. The combinatorial benefit depended on ALK1-mediated modulation of the differentiation potential of bone marrow-derived granulocyte-macrophage progenitors, the release of CD14+ monocytes into circulation, and their eventual extravasation. Notably, ACVRL1+ TAMs coincided with an immunosuppressive phenotype, and were over-represented in human cancers progressing on therapy. Accordingly, breast cancer patients with a prominent ACVRL1hi TAM signature exhibited a significantly shorter survival. In conclusion, we shed light on an unexpected multimodal regulation of tumorigenic phenotypes by ALK1 and demonstrate its utility as a target for anti-angiogenic immunotherapy. Graphical abstractSee submitted file

cancer biology↗

bioRxiv2022

A novel dimeric FAP-targeting small molecule-radio conjugate with high and prolonged tumour uptake

Imaging procedures based on small molecule-radio conjugates (SMRCs) targeting fibroblast activation protein (FAP) have recently emerged as a powerful tool for the diagnosis of a wide variety of tumours. However, the therapeutic potential of radiolabeled FAP-targeting agents is limited by their short residence time in neoplastic lesions. In this work, we present the development and in vivo characterization of BiOncoFAP, a new dimeric FAP-binding motif with extended tumour residence time and favorable tumour-to-organ ratio. MethodsThe binding properties of BiOncoFAP and its monovalent OncoFAP analogue were assayed against recombinant hFAP. Preclinical experiments with [177Lu]Lu-OncoFAP-DOTAGA (177Lu-OncoFAP) and [177Lu]Lu-BiOncoFAP-DOTAGA (177Lu-BiOncoFAP) were performed in mice bearing FAP-positive HT-1080 tumours. ResultsOncoFAP and BiOncoFAP displayed comparable sub-nanomolar dissociation constants towards hFAP in solution, but the bivalent BiOncoFAP bound more avidly to the target immobilized on solid supports. In a comparative biodistribution study, 177Lu-BiOncoFAP exhibited a more stable and prolonged tumour uptake than 177Lu-OncoFAP ([~]20% ID/g vs [~]4% ID/g, at 24h p.i., respectively). Notably, 177Lu-BiOncoFAP showed favorable tumour-to-organ ratios with low kidney uptake. Both 177Lu-OncoFAP and 177Lu-BiOncoFAP displayed potent anti-tumour efficacy when administered at therapeutic doses in tumour bearing mice. Conclusions177Lu-BiOncoFAP is a promising candidate for radioligand therapy of cancer, with favorable in vivo tumour-to-organ ratio, long tumour residence time and potent anti-cancer efficacy.

pharmacology and toxicology↗

bioRxiv2021

Infection of brain pericytes underlying neuropathology of COVID-19 patients

A wide range of neurological manifestations have been associated with the development of COVID-19 following SARS-CoV-2 infection. However, the etiology of the neurological symptomatology is still largely unexplored. Here, we used state-of-the-art multiplexed immunostaining of human brains (n = 6 COVID-19, median age = 69,5 years; and n = 7 control, median age = 68 years), and demonstrated that expression of the SARS-CoV-2 receptor ACE2 is restricted to a subset of neurovascular pericytes. Strikingly, neurological symptoms were exclusive to, and ubiquitous in, patients that exhibited moderate to high ACE2 expression in peri-vascular cells. Viral particles were identified in the vascular wall and paralleled by peri-vascular inflammation, as signified by T cell and macrophage infiltration. Furthermore, fibrinogen leakage indicated compromised integrity of the blood-brain barrier. Notably, cerebrospinal fluid from an additional 16 individuals (n = 8 COVID-19, median age = 67 years; and n = 8 control, median age = 69,5 years) exhibited significantly lower levels of the pericyte marker PDGFR{beta} in SARS-CoV-2-infected cases, indicative of disrupted pericyte homeostasis. We conclude that pericyte infection by SARS-CoV-2 underlies virus entry into the privileged central nervous system space, as well as neurological symptomatology due to peri-vascular inflammation and a locally compromised blood-brain barrier.

pathology↗