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The nervous system undergoes dynamic structural remodeling to infiltrate cancerous tumors, contributing to their growth and progression. Emerging evidence indicates that neuroplasticity initiates early, with nerve terminals detecting and responding to tissue changes even during precancerous stages. Notably, dense sympathetic axon sprouting has been observed around pancreatic intraepithelial neoplasia (PanIN), a common precursor lesion to pancreatic cancer. However, the molecular signals driving this early neuroplasticity and its functional consequences remain poorly understood. Here, we identify the axon guidance molecule Netrin-1 as a key factor secreted by pancreatic cells within precursor lesions of pancreatic cancer. Netrin-1 promotes sympathetic axon growth and branching through its receptor, Deleted in Colorectal Cancer (DCC). Inhibition of Netrin-1 disrupts sympathetic axon remodeling while accelerating PanIN formation and progression, driven by increased precancerous cell proliferation. Furthermore, human pancreatic tissue analysis corroborates Netrin-1 expression in precursor lesions. These findings suggest that Netrin-1-driven sympathetic neuroplasticity plays a protective role in the precancerous microenvironment by modulating local cellular dynamics, providing insights into early cancer progression. The nervous system can influence cancer progression. Here, authors show in mouse models that Netrin-1 promotes sympathetic nerve remodeling in early pancreatic cancer lesions and has a protective effect against their progression.

Background Breast cancer is the second most common cancer in the world. Despite advances in therapies, the mechanisms of resistance remain the underlying cause of morbidity and mortality. Lipoic acid (LA) is an antioxidant and essential cofactor in oxidative metabolism. Its potential therapeutic effects have been well documented, but its mechanisms of action (MOA) are not fully understood. Methods The aim of this study is to validate the inhibitory LA effect on the proliferation of various breast cancer cell lines and to investigate the MOA that may be involved in this process. We tested LA effects by ex vivo studies on fresh human mammary tumour samples. Results We demonstrate that LA inhibits the proliferation and Akt and ERK signalling pathways of several breast cancer cells. While searching for upstream dysregulations, we discovered the loss of expression of IGF-1R upon exposure to LA. This decrease is due to the downregulation of the convertase, furin, which is implicated in the maturation of IGF-1R. Moreover, ex vivo studies on human tumour samples showed that LA significantly decreases the expression of the proliferation marker Ki67. Conclusion LA exerts its anti-proliferative effect by inhibiting the maturation of IGF-1R via the downregulation of furin.

In mouse embryonic stem cells (mESCs), chemical blockade of Gsk3α/β and Mek1/2 (2i) instructs a self-renewing ground state whose endogenous inducers are unknown. Here we show that the axon guidance cue Netrin-1 promotes naive pluripotency by triggering profound signalling, transcriptomic and epigenetic changes in mESCs. Furthermore, we demonstrate that Netrin-1 can substitute for blockade of Gsk3α/β and Mek1/2 to sustain self-renewal of mESCs in combination with leukaemia inhibitory factor and regulates the formation of the mouse pluripotent blastocyst. Mechanistically, we reveal how Netrin-1 and the balance of its receptors Neo1 and Unc5B co-regulate Wnt and MAPK pathways in both mouse and human ESCs. Netrin-1 induces Fak kinase to inactivate Gsk3α/β and stabilize β-catenin while increasing the phosphatase activity of a Ppp2r2c-containing Pp2a complex to reduce Erk1/2 activity. Collectively, this work identifies Netrin-1 as a regulator of pluripotency and reveals that it mediates different effects in mESCs depending on its receptor dosage, opening perspectives for balancing self-renewal and lineage commitment.Netrin-1, via precise Neo1/Unc5B stoichiometry, promotes naive pluripotency, embryonic stem cell self-renewal in combination with leukaemia inhibitory factor, and the formation of the mouse epiblast in vivo.

Notch signaling is a conserved signaling pathway that participates in many aspects of mammary gland development and homeostasis, and has extensively been associated with breast tumorigenesis. Here, to unravel the as yet debated role of Notch3 in breast cancer development, we investigated its expression in human breast cancer samples and effects of its loss in mice. Notch3 expression was very weak in breast cancer cells and was associated with good patient prognosis. Interestingly, its expression was very strong in stromal cells of these patients, though this had no prognostic value. Mechanistically, we demonstrated that Notch3 prevents tumor initiation via HeyL-mediated inhibition of Mybl2, an important regulator of cell cycle. In the mammary glands of Notch3-deficient mice, we observed accelerated tumor initiation and proliferation in a MMTV-Neu model. Notch3-null tumors were enriched in Mybl2 mRNA signature and protein expression. Hence, our study reinforces the anti-tumoral role of Notch3 in breast tumorigenesis.

Notch signalling is a causal determinant of cancer and efforts have been made to develop targeted therapies to inhibit the so-called canonical pathway. Here we describe an unexpected pro-apoptotic role of Notch3 in regulating tumour angiogenesis independently of the Notch canonical pathway. The Notch3 ligand Jagged-1 is upregulated in a fraction of human cancer and our data support the view that Jagged-1, produced by cancer cells, is inhibiting the apoptosis induced by the aberrant Notch3 expression in tumour vasculature. We thus present Notch3 as a dependence receptor inducing endothelial cell death while this pro-apoptotic activity is blocked by Jagged-1. Along this line, using Notch3 mutant mice, we demonstrate that tumour growth and angiogenesis are increased when Notch3 is silenced in the stroma. Consequently, we show that the well-documented anti-tumour effect mediated by γ-secretase inhibition is at least in part dependent on the apoptosis triggered by Notch3 in endothelial cells. Notch signalling is deregulated in several cancers; therefore, strategies targeting this pathway are currently being explored. Here the authors report a pro-apoptotic function of Notch3 in endothelial cells; consequently, when Notch3 is silenced in stroma cells, tumour growth and angiogenesis are increased.

Dysregulated androgen receptor (AR) plays a crucial role in prostate cancer (PCa) development, though further factors involved in its regulation remain to be identified. Recently, paradoxical results were reported on the implication of the MEN1 gene in PCa. To dissect its role in prostate luminal cells, we generated a mouse model with inducible Men1 disruption in Nkx3.1 -deficient mice in which mouse prostatic intraepithelial neoplasia (mPIN) occur. Prostate glands from mutant and control mice were analyzed pathologically and molecularly; cellular and molecular analyses were carried out in PCa cell lines after MEN1 knockdown (KD) by siRNA. Double-mutant mice developed accelerated mPIN and later displayed microinvasive adenocarcinoma. Markedly, early-stage lesions exhibited a decreased expression of AR and its target genes, accompanied by reduced CK18 and E-cadherin expression, suggesting a shift from a luminal to a dedifferentiated epithelial phenotype. Intriguingly, over 60% of menin-deficient cells expressed CD44 at a later stage. Furthermore, MEN1 KD led to the increase in CD44 expression in PC3 cells re-expressing AR. Menin bound to the proximal AR promoter and regulated AR transcription via the H3K4me3 histone mark. Interestingly, the cell proliferation of AR-dependent cells (LNCaP, 22Rv1, and VCaP), but not of AR-independent cells (DU145, PC3), responded strongly to MEN1 silencing. Finally, menin expression was found reduced in some human PCa. These findings highlight the regulation of the AR promoter by menin and the crosstalk between menin and the AR pathway. Our data could be useful for better understanding the increasingly reported AR-negative/NE-negative subtype of PCa and the mechanisms underlying its development.

Background Epidemiological emerging evidence shows that human exposure to some nanosized materials present in the environment would contribute to the onset and/or progression of Alzheimer’s disease (AD). The cellular and molecular mechanisms whereby nanoparticles would exert some adverse effects towards neurons and take part in AD pathology are nevertheless unknown. Results Here, we provide the prime evidence that titanium dioxide (TiO 2 ) and carbon black (CB) nanoparticles (NPs) bind the cellular form of the prion protein (PrP C ), a plasma membrane protein well known for its implication in prion diseases and prion-like diseases, such as AD. The interaction between TiO 2 - or CB-NPs and PrP C at the surface of neuronal cells grown in culture corrupts PrP C signaling function. This triggers PrP C -dependent activation of NADPH oxidase and subsequent production of reactive oxygen species (ROS) that alters redox equilibrium. Through PrP C interaction, NPs also promote the activation of 3-phosphoinositide-dependent kinase 1 (PDK1), which in turn provokes the internalization of the neuroprotective TACE α-secretase. This diverts TACE cleavage activity away from (i) TNFα receptors (TNFR), whose accumulation at the plasma membrane augments the vulnerability of NP-exposed neuronal cells to TNFα -associated inflammation, and (ii) the amyloid precursor protein APP, leading to overproduction of neurotoxic amyloid Aβ40/42 peptides. The silencing of PrP C or the pharmacological inhibition of PDK1 protects neuronal cells from TiO 2 - and CB-NPs effects regarding ROS production, TNFα hypersensitivity, and Aβ rise. Finally, we show that dysregulation of the PrP C -PDK1-TACE pathway likely occurs in the brain of mice injected with TiO 2 -NPs by the intra-cerebro-ventricular route as we monitor a rise of TNFR at the cell surface of several groups of neurons located in distinct brain areas. Conclusion Our in vitro and in vivo study thus posits for the first time normal cellular prion protein PrP C as being a neuronal receptor of TiO 2 - and CB-NPs and identifies PrP C -coupled signaling pathways by which those nanoparticles alter redox equilibrium, augment the intrinsic sensitivity of neurons to neuroinflammation, and provoke a rise of Aβ peptides. By identifying signaling cascades dysregulated by TiO 2 - and CB-NPs in neurons, our data shed light on how human exposure to some NPs might be related to AD.

The navigation cue netrin‐1 is well‐documented for its key role in cancer development and represents a promising therapeutic target currently under clinical investigation. Phase 1 and 2 clinical trials are ongoing with NP137, a humanized monoclonal antibody against netrin‐1. Interestingly, the epitope recognized by NP137 in netrin‐1 shares 90% homology with its counterpart in netrin‐3, the closest member to netrin‐1 in humans, for which little is known in the field of cancer. Here, we unveiled that netrin‐3 appears to be expressed specifically in human neuroblastoma (NB) and small cell lung cancer (SCLC), two subtypes of neuroectodermal/neuroendocrine lineages. Netrin‐3 and netrin‐1 expression are mutually exclusive, and the former is driven by the MYCN oncogene in NB, and the ASCL‐1 or NeuroD1 transcription factors in SCLC. Netrin‐3 expression is correlated with disease stage, aggressiveness, and overall survival in NB. Mechanistically, we confirmed the high affinity of netrin‐3 for netrin‐1 receptors and we demonstrated that netrin‐3 genetic silencing or interference using NP137, delayed tumor engraftment, and reduced tumor growth in animal models. Altogether, these data support the targeting of netrin‐3 in NB and SCLC. Synopsis Expression and function of netrin‐3 have so far never been investigated in human cancers. Based on cohort analyses, this study shows that netrin‐3 is a putative therapeutic target in both small cell lung cancer (SCLC) and neuroblastoma (NB). Netrin‐3 expression is specific to the neuroendocrine/neuroepithelial cell lineage. Netrin‐1 and netrin‐3 are mutually exclusive in the vast majority of human cancer cell lines. Netrin‐3 expression is correlated with NB poor prognosis. MYCN, NEUROD1 and ASCL‐1 regulate transcription of netrin‐3. Netrin‐1 and netrin‐3 could be targeted by the same therapeutic monoclonal blocking antibody. Graphical Abstract Expression and function of netrin‐3 have so far never been investigated in human cancers. Based on cohort analyses, this study shows that netrin‐3 is a putative therapeutic target in both small cell lung cancer (SCLC) and neuroblastoma (NB).

Folliculostellate cells are S100B-expressing cells with numerous functions in the normal anterior pituitary. These cells have also been identified in pituitary neuroendocrine tumours (PitNETs), where their precise role remains elusive. Here, we aimed to build a refined cartography of S100B-expressing cells to characterise their interpatient and intratumoural spatial distribution, and to start identifying their potential functions in PitNETs. High-throughput histological analysis of S100B-stained tumour sections of 54 PitNETs revealed a significant decrease in S100B + cells in PitNETs compared to the normal anterior pituitary. A Ki67 index ≥ 3, a mitosis count > 2/10 per high power fields, and a proliferative status, were all associated with fewer S100B + cells in gonadotroph tumours. Gonadotroph tumours also showed interpatient and intratumoural heterogeneity in the spatial distribution of S100B + cells. The existence of an intratumoural heterogeneity was further confirmed by the incorporation to our spatial analysis of additional markers: Ki67, FSH, LH, ERα and SSTR2. The tumour areas with fewer S100B + cells displayed a higher percentage of Ki67 + cells, whereas strong positive correlations were observed between S100B + , FSH + , and ERα + cells. Such spatial associations suggest that S100B + folliculostellate cells could play a role in gonadotroph tumorigenesis, and may contribute to the maintenance of tumour cells in a low proliferating, FSH + /ERα + differentiated state. Albeit, further in-depth functional studies are required to decipher the mechanisms underlying these spatial associations and to potentially identify a therapeutic use.

BackgroundHead and neck squamous cell carcinoma (HNSCC) exhibits low response rates to immunotherapies, with only about 15–25% of patients responding to monotherapy and 30–45% to combination therapy. This limited effectiveness is attributed to significant intertumor and intratumor heterogeneity, which affects the immunological activity of individual tumors and their regions, thereby influencing immunotherapy outcomes. Various biomarkers at the gene and protein expression levels have been identified to predict the response to immunotherapy in HNSCC.MethodsIn this study, we evaluated intertumor heterogeneity using a 27-gene expression signature to stratify tumors by their immunologic activity status. We investigated intertumor heterogeneity at the molecular and cellular level and further analyzed intratumor spatial heterogeneity within and across these subgroups by using spatial multiomics approaches.ResultsImmunologically active tumors showed increased interferon-γ and interferon-α signaling and upregulation of major histocompatibility complex-I signaling and genes involved in antigen presentation. Chemokines such as CXCL8 and CXCL9, which are crucial for immune cell recruitment, were differentially regulated. The spatial analysis revealed that active tumors tended to show higher autocorrelation of homogeneous regions with immune cell infiltration compared with inactive tumors. Proximity measures showed an increased colocalization of immune cells, particularly CD8+ T cells, T helper cells, and regulatory T cells, near tumor cells in active tumors. Despite this high immune infiltration, HNSCC often has an immunosuppressive microenvironment, which we observed as a colocalization of programmed cell death protein-1+ (PD-1+) cytotoxic T cells and cytotoxic T cells, indicating regional differences in active and exhausted cell ratios. Furthermore, upregulation of JAK-STAT3 signaling in active tumors was potentially associated with immune evasion.ConclusionsThe spatial analysis at multiple omics levels allowed for a detailed investigation of molecular and cell type markers to further distinguish between immunologically active and immunosuppressive microenvironments and their spatial heterogeneity. Our study demonstrates that, besides gene expression signatures, cell colocalization signatures can infer immunological activity in HNSCC, thus predicting immunotherapy response.