Biology subjects

Mantamadiotis, T.

Publications and source records attributed to Mantamadiotis, T..

10 recordsLinked to original sources

bioRxiv2026

Multi-omic and spatial analysis reveals tumour-derived paracrine signals drive suppressive macrophage polarisation via activation of the cAMP-CREB axis in glioblastoma

Tumor-associated macrophages (TAMs) are key mediators of tumor immunosuppression, yet the factors governing their polarization remain poorly understood, especially in highly immunosuppressive cancers, including cancers affecting the central nervous system. This study investigates the molecular pathways underlying TAM polarization in glioblastoma, one of the most immunosuppressive cancer types. Using a multi-omics approach integrating spatial proteomics, RNA-sequencing, and proteomic profiling of tumor cells and macrophages, we demonstrate that circulating monocytes polarize toward an immunosuppressive state when they exit tumor blood vessels, in response to glioblastoma cell-secreted cytokines. In situ and in vitro data shows that macrophage polarization is regulated via the cAMP-CREB signaling-transcription axis.

cancer biology↗

bioRxiv2025

Exercise training improves sarcopenic muscle function via restoration of mitochondrial quality control

Mitophagy is an essential component of the mitochondrial quality control program, maintaining mitochondrial homeostasis in metabolic tissues such as skeletal muscle. With age, it is thought that mitochondrial quality control becomes dysregulated, leading to the progression of age-associated diseases such as sarcopenia. Exercise is known to enhance skeletal muscle mitochondrial health and may be an effective intervention to prevent sarcopenia, however the role of mitophagy in this process is unknown. Utilising mitophagy reporter mice (mito-QC), we assessed adaptations in skeletal muscle mitophagy in response to increased age (3-26 months) and following an 8-week endurance exercise training period. Immunofluorescent imaging revealed that ageing led to an accumulation of mitolysosomes in sarcopenic old mice indicative of increased mitophagy, an adaptive response that was reversed by exercise training. In parallel to reducing age-associated mitophagy, exercise training increased mitochondrial respiratory capacity and improved muscle strength, suggesting that alterations in mitochondrial quality control led to improvements in skeletal muscle function. Exercise-mediated alterations in mitophagy were accompanied by increases in BNIP3, FUNDC1 and BCL2L13 protein content post training. Collectively our data suggests that sarcopenia leads to dysregulation of mitophagy in skeletal muscle. Restoring mitophagy balance with exercise training leads to improvements in mitochondrial respiration and skeletal muscle strength, identifying a novel cellular mechanism to explain the benefits of exercise training in old age.

cell biology↗

bioRxiv2024

Testicular sex cord stromal tumors in mice with constitutive activation of PI3K and loss of Pten

Testicular tumors are the most common malignancy of young men and tumors affecting the testis are caused by somatic mutations in germ or germ-like cells. The PI3K pathway is constitutively activated in about one third of testicular cancers. To investigate the role of the PI3K pathway in transforming stem-like cells in the testis, we investigated tumors derived from mice with post-natal, constitutive activation of PI3K signaling and homozygous deletion of tumor suppressor Pten, targeted to nestin expressing cells. Mice developed aggressive tumors, exhibiting heterogeneous histopathology and hemorrhaging. The tumors resemble the rare testis tumor type, testicular sex cord-stromal Leydig cell tumors. Single cell resolution spatial tissue analysis demonstrated that T-cells are the dominant tumor infiltrating immune cell type, with very few infiltrating macrophages observed in the tumor tissue, with CD8+ T-cells predominating. Further analysis showed that immune cells preferentially localize to or accumulate within stromal regions. Graphical Abstract O_FIG O_LINKSMALLFIG WIDTH=200 HEIGHT=114 SRC="FIGDIR/small/613175v1_ufig1.gif" ALT="Figure 1"> View larger version (37K): org.highwire.dtl.DTLVardef@657f74org.highwire.dtl.DTLVardef@192bcc7org.highwire.dtl.DTLVardef@a7c63eorg.highwire.dtl.DTLVardef@c81d17_HPS_FORMAT_FIGEXP M_FIG C_FIG

cancer biology↗

bioRxiv2023

Her6 and Prox1 are novel regulators of photoreceptor regeneration in the zebrafish retina

Damage to light-sensing photoreceptors (PRs) occurs in highly prevalent retinal diseases. As humans cannot regenerate new PRs, these diseases often lead to irreversible blindness. Intriguingly, animals, such as the zebrafish, have the ability to regenerate PRs efficiently and restore functional vision. Upon injury, mature Muller glia (MG) undergo reprogramming to adopt a stem cell-like state. This process is similar to cellular dedifferentiation, and results in the generation of progenitor cells, which, in turn, proliferate and differentiate to replace lost retinal neurons. In this study, we tested whether factors involved in dedifferentiation of Drosophila CNS are implicated in the regenerative response in the zebrafish retina. We found that hairy-related 6 (her6) negatively regulates of PR production by regulating the rate of cell divisions in the MG-derived progenitors. prospero homeobox 1 (prox1) is expressed in differentiated PRs, and likely promotes PR differentiation through phase separation. Interestingly, upon Her6 downregulation, Prox1 is precociously upregulated in the PRs, to promote PR differentiation; conversely, loss of Prox1 also induces a downregulation of Her6. Together, we identified two novel candidates of PR regeneration that cross regulate each other, and may be exploited to promote human retinal regeneration and vision recovery.

genetics↗

bioRxiv2023

Discovery of NRG1-VII: a novel myeloid-derived class of NRG1 isoforms

The growth factor Neuregulin-1 (NRG1) has pleiotropic roles in proliferation and differentiation of the stem cell niche in different tissues. It has been implicated in gut, brain and muscle development and repair. Six isoform classes of NRG1 and over 28 protein isoforms have been previously described. Here we report a new class of NRG1, designated NRG1-VII to denote that these NRG1 isoforms arise from a myeloid-specific transcriptional start site (TSS) previously uncharacterized. Long-read sequencing was used to identify eight high-confidence NRG1-VII transcripts. These transcripts presented major structural differences from one another, through the use of cassette exons and alternative stop codons. Expression of NRG1-VII was confirmed in primary human monocytes and tissue resident macrophages and iPSC-derived macrophages. Isoform switching via cassette exon usage and alternate polyadenylation was apparent during monocyte maturation and macrophage differentiation. NRG1-VII is the major class expressed by the myeloid lineage, including tissue-resident macrophages. Analysis of public gene expression data indicates that monocytes and macrophages are a primary source of NRG1, suggesting that NRG1-VII is the most common class of NRG1 in most adult human tissues, except brain. The size and structure of type VII isoforms suggests that they may be more diffusible through tissues than other NRG1 classes. However, the specific roles of type VII variants in tissue homeostasis and repair have not yet been determined.

genomics↗

bioRxiv2022

Spatial analysis of the metastatic brain tumor immune and extracellular matrix microenvironment

Metastatic cancer is responsible for the overwhelming majority of cancer-related deaths with metastatic tumors being the most common neoplasms affecting the central nervous system. One of the major factors regulating tumor biology is the tumor microenvironment. However, little is known about the cellular and non-cellular composition of metastatic brain tumors and how tumor cell ontogeny influences the metastatic brain tumor microenvironment. By integrating multiplex immunohistochemistry and histopathological analysis to investigate composition and the spatial relationship between neoplastic cells, infiltrating and brain resident immune cells and the extracellular matrix, we demonstrate that metastatic brain tumors exhibit differences in ECM deposition, compared with the most common primary brain tumor type, glioblastoma, and that the dominant immune cell types in metastatic brain tumors are immunosuppressive macrophages, which preferentially localize to ECM-rich stromal regions.

cancer biology↗

bioRxiv2021

Tissue remodeling and cell signaling underpin changes in tumor microenvironment heterogeneity in glioma oncogenesis

Brain tumor cells thrive by adapting to the signals in their microenvironment. Understanding how the tumor microenvironment evolves during disease progression is crucial to deciphering the mechanisms underlying the functional behavior of cancer cells. To adapt, cancer cells activate signaling and transcriptional programs and migrate to establish micro-niches, in response to signals from neighboring cells and non-cellular stromal factors. Using multiple tissue analysis approaches to identify and measure immune cell infiltration and extracellular matrix deposition in brain tumors, we show that low-grade glioma is largely devoid of infiltrating immune cells and extracellular matrix proteins, while high-grade glioma exhibits abundant immune cell infiltration and activation, as well as extensive collagen deposition. Spatial analysis shows that most T-cells are sequestered in perivascular nests, but macrophages penetrate deep into tumor cell rich regions. High-grade gliomas exhibit heterogeneous PI3K and MAPK signaling, which correlates with distinct pathological hallmarks, including tumor angiogenesis, tumor cell density and extracellular matrix deposition. Our results also provide compelling evidence that tissue remodeling is an important element in glioma progression, and that targeting the extracellular matrix will be critical to improving GBM therapy.

cancer biology↗

bioRxiv2021

Immune-evasion of KRAS-mutant lung adenocarcinoma mediated by cAMP response element-binding protein

cAMP response element-binding protein (CREB) mediates proliferative and inflammatory gene transcription in neurodegeneration and cancer, but its role in malignant immune-evasion of lung adenocarcinoma (LUAD) is unknown. We show that human LUAD of smokers are frequently altered along the CREB pathway and we employ mouse models to discover that KRAS-mutant LUAD co- opt CREB to evade immune rejection by tumoricidal neutrophils. For this, KRAS- driven CREB activation suppresses CXC-chemokine expression and prevents recruitment of CXCR1+ neutrophils. CREB1 is shown to be pro-tumorigenic in five different LUAD models, a function that is dependent on host CXCR1. Pharmacologic CREB blockade prevents tumor growth and restores neutrophil recruitment only when initiated before immune-evasion of KRAS-mutant LUAD. CREB and CXCR1 expression in human LUAD are compartmentalized to tumor and stromal cells, respectively, while CREB-regulated genes and neutrophils impact survival. In summary, CREB-mediated immune evasion of KRAS-mutant LUAD relies on signaling to neutrophil CXCR1 and is actionable.

cancer biology↗

bioRxiv2018

Intratumoral MAPK and PI3K signaling pathway heterogeneity in glioblastoma tissuecorrelates with selective CREB signaling and specific functional gene signatures

Limitations in discovering useful tumor biomarkers and drug targets is not only due to patient-to-patient differences but also due to intratumoral heterogeneity. Heterogeneity arises due to the genetic and epigenetic variation of tumor cells in response to microenvironmental interactions and cytotoxic therapy. We explored specific signaling pathway activation in glioblastoma (GBM) by investigating the intratumoral activation of the MAPK and PI3K pathways. We present data demonstrating a striking preponderance for mutual exclusivity of MAPK and PI3K activation in GBM tissue, where MAPK activation correlates with proliferation and transcription factor CREB activation and PI3K activation correlates with CD44 expression. Bioinformatic analysis of signaling and CREB-regulated target genes supports the immunohistochemical data, showing that the MAPK-CREB activation correlates with proliferative regions. In-silico analysis suggests that MAPK-CREB signaling activates a pro-inflammatory molecular signature and correlates with a mesenchymal GBM subtype profile, while PI3K-CREB activation correlates with the proneural GBM subtype and a tumor cell invasive gene signature. Overall, the data suggests the existence of intratumoral subtype heterogeneity in GBM and that using combinations of both MAPK and PI3K drug inhibitors is necessary for effective targeted therapy.

pathology↗

bioRxiv2017

PI3K Activation In Neural Stem Cells Drives Tumorigenesis Which Can Be Suppressed By Targeting CREB

Hyperactivation of the PI3K signaling is common in human cancers, including gliomas, but the precise role of the pathway in glioma biology remains to be determined. Some limited understanding of PI3K signaling in brain cancer come from studies on neural stem/progenitor cells (NSPCs) where signals transmitted via the PI3K pathway cooperate with other intracellular pathways and downstream transcription factors to regulate NSPC proliferation. To investigate the role for the PI3K pathway in glioma initiation and development, we generated a mouse model targeting the inducible expression of a Pik3caH1047A oncogenic mutation and simultaneous deletion of the PI3K negative regulator, Pten, in NSPCs. We show that the expression of a Pik3caH1047A was sufficient to initiate tumorigenesis but that simultaneous loss of Pten, was required for the development of invasive, high-grade glioma. Mutant NSPCs exhibited enhanced neurosphere forming capacity which correlated with increased Wnt signaling. We also show that loss of CREB in Pik3ca-PTEN tumors led to a longer symptom-free survival in mice. Taken together, our findings present a novel mouse model for high-grade glioma with which we demonstrate that the PI3K pathway is important for initiation of tumorigenesis and that disruption of downstream CREB signaling attenuates tumor expansion.

cancer biology↗