Biology subjects

Baluszek, S.

Publications and source records attributed to Baluszek, S..

3 recordsLinked to original sources

bioRxiv2024

Integration of spatial transcriptomics with immunofluorescence staining reveals spatial heterogeneity and plasticity of astrocytes in experimental glioblastomas

Astrocytes comprise [~]50% of all brain cells and present distinct morphological, molecular and functional properties in different brain regions. In glioblastoma (GBM), an aggressive primary brain tumour, tumour-associated astrocytes (TAAs) become activated and exhibit different transcriptomic profiles, morphology and functions supporting disease progression. Heterogeneity and specific roles of TAAs within various regions of tumours are poorly known. Advancements of single-cell and spatial transcriptomics allow to profile tumours at unprecedented resolution revealing cell phenotypes, hidden functionalities and spatial architecture in disease-specific context. We combined spatial transcriptomics and multiple immunofluorescent staining to visualize TAAs heterogeneity and location of various subpopulations in intracranial murine gliomas. Using distinct gene expression profiles, we identified subtypes of TAAs with distinct localization and inferred their specialized functionalities. Gene signatures associated with TAAs reflected their reprograming in the tumour microenvironment (TME), revealed their multiple roles and potential contributing factors shaping the local milieu. Using spatial correlation analysis of the spots, we inferred the interactome of Slc1a2 (encoding a glutamate transporter) with the other markers of TAAs based on segregated areas of the tumour. The designer RGD peptide blocking tumour-microglia communications, alters the spatial distribution of TAAs in experimental gliomas providing insights into potential mechanisms. Spatial transcriptomics combined with multiple staining unveils multiple functional phenotypes of TAAs and interactions within TME. It shows their distinct morphology and unveils different roles in various regions of the tumour. We demonstrate the glioma-induced heterogeneity of TAAs and their adaption to the pharmacologically-induced modification of the immunosuppressive TME.

neuroscience↗

bioRxiv2024

Integrin blocking peptide reverses immunosuppression in experimental gliomas and improves anti-PD-1 therapy outcome

Immune checkpoint inhibitors (ICI) presented clinical benefits in many cancer patients but invariably fail in glioblastoma (GBM), the most common and deadly primary brain tumor. Lack of ICI efficacy in GBM is attributed to the accumulation of immunosuppressive myeloid cells that create the "cold" tumor microenvironment (TME) impeding infiltration and activation of effector T cells. We developed a designer RGD peptide that hindered glioma-instigated, integrin-mediated pro-tumoral reprogramming of myeloid cells and blocked microglia-dependent invasion of human and mouse glioma cells in co-cultures in vitro. Intratumorally-delivered RGD alone did not reduce glioma growth in syngeneic mice but prevented the emergence of immunosuppressive myeloid cells and led to peritumoral blood vessels normalization. Furthermore, combining RGD with immunotherapy using PD-1 blockade reduced tumor growth, led to upsurge of proliferating, interferon-{gamma} producing CD8+T cells and depleted regulatory T cells. Transcriptomic profiles of myeloid cells were altered by the combined treatment, consistently with the restored "hot" inflammatory TME and boosted immunotherapy responses. RGD modified the phenotypes of myeloid cells in human gliomas in nude mice. Thus, combining the integrin blockade with ICI reinvigorates antitumor immunity and paves the way to improve immunotherapy outcomes in GBM.

cancer biology↗

bioRxiv2022

Transcriptomic classification of pituitary neuroendocrine tumors causing acromegaly

Acromegaly results from growth hormone hypersecretion caused by somatotroph pituitary neuroendocrine tumor (PitNET). Our molecular profiling revealed that acromegaly-causing tumors form three distinct transcriptomic subgroups with different histological/clinical features. Transcriptomic subtypes of somatotroph tumors differ in the expression levels of numerous genes including those involved in hormone secretion and genes with known prognostic value. They can be distinguished by determining the expression of marker genes. Transcriptomic group 1 includes [~]20% of acromegaly patients with GNAS mutations-negative, mainly densely granulated tumors with NR5A1 (SF-1) and GIPR co-expression. Group 2 tumors are the most common (46%) and include mainly GNAS-mutated, densely granulated somatotroph and mixed PitNETs. They have significantly smaller size and express favorable prognosis-related genes. Group 3 includes predominantly sparsely granulated somatotroph PitNETs with low GNAS mutations frequency causing [~]35% of acromegaly cases. Ghrelin signaling is implied in their pathogenic mechanism, they have unfavorable gene expression profile, and invasive growth rate. Since a subgroup of somatotroph tumors have high NR5A1 expression, using SF-1 as classification marker specific to gonadotroph PitNETs could be reconsidered.

cancer biology↗