Biology subjects

Sarkisian, M.

Publications and source records attributed to Sarkisian, M..

3 recordsLinked to original sources

bioRxiv2025

Treatment Resistant Persister Cells Exploit Macrophage Lipid Metabolism to Sustain Glioblastoma Growth

Glioblastoma (GBM) displays pronounced intratumoral heterogeneity, posing significant challenges to understanding its biology and developing effective treatments. Using spatial multi-omics, in vivo functional assays, and systems-level analysis, we delineate the diverse metabolic and immune architecture of GBM. We identify a lipid-dependent lineage of treatment-resistant persister cells (TRPCs) that engage tumor-associated macrophages (TAMs) in a spatially organized, metabolically specialized crosstalk. TRPCs co-opt CCR2, CSF1R, CD163+ TAMs for lipid scavenging and acquisition, promoting a pro-tumorigenic and immunosuppressive microenvironment. This cooperative axis is critically dependent on lipid chaperones like FABPs, whose targeting disrupts TAM recruitment, remodels immune composition, and suppresses tumor growth. Retrospective clinical analyses reveal that elevated TRPC-associated transcriptome may serve as stratification criteria to identify patients benefiting from lipid-lowering therapies like statins. Our findings uncover a targetable immunometabolic circuit between TRPCs and TAMs and support the development of precision therapies that disrupt lipid-fueled tumor-immune cooperation in GBM. In briefTreatment-resistant persister cells (TRPCs) in glioblastoma spatially engage TAMs to facilitate lipid transfer, thereby sustaining tumor growth and promoting immune evasion. Targeting this TRPC-TAM metabolic axis reprograms the immunosuppressive microenvironment and improves therapeutic outcomes, revealing a clinically actionable metabolic vulnerability with potential for precision immune-metabolic interventions in GBM. HighlightsO_LIGBM exhibits spatially resolved heterogeneity revealing correlative metabolic and immune micro-niches C_LIO_LITRPC lineage promotes a pro-tumorigenic and immunosuppressive microenvironment by recruiting lipid-specialized TAMs C_LIO_LITRPC lineage hijacks TAMs for metabolic support via stimulating lipid transfer and acquisition C_LIO_LIDisruption of the TRPC-TAM lipid axis, including through FABP3 targeting, reprograms the immune landscape, limits TAM recruitment, and impairs tumor progression C_LIO_LITRPC lineage and associated micro-niche transcriptomic profiles can serve as criteria for patient stratification and identification of responders to lipid-lowering therapies, such as statins C_LI

cancer biology↗

bioRxiv2024

KR158 spheres harboring slow-cycling cells recapitulate GBM features in an immunocompetent system

Glioblastoma (GBM) poses a significant challenge in clinical oncology due to its aggressive nature, heterogeneity, and resistance to therapies. Cancer stem cells (CSCs) play a critical role in GBM, particularly in treatment-resistance and tumor relapse, emphasizing the need to comprehend the mechanisms regulating these cells. Also, their multifaceted contributions to the tumor-microenvironment (TME) underline their significance, driven by their unique properties. This study aimed to characterize glioblastoma stem cells (GSCs), specifically slow-cycling cells (SCCs), in an immunocompetent murine GBM model to explore their similarities with their human counterparts. Using the KR158 mouse model, we confirmed that SCCs isolated from this model exhibited key traits and functional properties akin to human SCCs. KR158 murine SCCs, expanded in the gliomasphere assay, demonstrated sphere forming ability, self-renewing capacity, positive tumorigenicity, enhanced stemness and resistance to chemotherapy. Together, our findings validate the KR158 murine model as a framework to investigate GSCs and SCCs in GBM-pathology, and explore specifically the SCC-immune system communications, understand their role in disease progression, and evaluate the effect of therapeutic strategies targeting these specific connections.

cancer biology↗

bioRxiv2023

Aurora Kinase A Inhibition plus Tumor Treating Fields Suppress Glioma Cell Proliferation in a Cilium-Independent Manner

Tumor Treating Fields (TTFields) have been shown to extend the survival of glioblastoma (GBM) patients. TTFields interfere with a broad range of cellular processes which may contribute to their efficacy. Among these, TTFields disrupt primary cilia stability on GBM cells. Here we asked if concomitant treatment of TTFields with other agents that interfere with GBM ciliogenesis can further suppress GBM cell proliferation in vitro. Aurora Kinase A (AURKA) promotes both cilia disassembly and GBM growth in vitro and in xenograft models. Inhibitors of AURKA such as Alisertib have been previously demonstrated to inhibit cilia disassembly and increase the frequency of cilia in various cell types. However, here we show that physiological concentrations of Alisertib treatment significantly reduced GBM cilia frequency in gliomaspheres across multiple patient derived cell lines, and in patient biopsies treated ex vivo with Alisertib. This activity of Alisertib seems to be glioma cell specific as it did not reduce neuronal or glial cilia frequencies in mixed primary cell cultures from mouse forebrain. Furthermore, Alisertib depletion of glioma cilia appears specific to AURKA inhibition, as a potent AURKB inhibitor, AZD1152, had no effect on GBM ciliary frequency. Treatment of two different GBM patient-derived cell lines with TTFields and Alisertib resulted in a significant reduction in cell proliferation compared to either treatment alone. However, this effect was not cilia-dependent as the combined treatment reduced proliferation in cilia-depleted cell lines lacking, ARL13b, or U87MG cells which are naturally devoid of ARL13B+ cilia. This result is not surprising given the wide range of pathways regulated by AURKA in addition to cilia. Nonetheless, Alisertib-mediated effects on glioma cilia may be a useful biomarker of drug efficacy within tumor tissue. Considering Alisertib has been shown to cross the blood brain barrier and inhibit intracranial growth of xenografted tumor models, our data warrant future studies to explore whether concomitant Alisertib and TTFields exposure prolongs survival of brain tumor-bearing animals in vivo.

cancer biology↗