Abstract
Glioblastoma multiforme (GBM) is a highly aggressive form of brain cancer with marginal survival rates. GBM extracellular acidosis can profoundly impact its cell fate heterogeneities and progression. However, the molecules and mechanisms that enable GBM tumor cells acid adaptation and consequent cell fate competencies are weakly understood. Since extracellular proton concentrations (pHe) directly intercept the tumor cell plasma membrane, surface lipids must play a crucial role in pHe-dependent tumor cell fate dynamics. Hence, a more detailed insight into the finely tuned pH-dependent modulation of surface lipids is required to generate strategies that can inhibit or surpass tumor cell acid adaptation, thereby forcing the eradication of heterogeneous oncogenic niches, without affecting the normal cells. By using image-based single cell analysis and physicochemical techniques, we made a small-scale survey of the effects of pH ranges (physiological: pHe 7.4, low: 6.2, and very low: 3.4) on LN229 glioblastoma cell line surface remodeling and analyzed the consequent cell fate heterogeneities with relevant molecular targets and behavioral assays. Through this basic study, we uncovered that the extracellular proton concentration (1) modulates surface cholesterol-driven cell fate dynamics and (2) induces 'differential clustering' of surface resident GM3 glycosphingolipid which together coordinates the proliferation, migration, survival, and death reprogramming via distinct effects on the tumor cell biomechanical homeostasis. A novel synergy of anti-GM3 antibody and cyclophilin A inhibitor was found to mimic the very low pHe-mediated GM3 supraclustered conformation that elevated the surface rigidity and mechano-remodeled the tumor cell into a differentiated phenotype which eventually succumbed to the anoikis type of cell death, thereby eradicating the tumorigenic niches. This work presents an initial insight into the physicochemical capacities of extracellular protons in the generation of glioblastoma tumor cell heterogeneities and cell death via the crucial interplay of surface lipids and their conformational changes. Hence, monitoring of proton-cholesterol-GM3 correlations in vivo through diagnostic imaging and in vitro in clinical samples may assist better tumor staging and prognosis. The emerged insights have further led to the translation of a 'pH-dependent mechanisms of oncogenesis control' into the surface targeted anti-GBM therapeutics.
Highlights
Extracellular tumor acidification is a well-recognized hallmark of cancer progression [1,2,3,4,5,6].Consolidated information from several studies has brought forth the knowledge that tumor masses can demonstrate heterogeneous pHe levels ranging from 7.4 to 6.2 units, in general, that can fall as low as 5.5–3.4 units and even below [1,2,3,4,5,6,7,8,9]
We further found that Oct4 (Figure 6C), an often used marker for substrate-independent growth, was diminished nuclearly in pH 6.2 −veCD condition and its total levels dropped in pHe Dynamics in Glioblastoma multiforme (GBM) Therapeutics the high cholesterol physiological and pH 6.2 conditions
We further considered that the cholesterol-independent GM3–self-glycan interactions, as seen in lactonized forms, may pHe Dynamics in GBM Therapeutics exist in low pH conditions, at least to some extent, and may contribute to observed GM3 clustering [17, 66]
Summary
Extracellular tumor acidification (pHe) is a well-recognized hallmark of cancer progression [1,2,3,4,5,6].Consolidated information from several studies has brought forth the knowledge that tumor masses can demonstrate heterogeneous pHe levels ranging from 7.4 to 6.2 units, in general, that can fall as low as 5.5–3.4 units and even below [1,2,3,4,5,6,7,8,9]. Results: By using image-based single cell analysis and physicochemical techniques, we made a small-scale survey of the effects of pH ranges (physiological: pHe 7.4, low: 6.2, and very low: 3.4) on LN229 glioblastoma cell line surface remodeling and analyzed the consequent cell fate heterogeneities with relevant molecular targets and behavioral assays Through this basic study, we uncovered that the extracellular proton concentration [1] modulates surface cholesterol-driven cell fate dynamics and [2] induces ‘differential clustering’ of surface resident GM3 glycosphingolipid which together coordinates the proliferation, migration, survival, and death reprogramming via distinct effects on the tumor cell biomechanical homeostasis. A novel synergy of anti-GM3 antibody and cyclophilin A inhibitor was found to mimic the very low pHe-mediated GM3 supraclustered conformation that elevated the surface rigidity and mechano-remodeled the tumor cell into a differentiated phenotype which eventually succumbed to the anoikis type of cell death, thereby eradicating the tumorigenic niches
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