Phospholipid Scramblases TMEM16F and Xkr8 regulate distinct features of Phosphatidylserine (PS) externalization and immune regulation in the tumor microenvironment to regulate tumor growth DOI Creative Commons
Varsha Gadiyar,

Rachael Pulica,

Ahmed Aquib

и другие.

bioRxiv (Cold Spring Harbor Laboratory), Год журнала: 2025, Номер unknown

Опубликована: Апрель 18, 2025

The phospholipid scramblases Xkr8 and TMEM16F externalize phosphatidylserine (PS) on cells by distinct molecular mechanisms. Xkr8, a caspase-activated scramblase, is activated caspase-mediated proteolytic cleavage, in synergy with inactivation of P4-type ATP-dependent flippases, results the irreversible externalization PS dying an "eat-me" signal for efferocytosis. In contrast, calcium scramblase that reversibly externalizes viable via transient increase intracellular or growth factor stimulated cells. By contrast to abovementioned homeostatic mechanisms under physiological conditions, becomes constitutively externalized tumor microenvironment (TME) many solid types complex mechanistic, posited both high apoptotic indexes tumors, but also prolonged oncogenic metabolic stresses occur TME. Such chronic persistent TME has been linked host immune evasion tonic interactions inhibitory receptors such as TAM (Tyro3, Axl, Mertk) TIM (T cell/transmembrane, immunoglobulin, mucin) family receptors. Here, effort better understand contributions vs live cell PS-externalization respect tumorigenesis evasion, we employed E0771 luminal B breast cancer orthotopic vivo model genetically ablated using CRISPR/Cas9. While neither knockout nor showed defects intrinsic properties related growth, sphere formation, migration, signaling, knockouts suppressed tumorigenicity immune-competent mice, not NOD/SCID RAG deficient immune-deficient strains. Mechanistically, at biological level, macrophage-mediated efferocytosis, ER stress/calcium-induced externalization. Our data support emerging idea immune-oncology immunotherapy constitutive externalization, mediated activation cells, can thereby linking combination apoptosis/efferocytosis stress involving dysregulation contribute PS-mediated escape progression.

Язык: Английский

Phospholipid Scramblases TMEM16F and Xkr8 regulate distinct features of Phosphatidylserine (PS) externalization and immune regulation in the tumor microenvironment to regulate tumor growth DOI Creative Commons
Varsha Gadiyar,

Rachael Pulica,

Ahmed Aquib

и другие.

bioRxiv (Cold Spring Harbor Laboratory), Год журнала: 2025, Номер unknown

Опубликована: Апрель 18, 2025

The phospholipid scramblases Xkr8 and TMEM16F externalize phosphatidylserine (PS) on cells by distinct molecular mechanisms. Xkr8, a caspase-activated scramblase, is activated caspase-mediated proteolytic cleavage, in synergy with inactivation of P4-type ATP-dependent flippases, results the irreversible externalization PS dying an "eat-me" signal for efferocytosis. In contrast, calcium scramblase that reversibly externalizes viable via transient increase intracellular or growth factor stimulated cells. By contrast to abovementioned homeostatic mechanisms under physiological conditions, becomes constitutively externalized tumor microenvironment (TME) many solid types complex mechanistic, posited both high apoptotic indexes tumors, but also prolonged oncogenic metabolic stresses occur TME. Such chronic persistent TME has been linked host immune evasion tonic interactions inhibitory receptors such as TAM (Tyro3, Axl, Mertk) TIM (T cell/transmembrane, immunoglobulin, mucin) family receptors. Here, effort better understand contributions vs live cell PS-externalization respect tumorigenesis evasion, we employed E0771 luminal B breast cancer orthotopic vivo model genetically ablated using CRISPR/Cas9. While neither knockout nor showed defects intrinsic properties related growth, sphere formation, migration, signaling, knockouts suppressed tumorigenicity immune-competent mice, not NOD/SCID RAG deficient immune-deficient strains. Mechanistically, at biological level, macrophage-mediated efferocytosis, ER stress/calcium-induced externalization. Our data support emerging idea immune-oncology immunotherapy constitutive externalization, mediated activation cells, can thereby linking combination apoptosis/efferocytosis stress involving dysregulation contribute PS-mediated escape progression.

Язык: Английский

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