Entosis: Mechanisms, Molecular Regulators, and Tumor Impact

Cells sometimes engulf their neighbors in a process called entosis, distinct from other forms of cell death. Initially observed in cancer cells, this phenomenon has since been linked to various physiological and pathological conditions. Unlike apoptosis or necrosis, entosis involves live-cell internalization, with significant implications for tumor progression and suppression.

Understanding entosis is crucial because it influences cancer development, metastasis, and treatment responses. Researchers continue to uncover the molecular mechanisms and regulatory factors driving this process.

Induction And Internalization Steps

Entosis begins when a cell detaches from the extracellular matrix, a condition known as matrix detachment. Some cells respond by initiating survival mechanisms, while others actively invade neighboring cells. Epithelial cells undergoing detachment experience cytoskeletal rearrangements that promote their engulfment by adjacent adherent cells. This process is particularly evident in cancerous environments, where altered adhesion dynamics and mechanical forces increase entotic events.

Once detached, the invading cell relies on actomyosin contractility for internalization. Rho-associated kinase (ROCK) signaling generates contractile forces that facilitate penetration into the host cell. This force-dependent mechanism sets entosis apart from passive engulfment processes like phagocytosis. The host cell undergoes cytoskeletal remodeling to accommodate the invading cell, forming a vacuole-like structure. Live-cell imaging has shown that internalized cells remain viable for extended periods before either degrading or escaping.

Cadherin-mediated adhesion also plays a role in entosis. E-cadherin stabilizes interactions between the invading and host cells, and its loss can disrupt the process. Additionally, lysosomal activity within the host cell determines the fate of the internalized cell, with some undergoing degradation while others escape and reintegrate into surrounding tissue.

Molecular Regulators

Entosis is regulated by signaling pathways that control cell adhesion, cytoskeletal dynamics, and intracellular trafficking. A key player is RhoA, a small GTPase that directs actomyosin contractility in the invading cell. Activation of RhoA, mediated through guanine nucleotide exchange factors (GEFs) like LARG and p115RhoGEF, enhances contractile force generation. Inhibiting RhoA or its downstream effector, ROCK, significantly reduces entotic events, highlighting its role in force generation.

Cadherin-mediated adhesion is also crucial. E-cadherin, essential for adherens junctions, tethers the invading cell to the host. Loss of E-cadherin, often seen in invasive cancers, reduces entotic efficiency, while overexpression strengthens adhesion and increases engulfment. β-catenin, a binding partner of E-cadherin, links cadherin complexes to the actin cytoskeleton, influencing the structural integrity of entotic vacuoles.

Lysosomal activity within the host cell determines whether the internalized cell is degraded or escapes. The autophagy-related protein LC3 localizes around entotic vacuoles, suggesting a role for autophagic machinery in processing engulfed cells. However, unlike conventional autophagy, entotic degradation does not always require ULK1. Instead, lysosomal hydrolases such as cathepsin B and cathepsin D contribute to the breakdown of internalized cells. Inhibiting lysosomal enzymes prolongs the survival of entotic cells, underscoring the role of intracellular digestion in determining cell fate.

Relationship To Other Cell Death Pathways

Entosis differs from apoptosis, necrosis, and autophagy in both mechanism and outcome. Unlike apoptosis, which involves caspase activation and controlled dismantling, entosis features active cellular invasion, often without immediate death. Apoptotic cells exhibit membrane blebbing and nuclear condensation, whereas entotic cells remain viable within the host before eventual degradation or release. This distinction is relevant in tumors, where apoptotic resistance is a hallmark of cancer progression, while entosis can act as both a survival strategy and a mechanism of cell elimination.

Necrosis, characterized by uncontrolled membrane rupture and inflammation, contrasts with entosis, which is a non-lytic process. Necrotic death results from external stressors like hypoxia or metabolic stress, leading to inflammatory responses. In contrast, entotic cells remain enclosed within vacuoles, preventing inflammatory spillover. However, if lysosomal degradation fails, entotic cells may undergo necrotic-like rupture within the host. This variability suggests entosis shares mechanistic overlaps with multiple pathways.

Autophagy, a catabolic process recycling intracellular components through lysosomal degradation, shares similarities with entosis in vacuolar processing. The presence of LC3 and lysosomal hydrolases in entotic vacuoles suggests partial convergence with autophagic pathways, yet entosis involves whole-cell engulfment rather than organelle turnover. While autophagy often promotes survival during nutrient deprivation, entosis can result in either survival or death depending on context. The extent to which autophagic signaling influences entotic cell fate remains under investigation.

Significance In Tumor Biology

Entosis plays a complex role in tumor biology, with evidence supporting both tumor-suppressive and tumor-promoting effects. In some cases, entosis eliminates malignant cells by facilitating their degradation within host cells, reducing tumor burden. Histological analyses of breast and pancreatic tumors have identified entotic structures, suggesting this process occurs in vivo and may help control abnormal cell populations.

Conversely, entosis can also support tumor progression by providing a survival advantage to internalized cells. Under metabolic stress, some entotic cells evade degradation and emerge with increased resistance to apoptosis and chemotherapy. This phenomenon is observed in aggressive cancers, where entotic cells display greater clonogenic potential after escaping host cells. Additionally, entotic engulfment can lead to genetic instability. Studies show entotic events can induce aneuploidy, a condition of abnormal chromosome numbers frequently associated with malignancy. Cells that survive entosis with altered genomic content may acquire oncogenic properties, fueling tumor evolution and heterogeneity.