Midbody Remnants as Signaling Centers in Cell Fate Determination and Tumorigenesis

Abstract

During final cell division, the cleaved midbody is either released or asymmetrically retained as a midbody remnant (MBR). MBRs play critical roles in cell communication, signal transduction, and translation regulation, influencing cellular fate. Here, we synthesize their functions as RNA-processing granules, polarity regulators, and signaling platforms, emphasizing their role in primary cilia formation. In polarized epithelial cells, the MBR moves along the apical surface to the centrosome, delivering membrane components to permit ciliogenesis. In ductal carcinoma cells, MBR-localized Shc1-binding protein (SHCBP1) interacts with TBC1 domain family member 30 (TBC1D30 to antagonize Ras-related protein Rab-8 (Rab8) GTPase activity, blocking MBR-centrosome proximity and silencing ciliogenesis. Beyond ciliary regulation, MBRs integrate Wnt, PDGF, TGF-β, and genomic stability networks, acting as dynamic signaling hubs during cancer development. Regarding therapeutic strategies targeting MBRs, High SHCBP1 expression correlates with ciliary loss and poor prognosis in breast, pancreatic, and cholangiocarcinoma. Targeting the SHCBP1/Rab8 axis to restore ciliogenesis by reestablishing MBR-centrosome proximity offers a potential therapeutic strategy. In addition, secreted MBRs are enriched in signaling components and transcripts, serving as intercellular carriers of oncogenic cargoes and promising liquid biopsy biomarkers. In summary, by tracing MBRs from their postmitotic origin to their pathogenic roles, we highlight vulnerabilities within MBR regulatory networks and provide novel insights for cancer therapeutics.

Keywords

midbody remnant cytokinesis primary cilium cancer cell signaling

Introduction

Midbody remnants (MBRs) are derived from the cleavage of midbodies, the transient structures that form during late cytokinesis to facilitate the physical separation of daughter cells (Kuriyama et al., 2025). Once considered little more than cellular debris, MBRs are now recognized as complex organelles enriched with proteins and RNAs that play active roles in cellular signaling and organization (Kuriyama et al., 2025; Park et al., 2023; Rai et al., 2021). Recent studies have underscored the critical role of MBRs in facilitating intercellular communication between daughter cells, thereby influencing their differentiation (Ettinger et al., 2011). The functional repertoire of MBRs extends far beyond structural contributions. They are implicated in a diverse array of fundamental processes, including the regulation of stem cell maintenance and tissue development (McNeely and Dwyer, 2020, 2021). Furthermore, their dysregulation has been linked to oncogenesis, highlighting their potential as biomarkers and therapeutic targets in certain cancers (Peterman et al., 2019). The recent application of advanced imaging and molecular tools has been instrumental in elucidating the dynamic nature and multifaceted functions of MBRs, opening new avenues for therapeutic intervention (Kuriyama et al., 2025).

While the general biology and translational potential of MBRs have been excellently synthesized in recent broad reviews (Kuriyama et al., 2025), the present review provides a distinct focus on how oncogene in MBRs impedes MBR-centrosome proximity to silent primary cilia, thereby promoting tumor development. We elucidate novel MBR-related signaling pathways implicated in cancer, including Rab8, Wnt, TGF-β, and genomic stability signaling. Furthermore, we elaborate in detail on targeting the SHCBP1-RAB8 axis to restore ciliogenesis in an MBR-dependent manner for cancer treatment and discuss the potential of developing strategies to clear extracellularly released MBRs, as well as the use of MBR-based liquid biopsy biomarkers for colon cancer diagnosis and monitoring.

Structural Characteristics of MBRs

The midbody is a transient yet essential structure that forms during cytokinesis, acting as the final physical bridge between dividing daughter cells. It consists of three major regions: the central midbody ring, flanking midbody arms, and the midbody core (Capalbo et al., 2019). Following cytokinesis, the midbody undergoes transformation into the MBR. Unlike the midbody, which is primarily composed of microtubules and associated proteins that facilitate daughter cell separation, the MBR retains a distinct set of proteins and structural features, enabling specialized post-mitotic functions (Ettinger et al., 2011). Understanding the structural organization of MBRs is therefore critical for elucidating their biological roles and their potential involvement in disease mechanisms (Kuriyama et al., 2025; Peterman et al., 2019).

Formation and degradation of MBRs

MBRs formation initiates during the late stages of cytokinesis. As a mother cell divides, the midbody is abscised and undergoes molecular transformations to become an MBR. Subsequently, MBRs are either released into the extracellular space or asymmetrically retained on the surface of one daughter cell, where they become attached and can be internalized (Fig. 1). Once internalized, MBRs adopt several fates that significantly influence cellular physiology and are eventually degraded via autophagic pathways (Chen et al., 2013; Casares-Arias et al., 2020).

FIG. 1.

Model for the generation of distinct midbody remnant (MBR). MBR is produced when the midbody is cleaved during cytokinesis. Variations in the local concentration of the ESCRT-III machinery lead to either symmetric or asymmetrical abscission of the midbody. Subsequently, MBR is either kept attached to one daughter cell, where it remains associated with its surface via factors such as Ca²⁺/Mg²⁺, BST2/tetherin, or CHMP4C (right), or is released into the extracellular space (left). Immunohistological images of MBR (anti-MKLP1, green) and actin filaments network (purple) of HK-2 cells show the asymmetrical and released MBR (created with BioRender.com).

The transition from midbodies to MBRs involves the recruitment of specific protein complex that promote the stabilization of the remnant structure. These include the following main categories: (1) Endosomal sorting complex required for transport (ESCRT), particularly midbody-localized ESCRT-III; (2) mitotic regulators, such as Aurora B kinase, HIPK2, MKLP1, and PLK1; (3) cytoskeletal dynamics, especially those involving microtubules and actin filaments. The detailed discussion of the molecular mechanisms regulating MBR formation is referred to in the comprehensive review by Kuriyama et al. (Kuriyama et al., 2025).

Post-cell division, the MBR is attached to the surface of one daughter cell, where it is stabilized by factors such as Ca²⁺/Mg²⁺, BST2/tetherin, or CHMP4C (Carlton et al., 2012; Casares-Arias et al., 2020; Presle et al., 2021). Subsequently, membrane-bound MBRs are recognized by engulfing cells via complexes including phosphatidylserine bridging proteins, integrins (αVβ3), and actin polymerization. Once internalized, the MBRs now exist as double-membrane structures (Chai et al., 2012; Crowell et al., 2013, 2014). They can adopt several fates that significantly influence cell polarity, establishing epithelial-mesenchymal transition (EMT) reprogramming and especially involvement in promotion of primary cilia formation and cancer development and progression (Labat-de-Hoz et al., 2021; Shafiq et al., 2026; Shi et al., 2024; Fig. 2). Ultimately, characterizing the protein networks that orchestrate MBRs assembly and disassembly is important for unraveling the molecular mechanisms governing their lifecycle.

FIG. 2.

The role of MBRs in physiological processes. Following cytokinesis, MBR is attached on cell surface through factors such as Ca²⁺/Mg²⁺ and BST2. Subsequently, the membrane-bound MBR is recognized by engulfing cells via a PS/integrin complex and actin polymerization. Once internalized, the MBR is fated for either functional roles or degradation. Retained MBRs can regulate several key processes, including SHCBP1-mediated primary ciliogenesis and EMT reprogramming involving Wnt and PDGF signaling, and serve as liquid biopsy diagnostics through the detection of transcripts, lncRNAs, and fusion genes. EMT, epithelial-mesenchymal transition; MBR, midbody remnant (created with BioRender.com).

Protein composition of MBRs

MBRs are protein-rich organelles. Proteomic analyses have identified ∼1,000 proteins enriched within them, many of which play pivotal roles in cell division and signaling (Kuriyama et al., 2025). Numerous studies have performed the proteomic analysis of MBRs and compared them with extracellular vesicles (EVs) and exosomes. These proteomic profiling of MBR mainly include components of the centralspindlin complex (e.g., RACGAP1 and KIF23/MKLP1), microtubule-bundling proteins (e.g., cofilin-1), regulators of cancer pathways (including MAPK and Ras signaling), and transmembrane proteoglycans (such as syndecan-4, ALIX, and syntenin), as well as RNA/stress granule proteins and mitochondrial proteins (Addi et al., 2020; Advedissian et al., 2024; Rai et al., 2021).

Recent studies demonstrate that MBRs possess unique protein signatures distinct from those of precursor structures. A proteomic analysis of MBRs released from Madin-Darby canine kidney (MDCK) cells found that oncogenic H-Ras reprograms the MDCK cell-derived MBR proteome following EMT. Proteomic profiling revealed that MBRs are enriched with factors of the centralspindlin complex (KIF23.1, KIF4A, INCENP, CEP55, PLK1) and further include components involved in mitochondrial networks, cytokinesis, microtubule movement, and intercellular connections. In contrast, MBRs from H-Ras-transformed cells are enriched for EMT-related pathways, including signaling receptor binding, regulation of cell differentiation, and Wnt, VEGF, and PDGF signaling. These findings reveal the dynamic alteration of the proteomic architecture of MBRs following oncogenic H-Ras-induced EMT during cell transformation and delineate the role of MBRs in driving cancer initiation, progression, and metastasis (Shafiq et al., 2026). Together, these findings highlight the need for time-course proteomics to track protein changes during cell abscission in order to fully elucidate MBR biology. Comparative proteomic analyses are advancing the characterization of MBR subtypes, enhancing our understanding of their compositions, biological functions, and roles in intercellular communication.

The Role of MBRs in Cellular Physiological Processes

The midbody acts as a signaling platform that ensures accurate chromosome segregation and successful abscission, after which the resulting MBR functions as a postmitotic signaling hub (Rai et al., 2021). Differentiating cells and normal dividing cells do not accumulate MBRs, but stem cells and cancer cells accumulate MBRs by evading autophagosome encapsulation. This MBR enrichment contributes to diverse physiological processes, including enhanced reprogramming into induced pluripotent stem cells, increased in vitro tumorigenicity of cancer cells, and promotion of cellular transformation and invasion (Kuo et al., 2011; Chen et al., 2013; Rai et al., 2021).

MBRs as an RNA granule in cytokinesis regulation

A critical discovery is that MBRs serve as assembly sites for RNA and ribonucleoprotein (RNP) complexes, with assembly of specific mRNAs, such as those encoding MKLP1, Jun, and KIF4. MBRs have also been identified as sites of active translation, containing RNP complexes that can influence protein synthesis during the cell cycle. This localized translation can impact the production of proteins that are important for various cellular processes, including those involved in cell growth and division (Kuriyama et al., 2025; Park et al., 2023; Patel et al., 2024).

Beyond their intracellular functions, MBRs also serve as vehicles for intercellular RNA and protein communication during cell division. The RNA and proteins carried by MBRs can act as signal molecules to transmit information between cells, thereby coordinating the behavior of cell populations. For instance, MBR functions as membrane-bound signaling structures termed “MBsomes,” delivering components of integrin- and EGFR-dependent pathways to regulate cancer cells proliferation and invasion (Peterman et al., 2019). Furthermore, RNA and fusion gene compositions within MBRs may impact EVs to regulate cancer progression. These RNA/fusion genes hold potential as candidate biomarkers for cancer detection (Suwakulsiri et al., 2024b). Therefore, it is reasonable to speculate that MBRs function as carrier within the tumor microenvironment to deliver specific-oncogenic mRNAs and proteins to recipient cells, regulating proliferation and invasion. However, more direct evidence is needed to identify the types of oncogenic mRNAs involved, elucidate the detailed mechanisms of mRNA translation within MBRs, and clarify how these mRNAs regulate tumor progression.

MBRs regulate primary cilia formation

Primary cilia are small, antenna-like structures protruding from the surface of most eukaryotic cells, playing a critical role in diverse pathophysiological processes (Labat-de-Hoz et al., 2021). Recent research has revealed that MBRs are involved in the formation of primary cilia. In polarized epithelial cells, MBR is accepted by one of the daughter cells and is initially located around the apical surface periphery. Then, this residual body moves along the apical surface. Once it is close to the centrosome located at the center of the apical surface, it can initiate the formation of primary cilium (Bernabé-Rubio et al., 2016; Ott, 2016). However, the detailed mechanism of MBR-centrosome proximity remains under investigation.

We recently reported that SHCBP1-controlled Rab GTPase represents a key molecular mechanism underlying MRR-regulated primary cilia formation in ductal carcinoma. Using clinical tumor specimen, genetic knockout mouse, and single-cell sequencing, we found that primary cilia are widely absent in ductal carcinomas, including breast, pancreatic, and cholangiocarcinoma. SHCBP1 localizes to MBRs, and its deficiency restores ciliogenesis in unciliated ductal carcinoma cells by promoting the proximity between the MBR and centrosome. Through time-lapse analyses, GST pulldown, and GDP-locked and GTP-locked Rab8 mutagenesis, we demonstrated that Rab8^GTP is located in MBR, and SHCBP1 interacts with GTP hydrolysis–activating protein TBC1D30 to antagonize Rab8 GTPase, leading to cilia loss. SHCBP1 ablation increases Rab8 GTPase activity, positioning Rab8^GTP within the MBRs and reestablishing MBR-centrosome proximity to induce ciliogenesis. More importantly, using MMTV-PyMT-driven spontaneous breast tumor model and patient-derived xenograft (PDX) model, we showed that induction of MBR-centrosome proximity through SHCBP1 deficiency reactivates ciliogenesis, offering unique opportunities for the treatment of unciliated ductal carcinomas. Our findings provide a different perspective on the biological functions and mechanisms of MBR in regulating tumor ciliogenesis, presenting an exceptional opportunity to treat ductal carcinomas (Shi et al., 2024; Fig. 3).

FIG. 3.

MBR-mediated ciliogenesis in ductal epithelial and cancer cells. In normal epithelial cells, MBR traffics along the cell surface to the centrosome and license primary ciliogenesis. In epithelial cancer cells, MBRs fail to reach the centrosome, leading to loss of primary cilia. This defect is driven by SHCBP1. In nonciliated ductal carcinoma cells, SHCBP1 interacted with the GTPase-activating protein (GAP), TBC1D30, to antagonize Rab8 GTPase activity, blocking MBR–centrosome proximity and subsequently silencing ciliogenesis. Following SHCBP1 deficiency, Rab8 GTPase is increased, resulting in Rab^GTP accumulation in MBRs, facilitating MBR–centrosome proximity and triggering ciliogenesis (created with BioRender.com).

Nevertheless, the detailed molecular mechanisms through which MBRs regulate ciliogenesis require further investigation. Recent studies indicate that MBRs are proposed to deliver specific membrane-associated factors and signaling molecules required for ciliary membrane assembly, thereby regulating ciliogenesis (Bernabé-Rubio et al., 2021). It is therefore plausible that MBRs function as carriers to deliver specific proteins, mRNAs, or membrane components to the centrosome to support primary cilia formation. However, the identity and function of these molecular cargoes require further investigation.

Impact of MBRs on cellular polarity

MBRs are increasingly recognized as key regulators of cellular polarity, which is contributes to proper tissue architecture and function (Labat-de-Hoz et al., 2021). The positioning of MBRs can influence the establishment and maintenance of cell polarity by localizing to specific regions of the daughter cells, facilitating the asymmetrical distribution of cellular components and fate determinants (Bernabé-Rubio et al., 2016; Ettinger et al., 2011; Mangan et al., 2016). Furthermore, MBRs can coordinate the delivery of factors such as RhoA, Aurora A, and Rab proteins, which contribute to the formation of polarized cellular structures (Klinkert et al., 2016; Mangan et al., 2016; Pollarolo et al., 2011).

Another important regulatory function of MBRs on cellular polarity is largely dependent on primary cilia. Primary cilia have been established as organelles that regulate cellular polarity. For example, in directed cell, CXCL12 targets the primary cilium to modulate the cAMP/cGMP ratio, thereby regulating cell polarity during migration (Atkins et al., 2023). In the inner ear, the arrangement of primary cilia confers polarity within the plane of the epithelium of each sensory organ (Jones and Chen, 2008). Bernabé-Rubio and colleagues reported the important role of MBRs in primary ciliogenesis in polarized epithelial cells. The MBR moves along the apical surface and, once proximal to the centrosome at the center of the apical surface, enables cilium formation in polarized epithelial cells (Bernabé-Rubio et al., 2016). It is therefore plausible that MBRs direct primary cilia formation at the apical surface to regulate cell polarity. Interestingly, epithelial cancer cells often lose their polarity, accompanied by the loss of primary cilia (Buckley and St Johnston, 2022). We reported that abnormal disruption of MBR-centrosome proximity is a leading cause of cilia loss in epithelial cancer cells (Shi et al., 2024). These results further provide evidence that MBRs may impact cell polarity by regulating ciliogenesis.

Another important molecule in MBR-regulated cell polarity is Rab8. We found that Rab8^GTP localizes to MBRs and confers ciliogenesis by reestablishing MBR-centrosome proximity (Shi et al., 2024). Rab8 is a crucial regulator of cell polarity, as it balances endocytosis and exocytosis to influence polarization. Removal of Rab8 from the cell surface restricts its activity during protrusion formation, thereby facilitating dynamic adjustment of the polarity axis (Vidal-Quadras et al., 2017). Therefore, MBR regulation of Rab8 GTPase activity to influence ciliogenesis is also important for cell polarity.

MBRs function as a signaling hub

MBRs function as dynamic signaling hubs that actively coordinate cellular processes, including growth, differentiation, and response to stimuli. They facilitate this function either by acting as platforms for the assembly of signaling complexes or through direct interaction with pathway components. Many MBRs-signaling pathways have been identified in previous reports, such as EGFR and integrin signaling, as well as tetherin/BST2 anchors regulatory pathways (Kuriyama et al., 2025). Several emerging signaling pathways are also implicated in MBR function: (1)

Rab signaling: We and others have demonstrated that MBRs regulate Rab signaling. Both Rab^GDP and RAB^GTP localize to MBRs, with Rab^GTP playing a key role in modulating the proximity between MBRs and the centrosome. Rab^GTP can be delivered from MBRs into primary cilia to regulate ciliogenesis (Bernabé-Rubio et al., 2021; Shi et al., 2024).

(2)

Wnt signaling: The non-canonical Wnt signaling pathway is essential for the midbody abscission and formation of MBRs. The Wnt receptor, Dishevelled 2 (Dvl2), forms complex with ESCRT-III subunit, CHMP4B, at the midbody. Wnt5a signaling stabilizes microtubules and correctly positions the ESCRT-III complex to ensure successful abscission and MBR formation (Fumoto et al., 2012). Although direct evidence for Wnt signaling components within MBRs is lacking, proteomic profiling of MBRs has demonstrated enrichment of Wnt signaling network proteins (Shafiq et al., 2026).

(3)

TGF-β signaling: The midbody functions as an active organelle in the TGF-β/Smad pathway. During fibroblast-to-myofibroblast transition, TGF-β1 stimulation enhances midbody formation, and the structure itself contains TGF-β receptors. Disruption of midbody formation impairs Smad signaling and reduces expression of differentiation markers such as α-SMA, highlighting its necessity for this cellular transformation (Jung et al., 2022). However, direct evidence of MBRs regulating TGF-β signaling requires further investigation.

(4)

Genomic stability signaling networks: MBRs also integrate signaling networks crucial for genomic stability. The tumor suppressor BRCA2 localizes to the midbody, where it facilitates the recruitment of ESCRT-associated proteins Alix and Tsg101. Cancer-associated mutations that disrupt these interactions lead to cytokinetic failure, revealing potential relationships between MBRs and associated signaling network (Mondal et al., 2012).

In addition, proteomic analyses of MBRs have identified various other signaling networks associated with MBRs, including EMT, PDGF, MAPK, and Ras signaling (Rai et al., 2021; Shafiq et al., 2026). In summary, growing evidence supports the role of MBRs as multifunctional regulator in signal transduction, though further research is needed to fully elucidate their detailed regulatory mechanisms and biological implications.

The Role of MBRs in Diseases and as Potential Therapeutic Targets

Once considered cellular debris, MBRs are now implicated in the pathogenesis of some human diseases, particularly cancer and neurodegenerative disorders. Their multifunctional nature positions them as critical players in disease progression and promising targets for novel therapeutic strategies (Kuriyama et al., 2025).

MBRs regulate tumor growth and progression in multiple mechanisms

MBRs have been established as contributors to oncogenesis through a multitude of interconnected mechanisms. By carrying signaling proteins and nucleic acids, they can transfer oncogenic factors that activate proliferation, survival, and angiogenic pathways in recipient cells, thereby driving tumor growth (Choi et al., 2017). Recent studies have uncovered novel roles for MBRs in tumor development and progression, which can be broadly categorized into intracellular and extracellular mechanisms.

An important aspect is their role in primary cilium formation to regulate tumors. Primary cilia have been widely studied as mediators of tumorigenicity and as targets in cancer therapies (Han et al., 2009). Ductal epithelial tissues are widely ciliated, including the pancreatic duct, mammary lumen, bile duct, and renal tubule. Cilia emanate from the apical membrane of epithelial cells into the ductal lumen to sense mechanical and chemical stimuli. However, primary cilia are largely lost in various ductal carcinomas, including breast, pancreatic, and cholangiocarcinoma, and they function as tumor-suppressive organelles (Menzl et al., 2014; Seeley et al., 2009; Wilson et al., 2021). In normal epithelial cells, the MBR delivers specialized membranes to the centrosome, enabling the assembly of the ciliary membrane and thus promoting ciliogenesis (Ott, 2016). However, in carcinoma cells, the proximity between MBR and centrosome is disrupted, leading to the loss of primary cilium in cancer cell. SHCBP1 functions as an oncogene in ductal carcinomas, which binds with TBC1D30 to inhibit Rab8 GTPase activity and Rab8GTP positioning within the MBR, resulting in cilia loss. Targeting MBR-associated factors such as SHCBP1 or Rab8 can restore ciliogenesis by reestablishing MBR-centrosome proximity, thereby inhibiting tumor progression. This offers unique therapeutic opportunities for the treatment of unciliated ductal carcinomas (Labat-de-Hoz et al., 2021; Shi et al., 2024; Fig. 3).

Beyond their intracellular roles, released MBRs function as intercellular signaling vehicles in tumor microenvironment. When internalized by neighboring non-sister cells, they transfer functional proteins to recipient cells. Notably, in colon and colorectal cancer, uptake of released MBRs by quiescent fibroblasts induces cellular transformation and an invasive phenotype, suggesting that MBRs actively remodel the tumor microenvironment to promote invasion. Proteomic profiling of EVs and shed MBRs human isogenic primary (SW480) and metastatic (SW620) colorectal cancer revealed that MDK, STAT1, and TGM2 are selectively enriched in SW480- released MBRs, and ADAM15 to SW620-released MBRs. These findings indicate that released MBRs from different cancer cells possesses distinct protein signatures that influence diverse malignant phenotypes and open potential diagnostic avenues for clinical utility using distinct EV subtypes (Kuriyama et al., 2025; Rai et al., 2021; Suwakulsiri et al., 2024a).

Indeed, transcript expression analysis of released MBRs in colorectal cancer cells showed that MBRs have a distinct transcriptomic profile compared with exosomes, with a high enrichment of mitochondrial transcripts, as well as lncRNA/pseudogene transcripts predicted to bind RNP complexes, spliceosomes, and RNA/stress granule proteins. For example, several fusion genes, such as MSH2, are highly enriched in MBRs, suggesting potential EV-liquid biopsy targets for cancer detection. Therefore, RNA and fusion gene compositions within MBRs have crucial impact on cancer progression and on the development of EV-based RNA/fusion gene candidates as cancer liquid biopsy/biomarker development (Suwakulsiri et al., 2024a; Suwakulsiri et al., 2024b).

In summary, future studies should focus on deciphering the spatiotemporal dynamics of MBR signaling networks and developing therapeutic strategies that target MBR formation, cargo loading, or intercellular transfer, which may yield novel biomarkers and precision therapies for unciliated ductal carcinomas and other MBR-driven malignancies.

MBRs and other disorders

The relationship between MBRs and developmental disorders represents an emerging frontier in research. This connection is supported by the established role of MBRs as key regulators of ciliogenesis. Defects of the primary cilium cause up to 35 human diseases, collectively known as clinical ciliopathies, which include renal-cystic ciliopathies, skeletal disorders, and Bardet-Biedl Syndrome (Bachmann-Gagescu and Sayer, 2025). Given the central role of MBRs in regulating ciliogenesis, specifically through SHCBP1-mediated control of MBR-centrosome proximity and Rab8 GTPase activity, it is plausible that MBR dysregulation contributes to the pathogenesis of these ciliary disorders. Beyond ciliopathies, mutations in the MBR-localized protein KIF14 cause microcephaly and renal hypodysplasia, with KIF14-positive MBRs accumulating in the developing ureteric bud (Reilly et al., 2019). Collectively, these observations position MBRs as potential regulators of developmental disease and underscore the broader therapeutic relevance of targeting MBR-centered mechanisms, such as the SHCBP1/Rab8 axis, to restore ciliary function across multiple disease contexts. However, the precise mechanistic links between MBRs and various disorders remain to be fully elucidated, underscoring the need for continued investigation.

Cancer therapeutic strategies targeting MBRs

The multifaceted roles of MBRs in disease pathogenesis have positioned them as attractive targets for therapeutic intervention. Various strategies are being explored to disrupt their formation, clearance, and function, with the most advanced approaches focused on oncology (Kuriyama et al., 2025).

Numbers of studies have reported that primary cilia function as tumor-suppressive organelles and are absent in ductal carcinomas. Recovery of primary cilia with normal functionality has demonstrated therapeutic potential in metastatic melanoma, cholangiocarcinoma, and colorectal cancer (Carotenuto et al., 2023). We recently reported that SHCBP1 in MBRs aggravated the inhibitory effect of TBC1D30 on Rab8 GTPase activity, thereby blocking Rab8^GTP positioning within the MBR, inhibiting MBR-centrosome proximity and suppressing ciliogenesis. Targeting SHCBP1 restores ciliogenesis in unciliated ductal carcinoma by promoting the proximity between MBR and centrosome, demonstrating therapeutic potential for cancer treatment. Importantly, Shcbp1 knockout in transgenic mice profoundly impeded tumor progression and metastasis, prolonging survival. Clinically, analysis of a large cohort of patients with ductal carcinoma revealed a negative correlation between SHCBP1-induced ciliary loss and patient prognosis in breast, pancreatic, and cholangiocarcinoma, supporting the therapeutic value of SHCBP1 ablation-induced ciliogenesis. Furthermore, AAV-delivered SHCBP1 shRNA markedly inhibited tumor growth in PDX models with reconstructed immune systems. Therefore, the development of effective strategies, such as small-molecule agents, to inhibit SHCBP1 for restoring ciliogenesis is crucial for its clinical translation in future (Shi et al., 2024).

Another potential cancer therapeutic strategy involves blocking the transfer of oncogenic MBRs. Accumulating evidence shows MBRs are secreted into the extracellular medium and engulfed by neighboring non-sister cells. Secreted MBRs are membrane-encapsulated and enriched in core cytokinetic proteins, rendering them molecularly distinct from exosomes and microparticles. Functional dissection of secreted MBRs has demonstrated that they are engulfed by and accumulate in quiescent fibroblasts, where they promote cellular transformation and an invasive phenotype (Rai et al., 2021). Therefore, developing strategies, such as antibody or small-molecule inhibitor, to clear MBRs and block oncogenic RNA or protein transfer represents a promising avenue for cancer treatment.

In addition, MBR-based biomarkers also hold promise for tumor diagnosis and treatment monitoring. In primary and metastatic colorectal cancer cells, RNA transcripts (protein-coding, lncRNA, pseudogene transcripts) and fusion genes selectively enriched in MBRs secreted from isogenic SW480 and SW620 human colorectal cancer cell lines. Notable transcripts in MBRs include mitochondrial transcripts (MT-CO1, MT-CO2, MT-CO3, MT-ND5), RNP complex-associated transcripts (NEAT1-202, SCAF1-201, LARP1-204), zinc finger-related transcripts (ZNF703-201, ZFPM1-201), and signaling-related transcripts (TGFB1-201). Enriched lncRNAs include KCNQ1OT1-201, GABPB1-AS1-202, and NEAT1-202. Fusion genes identified include PLAGL1-MSH2, METRNL-MSH2, and HNRPLL-MSH2. These findings support the development of MBR-based RNA and fusion gene signatures as potential candidate biomarkers for colon cancer diagnosis and monitoring (Suwakulsiri et al., 2024).

In summary, key priorities for future research include the development of potent and selective small-molecule inhibitors targeting SHCBP1, the elucidation of mechanisms governing MBR secretion and uptake to identify additional therapeutic nodes, and the validation of MBR-based biomarkers in large prospective clinical cohorts. These efforts hold the potential to translate MBR-centered biology into tangible clinical benefits for patients with ductal carcinomas and other MBR-driven malignancies.

Summary and Future Directions

Conclusions

MBRs have transitioned from being viewed as inert cytokinetic debris to being recognized as dynamic, multifunctional organelles that play critical roles in RNA processing, primary ciliogenesis, cellular signaling, and intercellular communication (Kuriyama et al., 2025). In this review, we focused on summarizing the specific mechanisms by which MBRs regulate primary cilia. In polarized epithelial cells, the MBR moves along the apical surface and, once proximal to the centrosome, delivers part of the membrane to the centrosome and permits ciliogenesis. In ductal carcinoma cells, SHCBP1 interacted with TBC1D30 to antagonize Rab8 GTPase activity, blocking MBR-centrosome proximity and subsequently silencing ciliogenesis. In addition, we summarized emerging signaling pathways implicated in MBR function. H-Ras-induced EMT reprogrammed the signaling in MBRs, including Wnt, VEGF, and PDGF signaling, underscoring the dynamic alteration of the proteomic architecture of MBRs during cancer developing. TGF-β signaling and genomic stability signaling networks are also enriched, further supporting the notion that MBRs function as dynamic signaling hubs that actively coordinate cellular processes.

We also highlighted that aberrant MBR handling contributes to malignancy through multiple interconnected mechanisms and discussed potential cancer treatment strategies targeting MBRs. High SHCBP1 expression negatively correlates with ciliary loss and poor patient prognosis in breast, pancreatic, and cholangiocarcinoma. Inhibition SHCBP1 using AAV-delivered shRNA enhances Rab8 GTPase activity, induces MBR-centrosome proximity, and triggers ciliogenesis, presenting therapeutic potential on unciliated ductal carcinomas. We also proposed that clearing extracellularly released MBRs to block oncogenic RNA or protein transfer and reprogram the tumor environment represents a promising avenue for cancer treatment. Furthermore, developing MBR-based RNA and fusion gene signatures as liquid biopsy biomarkers offers potential candidates for colon cancer diagnosis and monitoring.

In summary, MBRs are important regulators of ciliogenesis and cellular signaling, and their dysregulation drives tumor progression through SHCBP1-mediated disruption of MBR-centrosome proximity and intercellular transfer of oncogenic cargoes. Targeting the SHCBP1/Rab8 axis to restore ciliogenesis, blocking oncogenic MBR transfer, and leveraging MBR-specific molecular signatures for liquid biopsy represent three complementary strategies with significant therapeutic and diagnostic potential.

Limitations and prospects

Although this review summarized recent important findings on the functions and mechanism of MBRs in physiology and pathology, particularly in cancer, the following questions warrant further attention and investigation: (1)

Many MBR-related signaling components are pleiotropic and also function outside of MBRs. For example, SHCBP1 localizes to MBRs and regulates ciliogenesis through MBR-centrosome proximity. However, we also report that SHCBP1 acts as a cytoplasmic scaffold protein transducing HER2 signaling to directly regulate cell mitosis in gastric cancer (Shi et al., 2021). Other MBR-associated factors, such as Rab8, VEGFR, and integrins, likewise play fundamental roles in signal transduction and protein transport beyond their MBR-localized functions (Peterman et al., 2019; Vidal-Quadras et al., 2017). There remains a lack of MBR-specific experimental tools to elucidate their function specifically through MBRs. Future studies employing conditional knockout models, high-resolution live-cell imaging, and super-resolution techniques are needed to clarify the detailed mechanisms of MBR signaling in physiology and pathology.

(2)

It is worth noting that MBRs are derived from the cleavage of midbodies during the final stages of cell division, and the potential functions of MBRs and midbodies may differ. Many factors regulating MBR formation and signaling components, such as those involved in Wnt, TGF-β, and genomic stability pathways, have been demonstrated to localize to the midbody and play important roles in midbody abscission (Fumoto et al., 2012; Jung et al., 2022; Mondal et al., 2012). Therefore, we propose that these factors may also exert potential functions within MBRs. However, direct evidence to elucidate the consistency and divergence of these signaling factors between midbodies and MBRs is needed in the future.

(3)

Although we have proposed that targeting MBRs holds therapeutic potential for cancers, inhibition of individual targets within MBRs does not equate to blockade of the MBR structure itself. Therefore, developing standardized functional readouts of MBR activity, establishing approaches to clear MBRs, and systematically evaluating their therapeutic potential and translational prospects for tumor treatment are necessary.

(4)

We reported that SHCBP1-Rab8 axis regulates primary ciliogenesis by controlling MBR-centrosome proximity (Shi et al., 2024). However, the detailed mechanism by which MBR contributes to ciliogenesis remains to be fully elucidated. Studies have proposed that a microtubular connection exists between the MBR, the centrosome, and the nascent cilium and that MBRs may deliver specific membrane-associated factors for ciliary membrane assembly, thereby regulating ciliogenesis (Bernabé-Rubio et al., 2016; Ott, 2016). Nevertheless, more direct evidence is required in the future.

Authors’ Contributions

H.L., X.M., J.L., and K.X.: Conceptualization and writing of the draft. W.S., W.L., and H.L.: Conceptualization, resources, review, and editing.

Footnotes

Disclosure Statement

The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this article.

Funding Information

This work was supported by the Fundamental Research Funds for the Central Universities (lzujbky-2024-ey05), Gansu Provincial Youth Talent (Individual Project) (Grant No. 2026QNGR023), and the Joint Research Fund Project of Gansu Province (24JRRA932).

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