Integrin β1 signaling at the crossroads of cellular plasticity, the tumor microenvironment, and therapy resistance in medulloblastoma

Abstract

Medulloblastoma (MB), the most common malignant pediatric brain tumor, remains associated with relapse and long-term treatment-related toxicities. Tumor–microenvironment interactions increasingly appear to contribute to progression, stemness, and therapy resistance in brain cancers. Integrin β1, a major mediator of cell–extracellular matrix interactions, regulates survival signaling, mechanotransduction, and cancer stem cell maintenance in several tumor types, particularly glioblastoma. This mini-review discusses how developmental programs, extracellular matrix remodeling, hypoxia, and cancer stem cell plasticity may converge through integrin-dependent signaling in MB. Although direct evidence remains limited, converging findings from developmental neurobiology, stem cell biology, and cancer research support integrin β1 as an underexplored candidate regulator of MB progression and therapeutic resistance.

1. Introduction

Medulloblastoma (MB) is the most common malignant pediatric brain tumor and remains associated with significant long-term morbidity and mortality despite advances in multimodal therapies combining surgery, radiotherapy, and chemotherapy (1–3). Survivors frequently experience severe neurocognitive, endocrine, and developmental impairments resulting from treatment-related toxicities (4, 5). Relapse remains frequent and is associated with poor prognosis and limited therapeutic options (6, 7).

Large-scale genomic and epigenomic studies have redefined MB as a heterogeneous disease composed of four principal molecular subgroups—WNT, SHH, Group 3, and Group 4—each characterized by distinct developmental origins, molecular alterations, and clinical outcomes (8–10). While WNT tumors are generally associated with favorable prognosis, Group 3 tumors display the poorest prognosis. Despite these advances in molecular classification, current therapeutic strategies remain relatively similar across subgroups, highlighting the need for biologically informed therapeutic approaches (11).

Increasing evidence indicates that tumor progression and therapy resistance are not solely driven by tumor-intrinsic alterations but are also strongly influenced by interactions with the tumor microenvironment (TME) (12, 13). The extracellular matrix (ECM), a major component of the TME, regulates proliferation, migration, survival, and cellular plasticity through biochemical and mechanical signaling. In brain tumors, ECM remodeling and microenvironmental signaling have emerged as important regulators of stemness and therapeutic response (14, 15).

Integrins are transmembrane receptors that mediate cell–ECM interactions and transduce extracellular signals into intracellular signaling pathways (15, 16). Among them, integrin β1 is of particular interest because of its ability to form multiple heterodimers and interact with diverse ECM ligands, including laminins, fibronectin, and collagens (17, 18). Through activation of FAK, PI3K/AKT, and MAPK pathways, integrin β1 regulates survival, migration, mechanotransduction, and stem-like behavior (19, 20).

In several cancers, particularly glioblastoma, integrin β1 signaling has been implicated in cancer stem cell maintenance, invasion, and resistance to therapy (20–22). However, despite the growing recognition of microenvironmental regulation in MB biology, the role of integrin β1 in this disease remains poorly characterized.

Recent reviews have highlighted the importance of the tumor microenvironment in MB biology (23), while integrin signaling and cellular plasticity have been extensively reviewed in the broader context of cancer (17, 20, 21). However, these concepts have rarely been integrated into a unified framework in medulloblastoma. In this mini-review, we discuss how developmental signaling, extracellular matrix interactions, and tumor cell plasticity may converge through integrin β1-dependent pathways in MB. By considering integrin β1 as a potential molecular link between these processes, we explore the implications of this integrative framework for therapy resistance and future therapeutic strategies.

2. Developmental and microenvironmental context of medulloblastoma

MB is widely regarded as a developmental tumor arising from dysregulation of cerebellar ontogeny (24, 25). Cerebellar development depends on coordinated proliferation, migration, and differentiation of neural progenitor populations controlled by SHH and WNT signaling. Granule cell progenitors (GCPs) within the external granular layer are considered a major cell population involved in MB tumorigenesis (26–28). SHH signaling secreted by Purkinje cells promotes GCP proliferation during normal development, whereas aberrant activation of this pathway through mutations in PTCH1 or SMO drives uncontrolled proliferation in SHH-subgroup MB. Similarly, activation of the WNT pathway through CTNNB1 mutations characterizes the WNT subgroup and is associated with favorable prognosis (29, 30).

Unlike many adult cancers, MB exhibits a relatively low mutational burden and appears to rely more heavily on epigenetic dysregulation and persistence of developmental programs (31–33). This supports the idea that MB arises from hijacking developmental programs rather than from progressive accumulation of genomic alterations.

Importantly, cerebellar development is strongly influenced by interactions with the extracellular matrix (ECM) (34–37). ECM components such as laminins, fibronectin, and collagens regulate progenitor adhesion, migration, and differentiation through integrin-mediated signaling (34, 36). Among integrins, β1-containing integrins play essential roles in neural development by regulating progenitor adhesion, survival, and tissue organization (38–40). Experimental disruption of integrin β1 signaling leads to defects in brain architecture and abnormal cell positioning, highlighting its importance in neural morphogenesis.

Moreover, the contribution of integrin β1 is likely to vary across MB molecular subgroups. Single-cell transcriptomic studies have shown that WNT, SHH, Group 3, and Group 4 tumors contain distinct malignant cell states that reflect different developmental lineages and differentiation programs (31, 33). In addition, subgroup-specific differences have been reported in the composition of the immune and stromal microenvironment (41, 42). Group 3 and Group 4 tumors should not be regarded as entirely discrete biological entities, as transcriptomic analyses indicate that they form a biological continuum containing multiple intermediate states (43). These differences in cellular identity and microenvironmental organization may influence ECM composition and consequently β1-dependent signaling. However, whether specific MB subgroups or cellular states exhibit preferential dependence on integrin β1 remains to be directly established, representing an important area for future investigation.

These differences in cellular identity and microenvironmental organization may influence ECM composition and consequently β1-dependent signaling. Single-cell transcriptomic studies have refined our understanding of MB cellular heterogeneity; however, the functional contribution of integrin β1 across these transcriptionally defined cellular states remains poorly characterized.

Collectively, these observations suggest that integrin-mediated signaling may contribute not only to normal cerebellar development but also to tumor initiation and progression in MB. Although direct evidence remains limited, the developmental dependence of MB on ECM-regulated signaling pathways provides a strong rationale for investigating integrin β1 as a regulator of tumor cell identity and microenvironmental interactions.

3. Cancer stem cell plasticity and ECM niches in medulloblastoma

Tumor heterogeneity in medulloblastoma is increasingly understood as a dynamic process driven by cancer stem cell (CSC) plasticity and microenvironmental regulation (44–47). CSCs were initially described as tumor-propagating cells capable of self-renewal and long-term tumor maintenance (48, 49). These populations are now recognized as major contributors to relapse, therapeutic resistance, and tumor adaptation (50).

However, the classical hierarchical CSC model has progressively evolved toward a more dynamic view in which tumor cells transition between stem-like and differentiated states in response to intrinsic transcriptional programs and extrinsic environmental cues (46, 47). In brain tumors, including MB, this plasticity appears particularly relevant because tumor cells retain features of developmental lineages and progenitor programs.

Single-cell transcriptomic studies further support this model by showing that MB cells occupy multiple differentiation states reflecting developmental trajectories rather than rigid hierarchies (31, 33). These studies reveal that tumor cells retain considerable phenotypic plasticity and can occupy distinct transcriptional states associated with neural progenitor differentiation programs. Together, these findings support a dynamic continuum of tumor cell states shaped by both intrinsic developmental programs and extrinsic microenvironmental cues. Although direct evidence linking integrin β1 to these transcriptionally defined cell states remains limited, its established role in ECM sensing, mechanotransduction, and stem cell regulation suggests that it may contribute to the maintenance and adaptation of these plastic cell populations.

Hypoxia also promotes stem-like phenotypes, metabolic adaptation, and therapeutic resistance through HIF signaling, and has been associated with aggressive behavior in MB (51–53). The ECM constitutes a major functional component of the TME and strongly influences CSC behavior (14, 54). Laminin-rich environments promote neural stem cell maintenance and proliferation, whereas fibronectin-rich matrices are more frequently associated with migration and invasion (55–57). These effects are mediated largely through β1-containing integrins, which connect ECM-derived signals to intracellular pathways regulating adhesion, survival, and self-renewal (16, 18, 58).

In addition to regulating stem cell behavior, integrin β1 may also contribute to the invasive properties of MB. Unlike gliomas, which primarily invade the surrounding brain parenchyma, MB characteristically disseminates through the cerebrospinal fluid and colonizes the leptomeninges and is associated with poor clinical outcome. Experimental studies have demonstrated that β1-containing integrins, particularly the α9β1 heterodimer, mediate MB cell adhesion to tenascin-C, an extracellular matrix glycoprotein enriched within the leptomeningeal environment (59). This interaction promotes activation of signaling pathways involved in cell survival and proliferation, suggesting that integrin β1-dependent adhesion may facilitate the establishment and persistence of disseminated tumor cells. Although the precise contribution of β1 signaling to leptomeningeal colonization remains poorly understood, its central role in ECM recognition and cell–matrix interactions provides a compelling rationale for further investigation.

In glioblastoma, integrin β1 signaling promotes CSC maintenance and tumor initiation through activation of focal adhesion kinase (FAK) and PI3K/AKT pathways (20, 21). Integrin β1 also contributes to invasion and interactions with vascular niches, reinforcing its role as a central regulator of tumor progression (21, 60, 61). Beyond biochemical signaling, integrin β1 mediates mechanotransduction, allowing tumor cells to sense ECM stiffness and architecture (62, 63). Increased matrix stiffness has been associated with enhanced stemness and aggressive behavior in multiple cancers (63, 64).

Importantly, integrin β1 signaling intersects with developmental pathways central to MB biology, including SHH and WNT signaling. Crosstalk between integrins and receptor tyrosine kinases further amplifies downstream signaling networks involved in survival and proliferation (17, 65). Together, these observations support the hypothesis that integrin β1 may function as an integrative hub coordinating developmental and microenvironmental signals in MB.

Although direct evidence specifically implicating integrin β1 in MB CSC regulation remains limited, the strong parallels with other brain tumors provide a compelling rationale for further investigation.

4. Integrin β1 and radioresistance in medulloblastoma

Radiotherapy remains a cornerstone of medulloblastoma treatment and is a major determinant of patient outcome (2, 3). Nevertheless, resistance to ionizing radiation remains a major clinical challenge, particularly in recurrent disease where prognosis is poor and therapeutic options are limited (6, 7).

Radioresistance results from tumor-intrinsic and microenvironment-dependent mechanisms, including efficient DNA damage repair, redox control, hypoxia, and therapy-induced plasticity (22, 53, 66, 67). CSC-like populations often display enhanced DNA repair, reduced ROS levels, and lower sensitivity to genotoxic stress (68, 69). Hypoxia further limits radiation-induced DNA damage fixation while promoting stem-like phenotypes through HIF signaling (51, 53, 70). Together, these processes may contribute to MB relapse, although direct evidence remains limited.

Beyond tumor-intrinsic mechanisms, the tumor microenvironment plays a central role in regulating radiation response (12, 13, 22). Adhesion to ECM components activates integrin-mediated signaling pathways that enhance survival and resistance to apoptosis following irradiation (22, 71). This phenomenon, referred to as cell adhesion-mediated radioresistance (CAM-RR), has been described in several tumor types.

Integrin β1 appears to be a major mediator of CAM-RR through activation of signaling pathways such as FAK, PI3K/AKT, and MAPK (19, 22). Inhibition of integrin β1 enhances radiosensitivity in several cancer models by increasing apoptosis and impairing DNA repair (71, 72). In glioblastoma, ECM-dependent integrin signaling contributes to resistance through interactions with laminin- and fibronectin-rich microenvironments (21, 44).

Integrin signaling may also modulate chromatin organization and accessibility of DNA repair machinery (73). In parallel, radiation-induced ECM remodeling, including increased collagen and fibronectin deposition, may further reinforce integrin signaling and establish a protective niche favoring tumor survival (74, 75).

Collectively, these observations position integrin β1 as a potential regulator linking ECM interactions, CSC plasticity, developmental signaling, and radioresistance in MB (Figure 1). Although direct experimental evidence remains scarce, the strong biological convergence observed across developmental biology, stem cell regulation, and radiobiology supports further investigation of this pathway in pediatric brain tumors.

Figure 1.

Integrin β1 as a central hub linking developmental signaling, extracellular matrix interactions, stemness, and radioresistance in medulloblastoma. Integrin β1 signaling integrates extracellular matrix (ECM)-derived cues, including laminin, fibronectin, and collagen interactions, with developmental pathways such as SHH and WNT. Through activation of downstream signaling pathways including FAK, PI3K/AKT, and MAPK, β1 integrin may regulate cancer stem cell features, cellular plasticity, tumor progression, and mechanisms associated with radioresistance, including DNA repair, ROS regulation, and survival signaling.

5. Integrin β1 as a signaling and mechanotransduction hub

Integrin β1 forms heterodimeric receptors with multiple α subunits, enabling interactions with ECM ligands such as laminins, fibronectin, and collagens (16, 18). Upon ligand engagement, integrin β1 promotes focal adhesion assembly and activates FAK/Src signaling, which integrates biochemical and mechanical signals originating from the extracellular matrix. Through downstream PI3K/AKT, MAPK/ERK, and Rho GTPase pathways, integrin β1 regulates cell survival, proliferation, migration, cytoskeletal remodeling, and mechanotransduction (19, 20). Mechanical forces transmitted through integrin β1-dependent adhesions can regulate the activity and nuclear localization of the mechanosensitive transcriptional co-activators YAP and TAZ, thereby coupling extracellular matrix stiffness to transcriptional programs involved in proliferation, survival, and cellular plasticity (76, 77).

Importantly, the functional consequences of integrin β1 signaling depend strongly on its α-subunit partner and microenvironmental context. For example, α6β1 integrin preferentially interacts with laminin-rich niches associated with stem cell maintenance, whereas α5β1 integrin primarily binds fibronectin-rich matrices linked to migration and invasion (44, 55, 78). This functional diversity enables integrin β1 to regulate distinct tumor cell states depending on ECM composition (Figure 2).

Figure 2.

Distinct extracellular matrix niches may regulate tumor cell states through β1 integrin signaling in medulloblastoma. Laminin-rich microenvironments interacting predominantly with α6β1 integrin are associated with stem-like properties, including self-renewal, quiescence, and therapy resistance. In contrast, fibronectin-rich niches engaging α5β1 integrin are linked to migratory and invasive phenotypes associated with tumor dissemination. Bidirectional transitions between these cellular states illustrate tumor plasticity driven by extracellular matrix composition and microenvironmental signaling.

Integrin β1 signaling also displays extensive crosstalk with receptor tyrosine kinases and developmental signaling pathways (17, 65). Interactions with EGFR, SHH, and WNT pathways may amplify survival signaling and influence tumor cell plasticity (17, 20). Such integrative signaling networks suggest that integrin β1 functions not merely as an adhesion receptor but rather as a central signaling hub coordinating biochemical and mechanical inputs from the tumor microenvironment.

Beyond its interactions with the extracellular matrix, the MB tumor microenvironment also comprises immune cell populations, including resident microglia, infiltrating macrophages, and, to a lesser extent, lymphocytes, which may influence tumor progression and therapeutic response. The composition and functional organization of this immune microenvironment vary across MB molecular subgroups (41, 42). More broadly, the ECM contributes to bidirectional communication between tumor cells, stromal cells, and immune populations by regulating cell adhesion, cytokine availability, and tissue remodeling (14). In other solid tumors, integrin-dependent signaling contributes to bidirectional communication between tumor and immune cells by modulating cytokine signaling, immune cell recruitment, and macrophage polarization, thereby promoting an immunosuppressive tumor microenvironment (16, 79). Although the specific contribution of integrin β1 to immune regulation in MB remains poorly understood, its central role in cell–matrix interactions and bidirectional communication between tumor cells and the surrounding microenvironment suggests that it may influence immune cell recruitment, localization, or functional polarization within the tumor microenvironment.

Although these mechanisms have been extensively characterized in other tumor types, their relevance in MB remains insufficiently explored. Given the developmental origin of MB and the importance of ECM-dependent signaling in cerebellar biology, integrin β1 may represent a critical regulator of tumor adaptation and progression (24, 34, 38).

6. Therapeutic opportunities and translational challenges

Given its central role in stemness, survival signaling, and microenvironmental interactions, integrin β1 represents an attractive therapeutic target in cancer. Preclinical studies in multiple tumor types have demonstrated that inhibition of integrin β1 signaling can enhance sensitivity to chemotherapy and radiotherapy by disrupting survival pathways and impairing ECM-mediated protection (22, 71, 72, 80).

Several therapeutic approaches targeting integrin β1 signaling have been explored, including β1-blocking monoclonal antibodies such as AIIB2 (Park et al., 2006), peptide antagonists, and inhibitors of downstream signaling molecules such as focal adhesion kinase (FAK) (17, 81, 82). Preclinical studies using β1-blocking antibodies have demonstrated reduced tumor growth and enhanced sensitivity to radiotherapy in several cancer models (72, 81), whereas clinically investigated FAK inhibitors, including defactinib and GSK2256098, represent complementary strategies to disrupt integrin-dependent signaling (82, 83). Although β1-targeting antibodies have shown encouraging activity in preclinical models and FAK inhibitors have advanced into early-phase clinical evaluation, none has yet been specifically evaluated in MB.

However, clinical translation of integrin-targeting therapies has proven challenging. Cilengitide, a cyclic RGD peptide developed primarily to target αvβ3 and αvβ5 integrins (84), failed to improve overall survival when combined with standard radiotherapy and temozolomide in patients with newly diagnosed glioblastoma in the phase III CENTRIC trial (85). Importantly, this lack of clinical benefit should not be interpreted as evidence against integrin β1-directed therapeutic strategies, as cilengitide was not developed as a selective β1 inhibitor and integrin signaling is highly dependent on receptor subtype, cellular context, ligand availability, and compensatory signaling among different integrin heterodimers (17, 20, 86).

Another major challenge is tumor heterogeneity. Integrin expression and activity vary between tumor subtypes and even between distinct cellular states within the same tumor (10, 86). This suggests that effective therapeutic targeting will likely require improved patient stratification and identification of biomarkers predicting integrin dependency.

In MB, β1 targeting remains largely unexplored, but developmental signaling, CSC plasticity, ECM-mediated resistance, and the central role of radiotherapy support its investigation (20–22). Future therapeutic approaches will likely require rational combination strategies rather than integrin inhibition alone. Combining integrin β1 targeting with radiotherapy could simultaneously enhance DNA damage while blocking ECM-mediated survival signaling (22, 71). Similarly, combining integrin inhibition with SHH or WNT pathway inhibitors may improve efficacy by targeting both tumor-intrinsic and microenvironmental mechanisms.

Beyond direct β1 inhibition, targeting downstream effectors such as FAK may represent an alternative therapeutic strategy capable of overcoming compensatory signaling and some limitations associated with integrin-directed therapies (82, 83). In parallel, advances in molecular profiling and spatial transcriptomics may facilitate identification of MB subgroups or microenvironmental contexts particularly dependent on integrin signaling (31, 33).

Overall, despite significant translational challenges, integrin β1 remains a promising candidate for therapeutic investigation in MB, particularly in the context of combination therapies aimed at overcoming stemness-associated resistance mechanisms.

7. Future perspectives and conclusions

Increasing evidence indicates that medulloblastoma progression and therapeutic resistance are shaped not only by tumor-intrinsic genetic alterations but also by dynamic interactions with the tumor microenvironment (12, 13, 20). Within this framework, integrin β1 emerges as a potentially important regulator linking extracellular matrix signaling, stemness, cellular plasticity, and resistance to therapy.

Although direct evidence specifically implicating integrin β1 in MB remains limited, strong biological parallels with neural development, glioblastoma, and other cancers support the hypothesis that this pathway may play an important role in disease progression (20, 38, 44). The convergence of developmental signaling, ECM remodeling, mechanotransduction, and CSC regulation around integrin β1 suggests that it may function as a central integrative hub in MB biology (63, 74).

Future studies should aim to characterize integrin β1 expression and activity across MB molecular subgroups and determine whether specific tumor contexts exhibit increased dependency on ECM-mediated signaling. Emerging technologies such as spatial transcriptomics, single-cell multiomics, organoid models, and engineered ECM systems may provide new opportunities to investigate these mechanisms in physiologically relevant settings.

Particular attention should also be given to therapy-induced microenvironmental remodeling (75). Radiotherapy may alter ECM composition and mechanical properties in ways that reinforce integrin signaling and promote tumor adaptation. Understanding these dynamic interactions could help identify new therapeutic vulnerabilities.

Ultimately, integrating microenvironmental biology into the study of medulloblastoma may help bridge the gap between molecular classification and therapeutic innovation. In this context, integrin β1 represents a compelling but underexplored candidate deserving further investigation in pediatric neuro-oncology.

Funding Statement

The author(s) declared that financial support was received for this work and/or its publication. This work was supported by the Government of Monaco and Enfants Cancers Santé.

Author contributions

WE: Data curation, Writing – review & editing, Methodology, Writing – original draft, Investigation. VP: Writing – original draft, Investigation, Writing – review & editing, Supervision. CM: Conceptualization, Writing – review & editing, Supervision, Writing – original draft.

Conflict of interest

The author(s) declared that this work was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.

Generative AI statement

The author(s) declared that generative AI was not used in the creation of this manuscript.

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