Blood vessels are not static pipes. During development, and indeed whenever tissues grow or repair themselves, vascular networks must be extensively remodeled: new sprouts extend into avascular territory, redundant branches regress, and existing vessels adapt their caliber and shape to match the demands of blood flow. In the central nervous system, this orchestration is guided in part by Wnt signaling, a family of pathways with two major branches. The canonical Wnt/β-catenin branch is well established as a regulator of endothelial specialization and of the blood–brain barrier, the selective fortress that shields neural tissue from the bloodstream. The non-canonical Wnt/Planar Cell Polarity (PCP) branch, by contrast, is known to govern vascular remodeling and the ability of endothelial cells to sense and adapt to the mechanical forces of flowing blood. What has remained stubbornly unclear is how the PCP pathway—activated at the cell surface—translates its instructions into the internal polarity machinery that tells a cell which way is forward.

The new study, led by Cécile Duplàa and Thierry Couffinhal of Inserm unit UMR1034 at the University of Bordeaux, with contributions from Alexandre Dubrac at the Sainte-Justine Research Center and Université de Montréal, answers that question by zeroing in on MCC, short for Mutated in Colorectal Cancer. MCC is a PDZ-domain protein, a class of scaffold molecules that physically assemble signaling complexes at specific cellular locations. It had previously been implicated in cell migration in epithelial cells and identified as an effector of non-canonical Wnt signaling during convergence and extension movements in zebrafish embryos—developmental processes that depend intimately on planar cell polarity. The Bordeaux team, building on their laboratory’s long-standing interest in vascular morphogenesis, hypothesized that MCC might perform an analogous role inside endothelial cells.

The researchers’ mechanistic work centered on a striking molecular partnership. Using proximity-dependent biotinylation (BioID), a technique that maps proteins sitting close to a protein of interest within living cells, combined with mass spectrometry proteomics, they found that MCC interacts with CEP131, a component of centriolar satellites. Centriolar satellites are electron-dense granules that cluster around the centrosome—the cell’s principal microtubule-organizing center—and help regulate centrosome function, protein turnover and cilia biology. The team’s proteomics data, deposited in the ProteomeXchange Consortium, show that MCC does not merely associate with CEP131; it actively promotes the satellite protein’s degradation, engaging both the proteasome, the cell’s cytosolic protein-shredding machinery, and autophagy, the lysosomal degradation system often used for bulk recycling of cellular components. In other words, MCC functions as a quality-control switch for the structures surrounding the centrosome.

Why would this matter for polarity? The answer lies in the geometry of a migrating endothelial cell. To move directionally, a cell must establish a front–rear axis: the microtubule cytoskeleton and the microtubule-organizing center must be positioned and oriented toward the leading edge, while the Golgi apparatus and nucleus reposition accordingly. Previous work from several groups, including studies showing that excess centrosomes scatter and derail endothelial migration, had established that centrosome-associated organization is a linchpin of directional movement. By keeping centriolar satellite material in check through regulated turnover, MCC appears to preserve the clean, polarized centrosomal architecture that directional migration demands. When the researchers depleted MCC from endothelial cells, this organization fell apart—and with it, the cells’ ability to polarize front-to-back.

One of the most intriguing findings of the study is what did not fall apart. When the team subjected MCC-depleted endothelial cells to flow, mimicking the shear stress that blood exerts on vessel walls in vivo, the cells still elongated and aligned their cytoskeletons with the direction of flow—indeed, this flow-induced elongation was preserved and even enhanced. This dissociation is biologically revealing. It demonstrates that two processes often lumped together as “endothelial alignment” are mechanistically separable: the passive morphological response to fluid shear, in which cells stretch along the flow axis, can proceed without MCC, while the active, directional front–rear polarization required for guided migration depends on it. For vascular biologists, this functional split offers a new framework for dissecting how vessels respond to hemodynamic forces.

The in vivo evidence came from the postnatal mouse retina, a classic and visually tractable model of angiogenesis in which a vascular plexus expands radially across the retinal surface during the first weeks of life, driven by proliferating “tip” cells at the angiogenic front. When the researchers deleted the Mcc gene specifically in endothelial cells of newborn mice, the retinal vasculature failed to remodel properly. Vessel density was abnormal, endothelial proliferation dropped, and—critically—the front–rear polarity of endothelial cells at the angiogenic front was disrupted. Tip cells, which must polarize and migrate persistently to lead the vascular sprout, lost their organizational bearings.

To rule out the possibility that these polarity defects were merely secondary consequences of a grossly malformed vasculature, the team employed an elegant pharmacological intervention. Captopril, an angiotensin-converting enzyme inhibitor long used as a blood pressure drug, is known to normalize vascular density and promote vessel regression in the remodeling retina. When the researchers treated the MCC-deficient mice with captopril, vascular density normalized and pruning proceeded—but endothelial polarity remained broken. This result is pivotal: it indicates that MCC’s role is cell-intrinsic. The protein is not simply required to generate a vascular environment in which polarity is possible; it is required within each endothelial cell to construct the polarity machinery itself.

The study also situates MCC within a broader signaling hierarchy. Prior work by the Bordeaux group and collaborators had identified the E3 ubiquitin ligase PDZRN3 as a Wnt/PCP pathway component required for vascular morphogenesis, and proteomic analyses had placed PDZRN3 downstream of Wnt5a–Ror signaling, a prototypical non-canonical Wnt cascade. The new findings extend this wiring: MCC now emerges as a downstream effector that converts PCP pathway activity into centrosome-associated proteostasis—the controlled degradation of satellite components—thereby closing the gap between a signal received at the membrane and a polarized cytoskeleton inside the cell.

Beyond developmental biology, the work carries implications for human disease. MCC was originally named for its frequent mutation in colorectal tumors, and it has since been characterized as a putative tumor suppressor that represses β-catenin-dependent transcription. Its newly described role in endothelial biology suggests that alterations in MCC could contribute to vascular pathologies as well. Aberrant angiogenesis and defective vascular remodeling underlie a wide range of conditions, from diabetic retinopathy—where neurovascular crosstalk fails and vessels in the retina deteriorate—to ischemic disease, where therapeutic revascularization is limited by the vessels’ inability to remodel productively. Cerebral small vessel disease, another area of active investigation by members of the consortium, may also intersect with pathways controlling endothelial polarity and mechanosensing. If the MCC–CEP131 axis proves druggable, it could offer a handle for promoting or restraining vascular remodeling in clinical contexts.

The technical breadth of the study is itself noteworthy. The team combined live-cell polarity assays and automated image analysis, single-cell RNA sequencing of mouse retina—data publicly available through the Gene Expression Omnibus under accession GSE175895—and quantitative proteomics to characterize the MCC interactome. Such multi-omics integration is increasingly the norm in vascular biology, where the behavior of a single endothelial cell must be understood simultaneously at the level of gene expression, protein interaction networks and subcellular architecture.

For the field, the study fills a genuine conceptual hole. The Wnt/PCP pathway has been implicated in angiogenesis for nearly two decades, with components such as Celsr1, DAAM1 and Kif26b variously shown to regulate endothelial junctions, proliferation and polarity. Yet the route from pathway activation at the plasma membrane to the microtubule-organizing center has remained speculative. By identifying MCC as the bridge—and by showing that the bridge is built from regulated protein degradation at the centrosome—the Bordeaux-led consortium has supplied both the missing connection and a mechanistic explanation for why it matters. As vascular biologists now probe how this axis operates in pathological angiogenesis and in the mature vasculature of the adult brain, MCC may shed its reputation as merely a cancer gene and take on a new identity: a master organizer of the cell’s sense of direction.

Kaposi sarcoma develops when HHV-8-infected cells acquire tumour-like properties and stimulate the formation of abnormal vascular networks. The disease can occur in people living with HIV, where immune suppression and HIV-associated inflammation may accelerate tumour development, but it also appears in classic form, most often in older adults and in particular geographic regions. Although both forms are driven by the same virus, their clinical settings are different. Comparing them offers researchers a way to distinguish immune changes linked to HHV-8 from those caused primarily by HIV infection, ageing or systemic immune suppression.

The tumour microenvironment is central to that comparison. Cancer cells do not act in isolation; they exchange chemical signals with neighbouring cells through cytokines, chemokines, growth factors and cell-surface receptors. In Kaposi sarcoma, these interactions can support blood-vessel growth, recruit inflammatory cells and create conditions that allow infected tumour cells to persist. The new analysis indicates that HHV-8 is a major organiser of this local environment, influencing how immune cells are distributed and how they function within the tumour rather than merely serving as the initiating infection.

HHV-8 has a sophisticated biological programme that alternates between latent and lytic phases. During latency, the virus maintains its genome in infected cells while producing a restricted set of proteins that help the cell survive and evade immune attack. During lytic reactivation, a broader group of viral genes is expressed, generating new virus and altering the surrounding tissue through inflammatory and angiogenic signals. Viral proteins and non-coding RNAs can interfere with antigen presentation, antiviral signalling and programmed cell death. These mechanisms may create an immunologically abnormal niche in which tumour growth and viral persistence reinforce one another.

The study’s emphasis on both HIV-associated and classic disease is particularly significant because the two settings may contain overlapping, but not identical, immune landscapes. HIV infection can reduce the number and effectiveness of important T-cell populations, while antiretroviral therapy may partially restore systemic immune function without completely normalising tissues affected by cancer. Classic Kaposi sarcoma, by contrast, arises without HIV-driven immune depletion, yet it can still display local immune dysfunction. The comparison therefore suggests that HHV-8 itself has a distinct capacity to remodel immune activity inside the tumour.

A detailed view of this environment can reveal why immune cells that are capable of recognising infected or malignant cells fail to eliminate them. Tumours may contain cytotoxic lymphocytes, macrophages and other immune populations, but their presence does not necessarily mean they are active. Persistent exposure to viral and tumour-derived signals can produce functional exhaustion, alter cell differentiation or encourage regulatory pathways that suppress attack. At the same time, inflammatory cells may release factors that promote vascular remodelling and tumour survival. Kaposi sarcoma thus illustrates how inflammation can be both an attempted defence and a resource exploited by cancer.

These findings have implications for treatment strategy. Current management of Kaposi sarcoma may include antiretroviral therapy for people with HIV, chemotherapy, local treatment and, in selected cases, immune-based approaches. If HHV-8-dependent signals help establish an immunosuppressive microenvironment, therapies aimed only at rapidly dividing tumour cells may leave important drivers of disease untouched. Mapping the interaction between viral proteins, immune checkpoints, endothelial cells and inflammatory mediators could help identify combinations that block tumour support while restoring effective immune surveillance.

The research also underscores why tissue-level analysis matters. Blood tests can describe systemic immune status, but they cannot fully show which cells are physically adjacent within a lesion, what signals they are receiving or whether immune cells have entered a productive anti-tumour state. Modern tumour profiling can integrate cellular composition with gene-expression patterns and spatial organisation, allowing scientists to examine the microenvironment as a structured biological system. Such approaches are especially valuable for virus-associated cancers, where a small population of infected cells may influence many uninfected neighbouring cells.

For viral oncology, Kaposi sarcoma remains an important model of how chronic infection can transform tissue biology without relying on a single genetic alteration in the conventional sense. The new findings place HHV-8 at the centre of a regulatory network linking viral persistence, immune modulation, inflammation and abnormal vessel formation. They also reinforce the idea that the differences between HIV-associated and classic Kaposi sarcoma cannot be explained solely by the presence or absence of HIV. Understanding how the virus reshapes its surroundings may ultimately lead to more precise treatments that target both the tumour and the biological environment that allows it to endure.

Subject of Research: HHV-8-dependent immune regulation and the tumour microenvironment in HIV-associated and classic Kaposi sarcoma.

Article Title: In-depth characterisation of the tumour microenvironment reveals HHV-8-dependent immune regulation in HIV-associated and classic Kaposi sarcoma.

Article References: Fulgenzi, C.A.M., Dalla Pria, A., Zhao, Y. et al. “In-depth characterisation of the tumour microenvironment reveals HHV-8-dependent immune regulation in HIV-associated and classic Kaposi sarcoma.” British Journal of Cancer (2026). https://doi.org/10.1038/s41416-026-03536-5

Image Credits: AI Generated

DOI: 10.1038/s41416-026-03536-5

Keywords: HHV-8, KSHV, Kaposi sarcoma, HIV-associated cancer, classic Kaposi sarcoma, tumour microenvironment, immune regulation, viral oncology, cancer immunology, tumour immunity