Marine Fungus Compound MHO7 Blocks Spread of Triple-Negative Breast Cancer by Disabling FAK Signaling

Triple-negative breast cancer is the most unforgiving form of the most commonly diagnosed malignancy in women worldwide. It lacks the hormone receptors and HER2 protein that make other breast cancers targetable, it is intrinsically heterogeneous, and it metastasizes early and often. Chemotherapy remains the backbone of treatment, but drug resistance and limited survival gains, especially in metastatic disease, have left clinicians with few options. Even newer weapons such as immune checkpoint inhibitors and antibody-drug conjugates help only narrow, biomarker-defined patient groups. Against that backdrop, a team of researchers in Wuhan, China, reports that a molecule pulled from a marine fungus can dramatically slow the migration and invasion of triple-negative breast cancer cells by shutting down a signaling hub that tumors rely on to move through the body.

The compound, named MHO7, is the molecule 6-epi-ophiobolin G, a sesterterpenoid originally isolated from the secondary metabolites of the mangrove-derived fungus Aspergillus ustus 094,102. Sesterterpenoids are a structurally unusual class of fungal natural products built from five isoprene units, and ophiobolins in particular have attracted attention for potent and multi-pathway anticancer activity. The Wuhan group, led by Haiyan Wen, Feifei Zeng, Yu Lan and senior authors Juanjuan Li, Siqi Zhou and Kui Hong, had previously shown that MHO7 acts as an estrogen receptor alpha degrader in hormone-positive breast cancer and halts triple-negative tumor growth by inducing immunogenic cell death through the ER stress-CHOP pathway. What remained unknown was whether the compound could also stop cancer cells from physically spreading, the process that drives most breast cancer deaths.

To answer that question, the researchers used MDA-MB-231, a highly invasive, mesenchymal-like triple-negative breast cancer cell line, as their in vitro model, and a subcutaneous xenograft model in immunodeficient BALB/c nude mice for in vivo testing. In the laboratory assays, MHO7 treatment significantly reduced wound closure in scratch tests and sharply cut the number of cells that migrated or invaded through Transwell membranes, including through Matrigel-coated inserts that mimic the extracellular matrix barrier. The compound also reduced the ability of cells to attach to fibronectin-coated surfaces, a direct readout of how strongly tumor cells grip the matrix that anchors them before they crawl away.

Perhaps the most striking cellular effect involved the junctions that hold epithelial cells together. Immunofluorescence microscopy showed that MHO7 increased the accumulation of beta-catenin at E-cadherin-positive cell-cell junctions, meaning the two proteins colocalized more strongly, a sign of reinforced adherens junctions. At the same time, quantitative PCR revealed that the gene encoding E-cadherin, CDH1, was significantly upregulated, while the matrix-degrading enzymes MMP-2 and MMP-9 were downregulated. In plain terms, the compound appears to weld cancer cells more tightly to their neighbors while stripping them of the molecular scissors they use to cut through tissue, a double blow to the metastatic cascade.

To understand how MHO7 achieves this, the team re-analyzed transcriptome sequencing data from treated cells and identified 3,107 upregulated and 3,039 downregulated differentially expressed genes. When the downregulated genes were mapped onto biological pathways using KEGG and Gene Ontology enrichment analyses, the strongest signals pointed squarely at focal adhesion, regulation of the actin cytoskeleton, and adherens junctions. Network analysis of the affected genes placed PTK2, the gene encoding focal adhesion kinase, or FAK, and SRC at central nodes interconnected with upstream integrin signaling components. Western blotting confirmed the picture at the protein level: both total and phosphorylated FAK and Src dropped significantly after MHO7 treatment.

FAK is a non-receptor tyrosine kinase that sits at the intersection of cell-matrix interactions and integrin signaling, governing survival, motility and invasion. Its activation begins with autophosphorylation at tyrosine 397, an indispensable event that recruits and activates Src family kinases, which then drive cytoskeletal remodeling and downstream survival cascades. FAK is frequently overexpressed and hyperactivated in aggressive malignancies, and in triple-negative breast cancer it orchestrates invasion, chemoresistance and angiogenesis, in part by upregulating the vascular endothelial growth factor receptor VEGFR2. MHO7 treatment suppressed exactly the initiating steps of this axis, reducing p-FAK at Y397 and p-Src at Y419 both in cultured cells and in tumor tissue from treated mice.

The cytoskeletal consequences were visible under the microscope. Control MDA-MB-231 cells displayed the classic invasive morphology, with well-organized, prominent F-actin stress fibers traversing the cytoplasm. After MHO7 exposure, that architecture collapsed into profound disorganization, and in tumor tissues the adhesion scaffold protein paxillin showed disrupted localization alongside severe F-actin disarray. Downstream, the PI3K/AKT cascade, a major effector of FAK, was also quieted, with reduced phosphorylation of both PI3K and AKT confirmed by Western blot and immunohistochemistry. The compound also promoted tumor cell apoptosis, shown by increased cleaved caspase-3, and curtailed angiogenesis, shown by decreased CD31, in the xenograft tumors.

One of the study’s most intriguing findings concerns the crosstalk between FAK and the canonical Wnt/beta-catenin pathway, a bidirectional oncogenic partnership that coregulates cytoskeletal reorganization, cell motility and stemness. Transcriptomic profiling of tumor tissue from mice given 50 milligrams per kilogram of MHO7 identified 1,135 upregulated and 1,090 downregulated genes, with focal adhesion and Wnt signaling both significantly enriched among the downregulated pathways. Follow-up experiments showed a dose-dependent decrease in nuclear and cytoplasmic beta-catenin, consistent with enhanced proteasomal degradation of cytoplasmic beta-catenin and a blockade of its nuclear translocation, along with upregulated GSK-3beta and E-cadherin. By simultaneously dismantling the FAK axis and draining beta-catenin out of the nucleus, MHO7 appears to sever a dual oncogenic circuit rather than a single wire.

The in vivo results add weight to the translational promise. In the xenograft model, oral MHO7 at 50 and 100 milligrams per kilogram significantly suppressed tumor volume and growth rate, with final tumor weights significantly lower than in vehicle-treated mice and tumor growth inhibition comparable to doxorubicin at 3 milligrams per kilogram. But the safety contrast was stark: doxorubicin caused three treatment-related deaths, progressive body weight loss, myocardial deformation, hepatic congestion and nuclear changes in renal and splenic cells, plus altered serum markers of kidney and heart injury. MHO7-treated mice, by contrast, gained weight steadily, showed no pathological lesions in the heart, liver, kidney, spleen, stomach or intestines, and had normal serum levels of ALT, AST, creatinine, uric acid, creatine kinase, CK-MB and lactate dehydrogenase, indicating no hepatic, renal or cardiac toxicity.

The authors are careful about the limits of their work. The data do not yet establish FAK as a direct molecular target of MHO7; the pathway suppression could stem from an unidentified upstream regulator, and rescue experiments will be needed to prove strict causality. The in vitro findings rest on a single mesenchymal-like cell line, the bell-shaped in vivo dose response, with the intermediate 50 milligram per kilogram dose performing best numerically, may partly reflect experimental variability or pharmacokinetic constraints such as gastrointestinal absorption saturation at high oral doses, and all safety data remain preclinical. The team’s next phase will map the compound’s direct binding targets, profile its pharmacokinetics comprehensively, test it in patient-derived xenografts and optimize its structure. Still, the convergence of anti-migratory, pro-junctional, pro-apoptotic and anti-angiogenic effects, delivered through a dual FAK-Wnt mechanism with a clean toxicity profile, marks MHO7 as a rare kind of lead compound: one forged in the ocean’s fungal depths that may finally give clinicians a way to stop the deadliest part of triple-negative breast cancer, its spread.

Subject of Research: A marine-derived sesterterpenoid that inhibits triple-negative breast cancer cell migration and invasion via suppression of the FAK signaling pathway

Article Title: A marine-derived sesterterpenoid inhibits migration and invasion of triple-negative breast cancer cells by suppressing the FAK signaling pathway

Article References: Wen, H., Zeng, F., Lan, Y., Yin, Y., Huang, Y., Hu, Y., Yin, J., Li, J., Zhou, S., & Hong, K. (2026). A marine-derived sesterterpenoid inhibits migration and invasion of triple-negative breast cancer cells by suppressing the FAK signaling pathway. Frontiers in Cell and Developmental Biology, 14, Article 1967923. https://doi.org/10.3389/fcell.2026.1967923

Image Credits: AI Generated

DOI: 10.3389/fcell.2026.1967923

Keywords: triple-negative breast cancer, MHO7, sesterterpenoid, ophiobolin, FAK signaling, cell migration, invasion, Wnt beta-catenin, marine natural products, metastasis, PI3K AKT pathway, xenograft model