Integrin alpha-6 drives metabolic adaptation and breast cancer survival in leptomeningeal metastasis

Metastases to the leptomeninges (LM), the cerebrospinal fluid-containing membranes surrounding the brain and spinal cord, occur in a wide variety of hematologic and solid malignancies, including leukemia, lymphoma, lung cancer, melanoma, and breast cancer (BC). When LM metastases arise, they are often rapidly fatal. The molecular mechanisms that enable LM metastasis remain poorly understood, and there are limited interventions to prevent or treat this deadly disease complication. Our lab has discovered that the laminin receptor, integrin a6, critically regulates a novel pathway of metastasis between the calvarial and vertebral bone marrow (BM) and the adjacent central nervous system meninges. BC migration along the abluminal surface of emissary vessels that connect BM and LM vasculature is triggered by binding of tumor cell a6 to laminin in the vascular basement membrane. This metastatic program thereby directly links two unique and disparate tumor microenvironments: the hypoxic, nutrient-rich BM and the relatively hyperoxic, nutrient and glucose-poor LM. Our new preliminary data suggest that, after metastatic colonization, integrin a6 also plays an essential role in BC growth in the LM by promoting mitochondrial integrity and mediating an adaptive metabolic shift between glycolytic and oxidative metabolism. Our in vitro preliminary findings demonstrate that genetic deletion or antibody neutralization of a6 prevents BC cell transition to oxidative phosphorylation, induces mitochondrial dysfunction, and blocks BC survival during glucose deprivation. Moreover, in vivo pilot data show that anti-a6 blocking antibody treatment increases overall and clinical LM disease-free survival in a mouse model of BC LM metastasis. Our overarching hypothesis, therefore, is that integrin a6 plays a previously unrecognized role as a regulator of BC adaptive responses to metabolic stress, allowing tumor survival and growth in the nutrient-poor LM microenvironment. The specific aims of this proposal will 1) Establish the role of integrin a6 in mediating a metabolic transition to oxidative metabolism and protecting against mitochondrial dysfunction; 2) Investigate the function of integrin a6+ in pro-tumoral cross-talk between LM macrophages and BC; and 3) Test the efficacy of novel, therapeutic human anti-a6 antibodies (Abs) to block BC survival in the LM of xenografted mice through effects on metabolic and oxidative stress adaptations. In vitro models of the LM are highly useful but cannot recapitulate all aspects of the 3-dimensional microenvironment of this tissue, in part due to our limited understanding of the complex array of cell types, matrix molecules, and the cytokine milieu in this tissue during health and disease. For this reason, our in vivo models of LM metastasis are essential to validate in silico and in vitro observations. Insights from these studies will establish new functions of integrin a6 in the LM metastatic cascade and inform translation of anti-a6 Abs to the clinic. This approach aims to shift the treatment paradigm for LM disease away from minimally effective cytotoxic therapies toward molecularly targeted exploitation of microenvironment-based vulnerabilities. Project Number: 1R01CA314256-01 | Fiscal Year: 2026 | NIH Institute/Center: National Cancer Institute (NCI) | Principal Investigator: Dorothy Sipkins | Institution: DUKE UNIVERSITY, DURHAM, NC | Award Amount: $626,475 | Activity Code: R01 | Study Section: Special Emphasis Panel[ZRG1 BTC-Y (81)] View on NIH RePORTER: https://reporter.nih.gov/project-details/11389659