The current clinical care of glioblastomas leaves behind invasive, radio‐ and chemo‐resistant cells. We recently identified mammary‐derived growth inhibitor ( MDGI / FABP 3 ) as a biomarker for invasive gliomas. Here, we demonstrate a novel function for MDGI in the maintenance of lysosomal membrane integrity, thus rendering invasive glioma cells unexpectedly vulnerable to lysosomal membrane destabilization. MDGI silencing impaired trafficking of polyunsaturated fatty acids into cells resulting in significant alterations in the lipid composition of lysosomal membranes, and subsequent death of the patient‐derived glioma cells via lysosomal membrane permeabilization ( LMP ). In a preclinical model, treatment of glioma‐bearing mice with an antihistaminergic LMP ‐inducing drug efficiently eradicated invasive glioma cells and secondary tumours within the brain. This unexpected fragility of the aggressive infiltrating cells to LMP provides new opportunities for clinical interventions, such as re‐positioning of an established antihistamine drug, to eradicate the inoperable, invasive, and chemo‐resistant glioma cells from sustaining disease progression and recurrence.

Glioma stem cells (GSCs) drive propagation and therapeutic resistance of glioblastomas, the most aggressive diffuse brain tumors. However, the molecular mechanisms that maintain the stemness and promote therapy resistance remain poorly understood. Here we report CD109/STAT3 axis as crucial for the maintenance of stemness and tumorigenicity of GSCs and as a mediator of chemoresistance. Mechanistically, CD109 physically interacts with glycoprotein 130 to promote activation of the IL-6/STAT3 pathway in GSCs. Genetic depletion of CD109 abolished the stemness and self-renewal of GSCs and impaired tumorigenicity. Loss of stemness was accompanied with a phenotypic shift of GSCs to more differentiated astrocytic-like cells. Importantly, genetic or pharmacologic targeting of CD109/STAT3 axis sensitized the GSCs to chemotherapy, suggesting that targeting CD109/STAT3 axis has potential to overcome therapy resistance in glioblastoma.

Diffusive by nature, glioma challenges clinical care by the impossibility of complete surgical resection of tumor, leaving the radio-and chemoresistant cells responsible for recurrence intact. We identified mammary-

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Malignant brain tumors represent a surgical and therapeutic challenge. Despite major breakthrough in the precision neurosurgery and the personalized medicine, it remains impossible to circumvent the tumor relapse. This is due to the highly infiltrative nature of the glioma cells, with single tumor-initiating cells invading far distances in the brain. However, we recently identified a major flaw in the invasive tumor cell biology: a high sensitivity to the lysosomal membrane permeabilization (LMP). We first identified the fatty acid binding-protein 3 (FABP3) specifically expressed by invasive gliomas cells. Expression of FABP3 is indispensable to the transportation of poly-unsaturated fatty acids (PUFAs), which cannot be otherwise synthetized by the cells, from the extracellular space to biological membranes. Silencing of FABP3 stopped the supply of PUFAs that are essential to the lysosomal membrane maintenance. Induction of the LMP activated a cascade of events including the release of the lysosomal cathepsins in the cytosol, leading to the tumor cell death. Interestingly, the specific killing of invasive glioma cells through the LMP can be achieved by using lysosomotropic drugs, such as anti-histamines. These cationic amphiphilic molecules accumulate in the lysosome and induce the phospholipidosis of the lysosomal membrane. We therefore tested the ability of the blood-brain-barrier permeable clemastine, an anti-histamine, to reduce the tumorigenicity several patient-derived gliomas implanted in nude mice. Although clemastine treatment did not modify the primary tumor mass growth, it completely eradicated the invasive population. These promising results obtained by therapeutic activation of the LMP could also be beneficial for other aggressive cancers models, such as brain metastases of breast cancer or metastatic pancreatic cancer. Citation Format: Vadim Le Joncour, Pauliina Filppu, Minna Holopainen, Maija Hyvönen, S. Pauliina Turunen, Harri Sihto, Isabel Burghardt, Juha Jääskeläinen, Michael Weller, Kaisa Lehti, Reijo Käkela, Pirjo Laakkonen. Novel therapeutic option targeting the tumor cell lysosomes [abstract]. In: Proceedings of the Annual Meeting of the American Association for Cancer Research 2020; 2020 Apr 27-28 and Jun 22-24. Philadelphia (PA): AACR; Cancer Res 2020;80(16 Suppl):Abstract nr LB-055.