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• Bergundhaugen, Marie; Sneeggen, Marte & Progida, Cinzia (2026). Nexilin promotes calcium-dependent endo-lysosomal fission required for retrograde transport. Cell Communication and Signaling. 24(1), p. 1–18. doi: 10.1186/s12964-025-02628-8. Full text in Research Archive Show summary

  Late endosomes and lysosomes (LE/Lys) are dynamic organelles primarily involved in the degradation of macromolecules within cells. Beyond this role, they are crucial for nutrient sensing, calcium signalling, cell proliferation and migration. The cytoskeleton is essential for the proper trafficking and function of LE/Lys. However, while the role of microtubules is well-established, the function of the actin cytoskeleton at LE/Lys is less understood. In this work, we performed an siRNA screen to identify actin regulators that play a role at LE/Lys. The screen revealed that the F-actin-binding protein nexilin regulates LE/Lys size as its depletion leads to their enlargement. We show that this is a consequence of inhibited LE/Lys fission and affects the retrograde transport from late endosomes to Golgi. Moreover, our data demonstrate that nexilin interacts with the small GTPase Rab7b and the lysosomal calcium channel TRPML1, and that TRPML1 activation rescues the LE/Lys enlargement caused by nexilin depletion. Taken together, our results indicate that nexilin mediates the interaction between LE/Lys and the acto-myosin cytoskeleton required for the calcium-dependent fission of these organelles.

• Schink, Kay Oliver; Tan, Kia Wee; Spangenberg, Helene; Martorana, Domenica; Sneeggen, Marte & Stévenin, Virginie [Show all 10 contributors for this article] (2021). The phosphoinositide coincidence detector Phafin2 promotes macropinocytosis by coordinating actin organisation at forming macropinosomes. Nature Communications. 12(1), p. 1–17. doi: 10.1038/s41467-021-26775-x. Full text in Research Archive Show summary

  Abstract Uptake of large volumes of extracellular fluid by actin-dependent macropinocytosis has an important role in infection, immunity and cancer development. A key question is how actin assembly and disassembly are coordinated around macropinosomes to allow them to form and subsequently pass through the dense actin network underlying the plasma membrane to move towards the cell center for maturation. Here we show that the PH and FYVE domain protein Phafin2 is recruited transiently to newly-formed macropinosomes by a mechanism that involves coincidence detection of PtdIns3P and PtdIns4P. Phafin2 also interacts with actin via its PH domain, and recruitment of Phafin2 coincides with actin reorganization around nascent macropinosomes. Moreover, forced relocalization of Phafin2 to the plasma membrane causes rearrangement of the subcortical actin cytoskeleton. Depletion of Phafin2 inhibits macropinosome internalization and maturation and prevents KRAS-transformed cancer cells from utilizing extracellular protein as an amino acid source. We conclude that Phafin2 promotes macropinocytosis by controlling timely delamination of actin from nascent macropinosomes for their navigation through the dense subcortical actin network.

• Sneeggen, Marte; Guadagno, Noemi Antonella & Progida, Cinzia (2020). Intracellular Transport in Cancer Metabolic Reprogramming. Frontiers in Cell and Developmental Biology. 8. doi: 10.3389/fcell.2020.597608. Full text in Research Archive Show summary

  Tumor progression is a complex process consisting of several steps characterized by alterations in cellular behavior and morphology. These steps include uncontrolled cell division and proliferation, invasiveness and metastatic ability. Throughout these phases, cancer cells encounter a changing environment and a variety of metabolic stress. To meet their needs for energy while they proliferate and survive in their new environment, tumor cells need to continuously fine-tune their metabolism. The connection between intracellular transport and metabolic reprogramming during cancer progression is emerging as a central process of cellular adaptation to these changes. The trafficking of proteolytic enzymes, surface receptors, but also the regulation of downstream pathways, are all central to cancer progression. In this review, we summarize different hallmarks of cancer with a special focus on the role of intracellular trafficking in cell proliferation, epithelial to mesenchymal transition as well as invasion. We will further emphasize how intracellular trafficking contributes to the regulation of energy consumption and metabolism during these steps of cancer progression.

• Sneeggen, Marte; Schink, Kay Oliver & Stenmark, Harald (2019). Tumor suppression by control of matrix metalloproteinase recycling. Molecular and Cellular Oncology (MCO). 6(6), p. 1–3. doi: 10.1080/23723556.2019.1646606. Full text in Research Archive Show summary

  Secretion of matrix metalloproteinases (MMPs) enables cancer cells to degrade extracellular matrix, thus promoting tumor invasion and metastasis. We have recently found that the endosomal protein WDFY2 serves as a gatekeeper for MMP recycling from endosomes and that deletion of WDFY2, which is frequently lost in metastatic cancers, causes increased matrix degradation and cell invasion.

• Sneeggen, Marte; Pedersen, Nina Marie; Campsteijn, Coen; Haugsten, Ellen Margrethe; Stenmark, Harald & Schink, Kay Oliver (2019). WDFY2 restrains matrix metalloproteinase secretion and cell invasion by controlling VAMP3-dependent recycling. Nature Communications. 10(1), p. 1–20. doi: 10.1038/s41467-019-10794-w. Full text in Research Archive Show summary

  Cancer cells secrete matrix metalloproteinases to remodel the extracellular matrix, which enables them to overcome tissue barriers and form metastases. The membrane-bound matrix metalloproteinase MT1-MMP (MMP14) is internalized by endocytosis and recycled in endosomal compartments. It is largely unknown how endosomal sorting and recycling of MT1-MMP are controlled. Here, we show that the endosomal protein WDFY2 controls the recycling of MT1-MMP. WDFY2 localizes to endosomal tubules by binding to membranes enriched in phosphatidylinositol 3-phosphate (PtdIns3P). We identify the v-SNARE VAMP3 as an interaction partner of WDFY2. WDFY2 knockout causes a strong redistribution of VAMP3 into small vesicles near the plasma membrane. This is accompanied by increased, VAMP3-dependent secretion of MT1-MMP, enhanced degradation of extracellular matrix, and increased cell invasion. WDFY2 is frequently lost in metastatic cancers, most predominantly in ovarian and prostate cancer. We propose that WDFY2 acts as a tumor suppressor by serving as a gatekeeper for VAMP3 recycling.

• O'Farrell, Fergal; Lobert, Viola; Sneeggen, Marte; Jain, Ashish; Katheder, Nadja Sandra & Wenzel, Eva [Show all 11 contributors for this article] (2017). Class III phosphatidylinositol-3-OH kinase controls epithelial integrity through endosomal LKB1 regulation. Nature Cell Biology. ISSN 1465-7392. 19(12), p. 1412–1423. doi: 10.1038/ncb3631. Full text in Research Archive
• O'Farrell, Fergal; Lobert, Viola; Sneeggen, Marte; Jain, Ashish; Katheder, Nadja Sandra & Wenzel, Eva [Show all 11 contributors for this article] (2017). Class III phosphatidylinositol-3-OH kinase controls epithelial integrity through endosomal LKB1 regulation. Nature Cell Biology. ISSN 1465-7392. 19, p. 1412–1423. doi: 10.1038/ncb3631. Full text in Research Archive

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