Seminar Series: Microenvironments, Signalling and Cell Dynamics | Hanna Taipaleenmäki & Matthias Krause

Seminar Series: Microenvironments, Signalling and Cell Dynamics

Hanna Taipaleenmäki
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Institute of Musculoskeletal Medicine, Musculoskeletal University Center Munich, Planegg, Germany

Beyond the Vicious Cycle: Microenvironmental Control of Bone Metastasis

Bone is one of the most frequent sites of metastasis in advanced cancer, where metastatic lesions cause major morbidity through pain, fractures, hypercalcemia, and bone marrow dysfunction. Bone metastasis has classically been described through the concept of a “vicious cycle,” in which bone remodeling is disrupted by tumor cells, leading to osteolysis and the release of growth-promoting factors that further support metastatic progression. Although this framework remains influential, the cellular and molecular complexity of the bone metastatic niche is not fully captured by this model. In this seminar, new roles for osteoblast-lineage cells and osteoclasts will be discussed, with emphasis on how metastatic outgrowth is shaped by the bone microenvironment. Interactions between tumor cells and bone-resident remodeling compartments will be highlighted, as well as their roles in regulating niche architecture and creating therapeutically exploitable vulnerabilities. By revisiting the vicious cycle from a broader microenvironmental perspective, new insights into the mechanisms that drive bone metastasis and potential strategies for intervention will be presented.

Selected references

* Maeda M, Saito H, Ribet ABP, Hesse E, Taipaleenmäki H. Tgif1-deficiency impairs osteoclast differentiation through PP2A-mediated ERK1/2 dephosphorylation and attenuates bone loss in mice. J Bone Miner Res. 2025
* Bolamperti S, Saito H, Heerdmann S, Hesse E, Taipaleenmäki H. Tgif1-deficiency impairs cytoskeletal architecture in osteoblasts by activating PAK3 signaling. Elife. 2024 Apr 25;13:RP94265
* Taipaleenmäki H, Saito H, Schröder S, Maeda M, Mettler R, Ring M, Rollmann E, Gasser A, Haasper C, Gehrke T, Weiss A, Grimm SK, Hesse E. Antagonizing microRNA-19a/b augments PTH anabolic action and restores bone mass in osteoporosis in mice. EMBO Mol Med. 2022 Nov 8;14(11):e13617
* Hesse E, Schröder S, Brandt D, Pamperin J, Saito H, Taipaleenmäki H. Sclerostin inhibition alleviates breast cancer-induced bone metastases and muscle weakness. JCI Insight. 2019 Apr 9;5(9):e125543

Matthias Krause
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King's College London, UK

Actin cytoskeleton regulation at the intersection of endocytosis, Wnt signalling, and cell migration

How cells internalise surface receptors controls everything from embryonic development to tissue maintenance, yet the molecular machinery driving this remains incompletely understood. Canonical Wnt signalling is essential for both, and while Wnt receptor internalisation is required for pathway activation, how this uptake occurs has been controversial. Two endocytic routes exist: classical Clathrin-Mediated Endocytosis (CME), and the more recently discovered Fast Endophilin-Mediated Endocytosis (FEME) — a rapid, clathrin-independent mechanism operating at the leading edge of migrating cells. In the first of two stories, we show that Wnt3a simultaneously triggers both CME and FEME of Wnt receptors, even at low ligand concentrations sufficient for pathway activation, resolving previous controversies. This efficient endocytosis is specifically facilitated by the actin regulator Mena — identifying it as a key and unexpected mediator of Wnt receptor complex internalisation and Wnt activation.
In a second story, we address how actin dynamics are regulated during FEME itself — a question that has remained open since the pathway was discovered. NHSL1, a Nance-Horan Syndrome protein family member, controls cell protrusions and migration, but also localises to vesicular compartments where its function has been unknown. We show that NHSL1 and its uncharacterised family member NHSL2 cooperate with endophilin A2 and the actin regulators Ena/VASP to coordinate actin polymerisation and membrane invagination, thereby driving FEME. Together, these two stories reveal how actin cytoskeleton regulators operate at the interface of endocytosis, cell signalling, and migration, opening new questions about how cytoskeletal dynamics are coupled to receptor trafficking in development and disease.

Selected references

* Narayan KB, James HP, Cope J, Mondal S, Baeyens L, Milano F, Zheng J, Krause M, Baumgart T. Endophilin-lamellipodin-VASP, key components in fast endophilin-mediated endocytosis, control actin polymerization within liquid-like condensates. J Biol Chem. 2025 Dec;301(12):110834
* Law AL, Jalal S, Pallett T, Mosis F, Guni A, Brayford S, Yolland L, Marcotti S, Levitt JA, Poland SP, Rowe-Sampson M, Jandke A, Köchl R, Pula G, Ameer-Beg SM, Stramer BM, Krause M. Nance-Horan Syndrome-like 1 protein negatively regulates Scar/WAVE-Arp2/3 activity and inhibits lamellipodia stability and cell migration. Nat Commun. 2021 Sep 28;12(1):5687
* Vehlow A, Soong D, Vizcay-Barrena G, Bodo C, Law AL, Perera U, Krause M. Endophilin, Lamellipodin, and Mena cooperate to regulate F-actin-dependent EGF-receptor endocytosis. EMBO J. 2013 Oct 16;32(20):2722-34