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1. Pain-causing stinging nettle toxins target TMEM233 to modulate NaV1.7 function

Author

Jami, Sina, Deuis, Jennifer R., Klasfauseweh, Tabea, Cheng, Xiaoyang, Kurdyukov, Sergey, Chung, Felicity, Okorokov, Andrei L., Li, Shengnan, Zhang, Jiangtao, Cristofori-Armstrong, Ben, Israel, Mathilde R., Ju, Robert J., Robinson, Samuel D., Zhao, Peng, Ragnarsson, Lotten, Andersson, Åsa, Tran, Poanna, Schendel, Vanessa, McMahon, Kirsten L., Tran, Hue N. T., Chin, Yanni K.-Y., Zhu, Yifei, Liu, Junyu, Crawford, Theo, Purushothamvasan, Saipriyaa, Habib, Abdella M., Andersson, David A., Rash, Lachlan D., Wood, John N., Zhao, Jing, Stehbens, Samantha J., Mobli, Mehdi, Leffler, Andreas, Jiang, Daohua, Cox, James J., Waxman, Stephen G., Dib-Hajj, Sulayman D., Neely, G. Gregory, Durek, Thomas, and Vetter, Irina

Published
2023
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2. Persister state-directed transitioning and vulnerability in melanoma

Author

Chauvistré, Heike, Shannan, Batool, Daignault-Mill, Sheena M., Ju, Robert J., Picard, Daniel, Egetemaier, Stefanie, Váraljai, Renáta, Gibhardt, Christine S., Sechi, Antonio, Kaschani, Farnusch, Keminer, Oliver, Stehbens, Samantha J., Liu, Qin, Yin, Xiangfan, Jeyakumar, Kirujan, Vogel, Felix C. E., Krepler, Clemens, Rebecca, Vito W., Kubat, Linda, Lueong, Smiths S., Forster, Jan, Horn, Susanne, Remke, Marc, Ehrmann, Michael, Paschen, Annette, Becker, Jürgen C., Helfrich, Iris, Rauh, Daniel, Kaiser, Markus, Gul, Sheraz, Herlyn, Meenhard, Bogeski, Ivan, Rodríguez-López, José Neptuno, Haass, Nikolas K., Schadendorf, Dirk, and Roesch, Alexander

Published
2022
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4. Compression-dependent microtubule reinforcement enables cells to navigate confined environments

Author

Ju, Robert J., Falconer, Alistair D., Schmidt, Christanny J., Enriquez Martinez, Marco A., Dean, Kevin M., Fiolka, Reto P., Sester, David P., Nobis, Max, Timpson, Paul, Lomakin, Alexis J., Danuser, Gaudenz, White, Melanie D., Haass, Nikolas K., Oelz, Dietmar B., and Stehbens, Samantha J.

Abstract

Cells migrating through complex three-dimensional environments experience considerable physical challenges, including tensile stress and compression. To move, cells need to resist these forces while also squeezing the large nucleus through confined spaces. This requires highly coordinated cortical contractility. Microtubules can both resist compressive forces and sequester key actomyosin regulators to ensure appropriate activation of contractile forces. Yet, how these two roles are integrated to achieve nuclear transmigration in three dimensions is largely unknown. Here, we demonstrate that compression triggers reinforcement of a dedicated microtubule structure at the rear of the nucleus by the mechanoresponsive recruitment of cytoplasmic linker-associated proteins, which dynamically strengthens and repairs the lattice. These reinforced microtubules form the mechanostat: an adaptive feedback mechanism that allows the cell to both withstand compressive force and spatiotemporally organize contractility signalling pathways. The microtubule mechanostat facilitates nuclear positioning and coordinates force production to enable the cell to pass through constrictions. Disruption of the mechanostat imbalances cortical contractility, stalling migration and ultimately resulting in catastrophic cell rupture. Our findings reveal a role for microtubules as cellular sensors that detect and respond to compressive forces, enabling movement and ensuring survival in mechanically demanding environments.

Published
2024
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9. Pain-causing stinging nettle toxins target TMEM233 to modulate NaV1.7 function.

Author

Jami, Sina, Deuis, Jennifer R., Klasfauseweh, Tabea, Cheng, Xiaoyang, Kurdyukov, Sergey, Chung, Felicity, Okorokov, Andrei L., Li, Shengnan, Zhang, Jiangtao, Cristofori-Armstrong, Ben, Israel, Mathilde R., Ju, Robert J., Robinson, Samuel D., Zhao, Peng, Ragnarsson, Lotten, Andersson, Åsa, Tran, Poanna, Schendel, Vanessa, McMahon, Kirsten L., and Tran, Hue N. T.

Subjects
SODIUM channels, STINGING nettle, TOXINS, MEMBRANE proteins, PEPTIDES, SENSORY neurons
Abstract

Voltage-gated sodium (NaV) channels are critical regulators of neuronal excitability and are targeted by many toxins that directly interact with the pore-forming α subunit, typically via extracellular loops of the voltage-sensing domains, or residues forming part of the pore domain. Excelsatoxin A (ExTxA), a pain-causing knottin peptide from the Australian stinging tree Dendrocnide excelsa, is the first reported plant-derived NaV channel modulating peptide toxin. Here we show that TMEM233, a member of the dispanin family of transmembrane proteins expressed in sensory neurons, is essential for pharmacological activity of ExTxA at NaV channels, and that co-expression of TMEM233 modulates the gating properties of NaV1.7. These findings identify TMEM233 as a previously unknown NaV1.7-interacting protein, position TMEM233 and the dispanins as accessory proteins that are indispensable for toxin-mediated effects on NaV channel gating, and provide important insights into the function of NaV channels in sensory neurons. Voltage-gated sodium channels function as multiprotein signaling complexes. Here, authors show that the dispanin TMEM233 is essential for activity of stinging nettle toxins and that co-expression of TMEM233 modulates the gating properties of NaV1.7. [ABSTRACT FROM AUTHOR]

Published
2023
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10. A Microtubule Mechanostat Enables Cells to Navigate Confined Environments

Author

Ju, Robert J., primary, Falconer, Alistair D., additional, Tang, Caitlyn K.X., additional, Dean, Kevin M., additional, Fiolka, Reto P., additional, Sester, David P., additional, Nobis, Max, additional, Timpson, Paul, additional, Lomakin, Alexis J., additional, White, Melanie D., additional, Oelz, Dietmar B., additional, Haass, Nikolas K., additional, and Stehbens, Samantha J., additional

Published
2022
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13. A Single-Objective Light-Sheet Microscope with 200 nm-Scale Resolution

Author

Sapoznik, Etai, Chang, Bo-Jui, Ju, Robert J., Welf, Erik S., Broadbent, David, Carisey, Alexandre F., Stehbens, Samantha J., Lee, Kyung-min, Marín, Arnaldo, Hanker, Ariella B., Schmidt, Jens C., Arteaga, Carlos L., Yang, Bin, Kruithoff, Rory, Shepherd, Doug P., Millett-Sikking, Alfred, York, Andrew G., Dean, Kevin M., and Fiolka, Reto

Abstract

We present a single-objective light-sheet microscope, also known as an oblique-plane microscope, that uses a bespoke glass-tipped tertiary objective and improves the resolution, field of view, usability, and stability over previous variants. Owing to its high numerical aperture optics, this microscope achieves the highest lateral resolution in light-sheet fluorescence microscopy, and its axial resolution is similar to that of Lattice Light-Sheet Microscopy. Given this performance, we demonstrate high-resolution imaging of clathrin-mediated endocytosis, vimentin, the endoplasmic reticulum, membrane dynamics, and natural killer cell-mediated cell death. Furthermore, we image biological phenomena that would be otherwise challenging or impossible to perform in a traditional light-sheet microscope geometry, including cell migration through a confined space within a microfluidic device, photoactivation of PI3K, and diffusion of cytoplasmic rheological tracers at a volumetric rate of 14 Hz.

Published
2020
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14. The Janus-faced role of KDM5B heterogeneity in melanoma: differentiation as a situational driver of both growth arrest and drug-resistance

Author

Chauvistré, Heike, Daignault, Sheena M., Shannan, Batool, Ju, Robert J., Picard, Daniel, Vogel, Felix C. E., Egetemaier, Stefanie, Krepler, Clemens, Rebecca, Vito W., Sechi, Antonio, Kaschani, Farnusch, Keminer, Oliver, Stehbens, Samantha J., Váraljai, Renáta, Ninck, Sabrina, Liu, Qin, Yin, Xiangfan, Jeyakumar, Kirujan, Xiao, Min, Löffek, Stefanie, Kubat, Linda, Spassova, Ivelina, Gul, Sheraz, Rahmann, Sven, Horn, Susanne, Ehrmann, Michael, Paschen, Annette, Becker, Jürgen C., Helfrich, Iris, Rauh, Daniel, Kaiser, Markus, Remke, Marc, Herlyn, Meenhard, Haass, Nikolas K., Schadendorf, Dirk, and Roesch, Alexander

Abstract

Phenotypic intratumoral heterogeneity and temporal transitions between cell differentiation states represent major drivers of tumor fitness in melanoma. Expression of the histone H3K4 demethylase KDM5B/JARID1B follows a highly dynamic equilibrium across melanoma cells. When challenged for example with targeted or cytotoxic drugs, the intrinsically slow-cycling KDM5B high cell state becomes initially enriched, whereas under persistent drug-exposure melanomas decrease KDM5B expression again to re-enter cell proliferation for long-term tumor repopulation. However, the exact role of KDM5B for tumor cell differentiation and fate remained elusive so far. Here, we show that melanoma fitness can be overcome by molecular enforcement of high KDM5B expression levels. KDM5B-up-scaled melanoma cells are transcriptionally reprogramed towards a differentiated melanocytic profile including a slow-cycling state. This effect can be phenocopied by a newly identified chemical compound also leading to decelerated tumor growth. Mechanistically, KDM5B represents a checkpoint for coordinating the differentiation phenotype of melanoma cells via transcriptional reprograming, cell cycle delay, and attenuation of cytokinetic abscission. These findings indicate that tumor plasticity per se , i.e. the necessity of cancer cells to dynamically switch between different cell cycling and differentiation states, represents an important oncologic process that can be chemically overcome.

Published
2020
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15. A versatile oblique plane microscope for large-scale and high-resolution imaging of subcellular dynamics

Author

Sapoznik, Etai, primary, Chang, Bo-Jui, additional, Huh, Jaewon, additional, Ju, Robert J, additional, Azarova, Evgenia V, additional, Pohlkamp, Theresa, additional, Welf, Erik S, additional, Broadbent, David, additional, Carisey, Alexandre F, additional, Stehbens, Samantha J, additional, Lee, Kyung-Min, additional, Marín, Arnaldo, additional, Hanker, Ariella B, additional, Schmidt, Jens C, additional, Arteaga, Carlos L, additional, Yang, Bin, additional, Kobayashi, Yoshihiko, additional, Tata, Purushothama Rao, additional, Kruithoff, Rory, additional, Doubrovinski, Konstantin, additional, Shepherd, Douglas P, additional, Millett-Sikking, Alfred, additional, York, Andrew G, additional, Dean, Kevin M, additional, and Fiolka, Reto P, additional

Published
2020
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16. Caveolae Control Contractile Tension for Epithelia to Eliminate Tumor Cells

Author

Teo, Jessica L., primary, Gomez, Guillermo A., additional, Weeratunga, Saroja, additional, Davies, Elizabeth M., additional, Noordstra, Ivar, additional, Budnar, Srikanth, additional, Katsuno-Kambe, Hiroko, additional, McGrath, Meagan J., additional, Verma, Suzie, additional, Tomatis, Vanesa, additional, Acharya, Bipul R., additional, Balasubramaniam, Lakshmi, additional, Templin, Rachel M., additional, McMahon, Kerrie-Ann, additional, Lee, Yoke Seng, additional, Ju, Robert J., additional, Stebhens, Samantha J., additional, Ladoux, Benoit, additional, Mitchell, Christina A., additional, Collins, Brett M., additional, Parton, Robert G., additional, and Yap, Alpha S., additional

Published
2020
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17. Author response: A versatile oblique plane microscope for large-scale and high-resolution imaging of subcellular dynamics

Author

Sapoznik, Etai, primary, Chang, Bo-Jui, additional, Huh, Jaewon, additional, Ju, Robert J, additional, Azarova, Evgenia V, additional, Pohlkamp, Theresa, additional, Welf, Erik S, additional, Broadbent, David, additional, Carisey, Alexandre F, additional, Stehbens, Samantha J, additional, Lee, Kyung-Min, additional, Marín, Arnaldo, additional, Hanker, Ariella B, additional, Schmidt, Jens C, additional, Arteaga, Carlos L, additional, Yang, Bin, additional, Kobayashi, Yoshihiko, additional, Tata, Purushothama Rao, additional, Kruithoff, Rory, additional, Doubrovinski, Konstantin, additional, Shepherd, Douglas P, additional, Millett-Sikking, Alfred, additional, York, Andrew G, additional, Dean, Kevin M, additional, and Fiolka, Reto P, additional

Published
2020
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19. Persister state-directed transitioning and vulnerability in melanoma

Author

Chauvistré, Heike, primary, Shannan, Batool, additional, Daignault, Sheena M., additional, Ju, Robert J., additional, Picard, Daniel, additional, Egetemaier, Stefanie, additional, Váraljai, Renáta, additional, Sechi, Antonio, additional, Kaschani, Farnusch, additional, Keminer, Oliver, additional, Stehbens, Samantha J., additional, Liu, Qin, additional, Yin, Xiangfan, additional, Jeyakumar, Kirujan, additional, Vogel, Felix C. E., additional, Krepler, Clemens, additional, Rebecca, Vito W., additional, Kubat, Linda, additional, Lueong, Smiths S, additional, Forster, Jan, additional, Horn, Susanne, additional, Remke, Marc, additional, Ehrmann, Michael, additional, Paschen, Annette, additional, Becker, Jürgen C., additional, Helfrich, Iris, additional, Rauh, Daniel, additional, Kaiser, Markus, additional, Gul, Sheraz, additional, Herlyn, Meenhard, additional, Rodríguez-López, José Neptuno, additional, Haass, Nikolas K., additional, Schadendorf, Dirk, additional, and Roesch, Alexander, additional

Published
2020
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21. FGFR2-activating mutations disrupt cell polarity to potentiate migration and invasion in endometrial cancer cell models

Author

Stehbens, Samantha J., Ju, Robert J., Adams, Mark N., Perry, Samuel, Haass, Nikolas K., Bryant, David M., and Pollock, Pamela M.

Subjects
stomatognathic diseases
Abstract

Fibroblast growth factor receptors (FGFRs) are a family of receptor tyrosine kinases that control a diverse range of biological processes during development and in adult tissues. We recently reported that somatic FGFR2 mutations are associated with shorter survival in endometrial cancer. However, little is known about how these FGFR2 mutations contribute to endometrial cancer metastasis. Here, we report that expression of the activating mutations FGFR2N550K and FGFR2Y376C in an endometrial cancer cell model induce Golgi fragmentation, and loss of polarity and directional migration. In mutant FGFR2-expressing cells, this was associated with an inability to polarise intracellular pools of FGFR2 towards the front of migrating cells. Such polarization defects were exacerbated in three-dimensional culture, where FGFR2 mutant cells were unable to form well-organised acini, instead undergoing exogenous ligand-independent invasion. Our findings uncover collective cell polarity and invasion as common targets of disease-associated FGFR2 mutations that lead to poor outcome in endometrial cancer patients.

Published
2018

22. Caveolae set levels of epithelial monolayer tension to eliminate tumor cells

Author

Teo, Jessica L., primary, Gomez, Guillermo A., additional, Noordstra, Ivar, additional, Verma, Suzie, additional, Tomatis, Vanesa, additional, Acharya, Bipul R., additional, Balasubramaniam, Lakshmi, additional, Katsuno-Kambe, Hiroko, additional, Templin, Rachel, additional, McMahon, Kerrie-Ann, additional, Ju, Robert J., additional, Stebhens, Samantha J., additional, Ladoux, Benoit, additional, Parton, Robert G., additional, and Yap, Alpha S., additional

Published
2019
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26. FGFR2-activating mutations disrupt cell polarity to potentiate migration and invasion in endometrial cancer cell models.

Author

Stehbens SJ, Ju RJ, Adams MN, Perry SR, Haass NK, Bryant DM, and Pollock PM

Subjects
Biotinylation, Cell Line, Tumor, Cell Movement genetics, Cell Polarity genetics, Cell Proliferation genetics, Cell Proliferation physiology, Chemotaxis genetics, Chemotaxis physiology, Endometrial Neoplasms genetics, Female, Fluorescent Antibody Technique, HEK293 Cells, Humans, Immunoblotting, Lentivirus genetics, Mutation genetics, Receptor, Fibroblast Growth Factor, Type 2 genetics, Cell Movement physiology, Cell Polarity physiology, Endometrial Neoplasms metabolism, Receptor, Fibroblast Growth Factor, Type 2 metabolism
Abstract

Fibroblast growth factor receptors (FGFRs) are a family of receptor tyrosine kinases that control a diverse range of biological processes during development and in adult tissues. We recently reported that somatic FGFR2 mutations are associated with shorter survival in endometrial cancer. However, little is known about how these FGFR2 mutations contribute to endometrial cancer metastasis. Here, we report that expression of the activating mutations FGFR2 N550K and FGFR2 Y376C in an endometrial cancer cell model induce Golgi fragmentation, and loss of polarity and directional migration. In mutant FGFR2-expressing cells, this was associated with an inability to polarise intracellular pools of FGFR2 towards the front of migrating cells. Such polarization defects were exacerbated in three-dimensional culture, where FGFR2 mutant cells were unable to form well-organised acini, instead undergoing exogenous ligand-independent invasion. Our findings uncover collective cell polarity and invasion as common targets of disease-associated FGFR2 mutations that lead to poor outcome in endometrial cancer patients., Competing Interests: Competing interestsThe authors declare no competing or financial interests., (© 2018. Published by The Company of Biologists Ltd.)

Published
2018
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27. PI3K Inhibitors Synergize with FGFR Inhibitors to Enhance Antitumor Responses in FGFR2 mutant Endometrial Cancers.

Author

Packer LM, Geng X, Bonazzi VF, Ju RJ, Mahon CE, Cummings MC, Stephenson SA, and Pollock PM

Subjects
Aminopyridines pharmacology, Animals, Antineoplastic Combined Chemotherapy Protocols pharmacology, Cell Line, Tumor, Cell Proliferation drug effects, Cell Survival drug effects, Drug Synergism, Endometrial Neoplasms genetics, Female, Gene Expression Regulation, Neoplastic drug effects, Humans, Indazoles pharmacology, Mice, Morpholines pharmacology, Mutation, Phenylurea Compounds pharmacology, Phosphoinositide-3 Kinase Inhibitors, Pyrimidines pharmacology, Receptor, Fibroblast Growth Factor, Type 2 antagonists & inhibitors, Sulfonamides pharmacology, Thiazoles pharmacology, Xenograft Model Antitumor Assays, Aminopyridines administration & dosage, Antineoplastic Combined Chemotherapy Protocols administration & dosage, Endometrial Neoplasms drug therapy, Indazoles administration & dosage, Morpholines administration & dosage, Phenylurea Compounds administration & dosage, Pyrimidines administration & dosage, Receptor, Fibroblast Growth Factor, Type 2 genetics, Sulfonamides administration & dosage, Thiazoles administration & dosage
Abstract

Improved therapeutic approaches are needed for the treatment of recurrent and metastatic endometrial cancer. Endometrial cancers display hyperactivation of the MAPK and PI3K pathways, the result of somatic aberrations in genes such as FGFR2, KRAS, PTEN, PIK3CA , and PIK3R1 The FGFR2 and PI3K pathways, have emerged as potential therapeutic targets in endometrial cancer. Activation of the PI3K pathway is seen in more than 90% of FGFR2 mutant endometrial cancers. This study aimed to examine the efficacy of the pan-FGFR inhibitor BGJ398 with pan-PI3K inhibitors (GDC-0941, BKM120) and the p110α-selective inhibitor BYL719. We assessed synergy in three FGFR2 mutant endometrial cancer cell lines (AN3CA, JHUEM2, and MFE296), and the combination of BGJ398 and GDC-0941 or BYL719 showed strong synergy. A significant increase in cell death and decrease in long-term survival was seen when PI3K inhibitors were combined with BGJ398. Importantly, these effects were seen at low concentrations correlating to only partial inhibition of AKT. The combination of BGJ398 and GDC-0941 showed tumor regressions in vivo , whereas each drug alone only showed moderate tumor growth inhibition. BYL719 alone resulted in increased tumor growth of AN3CA xenografts but in combination with BGJ398 resulted in tumor regression in both AN3CA- and JHUEM2-derived xenografts. These data provide evidence that subtherapeutic doses of PI3K inhibitors enhance the efficacy of anti-FGFR therapies, and a combination therapy may represent a superior therapeutic treatment in patients with FGFR2 mutant endometrial cancer. Mol Cancer Ther; 16(4); 637-48. ©2017 AACR ., (©2017 American Association for Cancer Research.)

Published
2017
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