Dr Samantha Stehbens

ARC Future Fellow and IMB Fellow

Institute for Molecular Bioscience

Affiliate IMB & ARC Future Fellow

The University of Queensland Diamantina Institute
Faculty of Medicine

Affiliate Senior Research Fellow

School of Biomedical Sciences
Faculty of Medicine
s.stehbens@uq.edu.au
+61 7 334 62444

Overview

Dr Stehbens is a cell biologist with a long-standing interest in understanding the fundamental mechanisms that regulate cell adhesion and the cytoskeleton. She has made key contributions to the fields of quantitative microscopy, cell motility, adhesion and the cytoskeleton with publications spanning multiple fields from ion channels in brain cancer, to growth factor signalling and autophagy. Her research group aims to understand the fundamental principles of how cells integrate secreted and biomechanical signals from their local microenvironment to facilitate movement and survival. They have uncovered an entirely novel role for the microtubule cytoskeleton in protecting cells from cortical and nuclear rupture during cell migration in 3D cell migration and invasion. Using patient-derived tumour cells, coupled to genetic alteration and substrate microfabrication, they use state-of-the-art microscopy to understand the mechanisms of cell migratory behaviour required for cancer cells to traverse the body during metastasis.

Her graduate work in the laboratory of Alpha Yap (IMB IQ) discovered how the microtubule cytoskeleton regulates cell-cell adhesion. After which she relocated to The University of California San Francisco (UCSF) to work with Prof Wittmann, a microtubule biologist who is an expert in live-cell spinning disc microscopy. Here she worked at the cutting edge of biology imaging advancements as the greater bay area research community combines several of the top-laboratories for imaging technologies. Supported by a competitive American Heart Fellowship Post-Doctoral fellowship, she identified how microtubules coordinate protease secretion during migration to mediate cell-matrix adhesion disassembly. In 2013, she returned to Australia to expand her imaging-based skill set to focus on models of cancer cell biology. Working with Prof. Pamela Pollock (QUT) she uncovered how activating FGFR2 mutations resulted in a loss of cell polarity potentiating migration and invasion in endometrial cancer. Following this, she worked with Prof. Nikolas Haass (UQDI) a melanoma expert, investigating the role of microtubule +TIP proteins in 3D models of metastatic invasion before starting her lab at the Institute for Molecular Bioscience as an ARC Future Fellow.

Lab Overview

Cells in living organisms navigate highly crowded three-dimensional environments, where their coordinated migration provides the driving force behind developmental and homeostatic tissue maintenance. Our research aims to understand the fundamental principles underpinning how cells integrate secreted and biomechanical signals from their local microenvironment to facilitate cell movement and survival. We apply these findings to understand how cancer cells exploit this to metastasise or spread to distal tissues. We hypothesise that targeting the crosstalk between the cytoskeleton and the mechanical micro-environment, can be developed as an anti-metastatic approach.

Cancer cells spread aggressively through tissues by adapting their cell shape to fit the environment in addition to altering their environment so they can squeeze through tight tissue spaces. Cancer cells sense and become more invasive following changes in the biophysical properties their microenvironment including increases in stromal stiffness and interstitial fluid pressures. These changes make cancer cells mechanically compliant and adaptive to fluctuations in their surrounding environment allowing them to alter their shape to fit matrix physical attributes. As such, cells need mechanisms in place to 1) detect these physical limits, 2) deform their cortex whilst producing mechanical force for forward locomotion and 3) orient themselves to move through tissues. We focus on understanding- at the molecular level- how the microtubule cytoskeleton and microtubule associated proteins called +TIPs, regulate how cells move through physically challenging environments. To do this we utilize cutting-edge methodology including microchannel fabrication, novel light sheet microscopy, quantitative imaging methods in combination with patient-derived cell and 3D hydrogel models to recapitulate the 3D microenvironment.

Our research areas include:

  • Cytoskeleton
  • Cell adhesion
  • Cell migration
  • Cell mechanics
  • Cancer cell biology

Areas of Expertise

Microtubules and Cell-Cell Adhesion

My early research, in the laboratory of Professor Alpha Yap, focused on understanding how the microtubule cytoskeleton regulates E-cadherin-based cell-cell adhesion. This work was the first to discover that it was the dynamacity, not simply the tethering, of the microtubule cytoskeleton that was critical for E-cadherin accumulation and junctional reinforcement. This was in addition to defining a previously unappreciated role for the cytokinetic machinery (Ect2) in regulating cell-cell adhesion

  • Stehbens, S.J., …,and Yap, A. S. (2006). Dynamic Microtubules Regulate the Local Concentration of E-cadherin at Cell-Cell Contacts. Journal of Cell Science 119: 1801-1811
  • Ratheesh, A., … Stehbens, S.J., and Yap, A.S. (2012). Centralspindlin and α-catenin regulate Rho signalling at the epithelial zonula adherens. Nature Cell Biology 14(8): 818-28

Microtubules and Cell-Matrix Adhesion

Following my PhD, I relocated to the University of California San Francisco to work with Professor Torsten Wittmann, an expert in live-cell spinning disc microscopy and microtubule functions during cell motility. This work was dogma changing and established how the microtubule interacting protein, CLASP, facilitates targeted protease secretion at focal adhesions during epithelial sheet migration to mediate cell-matrix adhesion disassembly, from the inside-out. It includes the first observation of live, directed exocytosis of the matrix protease MT1MMP at focal adhesions. Our work pioneered the combined application of quantitative live-cell protein dynamics and the application of the novel super resolution imaging technique, SAIM (Scanning Angle Interference Microscopy). During my time at UCSF I learnt how to custom design live-cell microscopes with these live-cell imaging platforms now commercially distributed as the Spectral Diskovery and Andor Dragonfly.

  • Stehbens, S.J., … and Wittmann., T (2014). CLASPs link focal-adhesion-associated microtubule capture to localized exocytosis and adhesion site turnover. Nature Cell Biology 16(6): 558-570
  • Stehbens, S.J., and Witmann, T. (2014) Analysis of focal adhesion turnover: a quantitative live-cell imaging example. Methods in Cell Biology 123: 335-46
  • Stehbens, S.J., and Witmann, T. (2012) Targeting and transport: how microtubules control focal adhesion dynamics. Journal of Cell Biology 20, 198(4): 481-9

Cell Morphology and Cancer Biology

In 2013 I returned to Australia, joining the lab of Pamela Pollock with focus on applying my skill set to have translational impact. Here I described the impact of activating FGFR2b-mutations on endometrial cancer progession. These findings uncovered collective cell polarity and invasion as common targets of disease-associated FGFR2 mutations that lead to shorter survival in endometrial cancer patients.

Stehbens, S.J, Ju, R.J and Pollock P.M. (2018) FGFR2b activating mutations disrupt cell polarity to potentiate migration and invasion in endometrial cancer. Journal of Cell Science, 131(15)

Microtubules in Metastatic Plasticity

In 2017, I joined the Experimental Melanoma Group at UQDI, where I work together with Professor Nikolas Haass in applying innovative live-cell spinning disc confocal imaging and biosensor approaches to understand cell-cell and cell-matrix interactions of melanoma with its microenvironment. Our work explores the adaptive role that the microtubule cytoskeleton plays in facilitating cell shape plasticity, matrix remodelling and resistance to compression during migration in complex 3D matrix models of metastatic melanoma invasion. We are fundamentally interested in understanding the reciprocal biophysical relationship between the microtubule cytoskeleton and the microenvironment during melanoma invasion, with the aim to expand our findings to other metastatic cancers.

Ju, Robert J., Stehbens, Samantha J., Haass, Nikolas K. 2018, ‘The Role of Melanoma Cell-Stroma Interaction in Cell Motility, Invasion, and Metastasis’, Frontiers in Medicine, vol. 5

Research Interests

  • Microtubules, motility and mechanics
    Innovative imaging and cell biology approaches have recently uncovered novel biology that is unique to cells navigating confined 3Dimensional spaces vs 2D, underlining the significance of understanding cell migration and invasion in mechanically relevant cell culture models. As a cells navigates its local environment, the adaptive migration strategies they deploy are greatly influenced by the physical parameters of the microenvironment. As such, the mechanical interrelationship between the cell cytoskeleton, adhesion, matrix density, porosity, curvature and stiffness is an exciting emergent research theme. My lab's current work focuses on understanding the fundamental mechanisms governing the bi-directional relationship between cells and extracellular matrix during 3D invasion with a focus on the contribution of the microtuble cytoskeleon in a metastatic cancer setting. Metastatic success requires cells to navigate complex cellular environments, adapting either their shape to navigate between matrix fibres or adapting their environment to facilitate movement between tight spaces. We are interested in: Microtubule-dependent positioning of organelles, implications for cell migration Understanding the role of microtubules in protecting cells from mechanical stress Regulation of protease secretion in 3D environments by biophysical cues; can cells "digest on demand"?
  • Microtubules in Metastatic Melanoma Invasion
    We explore the adaptive role that the microtubule cytoskeleton plays in facilitating cell shape plasticity, matrix remodelling and resistance to compression during migration in complex 3D matrix models of metastatic melanoma invasion. We aim to understand the role of the mechano-environment in metastatic disease and therapy resistance. To do this we apply innovative live-cell imaging technologies, microfluidics and biosensor approaches to understand cell-cell and cell-matrix interactions of melanoma with its microenvironment.

Research Impacts

Our research aims to

  • facilitate the development of advanced imaging techniques and technology, by bridging the gap between optical physicists and fundamental biologists to facilitate the transition of these technologies into research institutes both within Australia and around the world.
  • Understanding metastasis to open new therapeutics opportunities. As tumours proliferate uncontrollably, the focus of clinical therapies for cancer have concentrated on the development of effective cytotoxic drugs. This era of tumour biology has defined the key response criteria for therapeutic agents targeting solid cancers as a reduction in tumour size. However, with the gain of an invasive phenotype being necessary for a tumour to metastasise, and the association of morbidity with metastatic disease, there is a strong precedent to refocus our efforts to understand metastasis. Thus, to bring about revolutionary improvements our understanding of cancer biology we need to not only study proliferation but focus towards the microenvironment and understanding how tumour cells adapt to move. Our work will open this new frontier by bringing key mechanistic insights of metastasis with the potential to reveal new therapeutical leads.

Qualifications

  • Bachelor of Science, The University of Queensland
  • Bachelor of Science with Honours Class 1, The University of Queensland
  • Doctor of Philiosophy, The University of Queensland

Publications

  • Sapoznik, Etai, Chang, Bo-Jui, Huh, Jaewon, Ju, Robert J., Azarova, Evgenia, Pohlkamp, Theresa, Welf, Erik S., Broadbent, David, Carisey, Alexandre F., Stehbens, Samantha J., Lee, Kyung-Min, Marin, Arnaldo, Hanker, Ariella B., Schmidt, Jens C., Arteaga, Carlos L., Bin Yang, , Kobayashi, Yoshihiko, Tata, Purushothama Rao, Kruithoff, Rory, Doubrovinski, Konstantin, Shepherd, Douglas P., Millett-Sikking, Alfred, York, Andrew G., Dean, Kevin M. and Fiolka, Reto P. (2020). A versatile oblique plane microscope for large-scale and high-resolution imaging of subcellular dynamics. eLife, 9 e57681, 1-39. doi: 10.7554/elife.57681

  • Wu, Selwin K., Gomez, Guillermo A., Stehbens, Samantha J. and Smutny, Michael (2020). Editorial: Forces in biology-cell and developmental mechanobiology and its implications in disease. Frontiers in Cell and Developmental Biology, 8 598179, 598179. doi: 10.3389/fcell.2020.598179

  • Harrington, Brittney S., He, Yaowu, Khan, Tashbib, Puttick, Simon, Conroy, Paul J., Kryza, Thomas, Cuda, Tahleesa, Sokolowski, Kamil A., Tse, Brian W.C ., Robbins, Katherine K., Arachchige, Buddhika J., Stehbens, Samantha J., Pollock, Pamela M., Reed, Sarah, Weroha, S. John, Haluska, Paul, Salomon, Carlos, Lourie, Rohan, Perrin, Lewis C., Law, Ruby H. P., Whisstock, James C. and Hooper, John D. (2020). Anti-CDCP1 immuno-conjugates for detection and inhibition of ovarian cancer. Theranostics, 10 (5), 2095-2114. doi: 10.7150/thno.30736

View all Publications

Supervision

  • Doctor Philosophy

  • Doctor Philosophy

  • Doctor Philosophy

View all Supervision

Available Projects

  • Extracerebral brain metastases account for 90% of all brain malignancies, outnumbering primary brain cancers. Melanoma originates in collagen rich skin, yet exhibits trophisim to the brain which exhibits unique mechanical properties due to the brain ECM being heavily composed of glycosaminoglycans (GAGs) including hyaluronic acid (HA) and tenascin. Mechanical stiffness of the microenvironement plays key roles in cell survivial, response to therapies and metastatic ability of cancer. The mechanical role of the brain microenvironment remains poorly explored for melanoma.

    As such, we are aiming to establish mechanically relevant three-dimensional cell culture models of MBM (melanoma brain metastases) from patient-derived cell lines. Investigate MBM motility, proliferation and survival in extra-cerebral (collagen I) and brain (HA) matrices using a combination of high-resolution live-cell microscopy, cutting-edge bio-reporters, immunofluorescence and 3D cell culture.

    We aim to understand the contribution of the mechanical microenvironment and the bi-directional role of the cytoskeleton and cell-matrix adhesions.

  • Innovative imaging and cell biology approaches have recently uncovered novel biology that is unique to cells navigating confined 3Dimensional spaces vs 2D, underlining the significance of understanding cell migration and invasion in mechanically relevant cell culture models. As a cells navigates its local environment, the adaptive migration strategies they deploy are greatly influenced by the physical parameters of the microenvironment. As such, the mechanical interrelationship between the cell cytoskeleton, adhesion, matrix density, porosity, curvature and stiffness is an exciting emergent research theme. My lab's current work focuses on understanding the fundamental mechanisms governing the bi-directional relationship between cells and extracellular matrix during 3D invasion with a focus on the contribution of the microtuble cytoskeleon in a metastatic cancer setting.Metastatic success requires cells to navigate complex cellular environments, adapting either their shape to navigate between matrix fibres or adapting their environment to facilitate movement between tight spaces.

    We have multiple projects including:

    • Microtubule-dependent positioning of organelles, implications for cell migration
    • Understanding the role of microtubules in protecting cells from mechanical stress
    • The role of the mechano-environment in metastatic disease and therapy resistance
    • Regulation of protease secretion in 3D environments; can cells "digest on demand"

View all Available Projects

Publications

Book Chapter

Journal Article

Conference Publication

  • Henser-Brownhill, Tristan, Ju, Robert J., Haass, Nikolas K., Stehbens, Samantha J., Ballestrem, Christoph and Cootes, Timothy F. (2020). Estimation of cell cycle states of human melanoma cells with quantitative phase imaging and deep learning. 2020 IEEE 17th International Symposium on Biomedical Imaging (ISBI), Iowa City, IA United States, 3-7 April 2020. Piscataway, NJ United States: Institute of Electrical and Electronics Engineers. doi: 10.1109/isbi45749.2020.9098458

  • Daignault, S. M., Ju, R. J., Spoerri, L., Stehbens, S. J., Dolcetti, R. and Haass, N. K. (2019). Bortezomib induces immunogenic cell death in melanoma and enhances immune responses in vivo. 49th Annual Meeting of the European Society for Dermatological Research (ESDR), Bordeaux, France, 18-21 September, 2019. Oxford, United Kingdom: Elsevier. doi: 10.1016/j.jid.2019.07.506

  • Daignault, S. M., Ju, R., Spoerri, L., Stehbens, S. J., Hill, D. S., Gabrielli, B., Dolcetti, R. and Haass, N. K. (2019). Bortezomib-induced immunogenic cell death enhances immune response in melanoma. Society for Investigative Dermatology (SID) Meeting, Chicago, Il, United States, 8-11 May, 2019. London, United Kingdom: Nature Publishing Group. doi: 10.1016/j.jid.2019.03.907

  • Daignault, S. M., Spoerri, L., Ju, R. J., Stehbens, S. J., Hill, D. S., Dolcetti, R. and Haass, N. (2019). Enforcing cellular stress promotes apoptotic and immunogenic responses in melanoma. 46th Annual Meeting of the Arbeitsgemeinschaft Dermatologische Forschung (ADF), Munich, Germany, 13-16 March, 2019. Chichester, West Sussex, United Kingdom: Wiley-Blackwell Publishing. doi: 10.1111/exd.13859

  • Ju, R. J., Chhabra, Y., Haass, N. and Stehbens, S. J. (2019). Uncovering microtubule-driven mechanisms of melanoma invasion. 46th Annual Meeting of the Arbeitsgemeinschaft-Dermatologische-Forschung (ADF), Munich Germany, Mar 13-16, 2019. Chichester, West Sussex, United Kingdom: Wiley-Blackwell Publishing.

  • Daignault, S. M., Hill, D. S., Spoerri, L., Stehbens, S., Weninger, W., Gabrielli, B., Dolcetti, R. and Haass, N. K. (2018). Targeting cell cycle phase-specific drug sensitivity for melanoma therapy. 45th Annual Meeting of the Arbeitsgemeinscha-Dermatologische-Forschung (ADF), Zurich, Switzerland, 7-10 March 2018. Chichester, West Sussex, United Kingdom: Wiley-Blackwell Publishing.

Other Outputs

  • Samantha Stehbens (2008). Cadherin-Microtubule Cooperativity. PhD Thesis, Institute for Molecular Bioscience, The University of Queensland.

PhD and MPhil Supervision

Current Supervision

  • Doctor Philosophy — Principal Advisor

    Other advisors:

  • Doctor Philosophy — Associate Advisor

  • Doctor Philosophy — Associate Advisor

    Other advisors:

  • Doctor Philosophy — Associate Advisor

  • Doctor Philosophy — Associate Advisor

  • Doctor Philosophy — Associate Advisor

Possible Research Projects

Note for students: The possible research projects listed on this page may not be comprehensive or up to date. Always feel free to contact the staff for more information, and also with your own research ideas.

  • Extracerebral brain metastases account for 90% of all brain malignancies, outnumbering primary brain cancers. Melanoma originates in collagen rich skin, yet exhibits trophisim to the brain which exhibits unique mechanical properties due to the brain ECM being heavily composed of glycosaminoglycans (GAGs) including hyaluronic acid (HA) and tenascin. Mechanical stiffness of the microenvironement plays key roles in cell survivial, response to therapies and metastatic ability of cancer. The mechanical role of the brain microenvironment remains poorly explored for melanoma.

    As such, we are aiming to establish mechanically relevant three-dimensional cell culture models of MBM (melanoma brain metastases) from patient-derived cell lines. Investigate MBM motility, proliferation and survival in extra-cerebral (collagen I) and brain (HA) matrices using a combination of high-resolution live-cell microscopy, cutting-edge bio-reporters, immunofluorescence and 3D cell culture.

    We aim to understand the contribution of the mechanical microenvironment and the bi-directional role of the cytoskeleton and cell-matrix adhesions.

  • Innovative imaging and cell biology approaches have recently uncovered novel biology that is unique to cells navigating confined 3Dimensional spaces vs 2D, underlining the significance of understanding cell migration and invasion in mechanically relevant cell culture models. As a cells navigates its local environment, the adaptive migration strategies they deploy are greatly influenced by the physical parameters of the microenvironment. As such, the mechanical interrelationship between the cell cytoskeleton, adhesion, matrix density, porosity, curvature and stiffness is an exciting emergent research theme. My lab's current work focuses on understanding the fundamental mechanisms governing the bi-directional relationship between cells and extracellular matrix during 3D invasion with a focus on the contribution of the microtuble cytoskeleon in a metastatic cancer setting.Metastatic success requires cells to navigate complex cellular environments, adapting either their shape to navigate between matrix fibres or adapting their environment to facilitate movement between tight spaces.

    We have multiple projects including:

    • Microtubule-dependent positioning of organelles, implications for cell migration
    • Understanding the role of microtubules in protecting cells from mechanical stress
    • The role of the mechano-environment in metastatic disease and therapy resistance
    • Regulation of protease secretion in 3D environments; can cells "digest on demand"