Menu

Close

Engineering T cells to enhance 3D migration through structurally and mechanically complex tumor microenvironments

Erdem D. Tabdanov, Nelson J. Rodríguez-Merced, Alexander X. Cartagena-Rivera, Vikram V. Puram, Mackenzie K. Callaway, Ethan A. Ensminger, Emily J. Pomeroy, Kenta Yamamoto, Walker S. Lahr, Beau R. Webber, Branden S. Moriarity, Alexander S. Zhovmer, Paolo P. Provenzano

Preprint posted on April 23, 2020 https://www.biorxiv.org/content/10.1101/2020.04.21.051615v1

T cells- Dancing on the grooves

Selected by Ankita Jha

Context:

Extra-cellular matrix (ECM) environments influence cell-migration by providing contact guidance for cells. ECM architecture and stiffness can influence different migratory phenotypes and this phenotypic switching is important for cells to navigate through ECM. Cancer cells utilize phenotypic switching to migrate out of the tumors and undergo metastasis. However, T cells need to effectively infiltrate into the solid tumors and how T cells migrate through complex ECM environments remains to be elucidated (Best et al., 2019; Ray et al., 2017; Provenzano et al., 2006a, 2008b; Tabdanov et al., 2018a, 2018b.)

Major findings:

To understand how T cells migrate through varied ECM architecture and stiffness, the authors have utilized engineered platforms with nano-topography of ‘ridges and grooves’ and variable stiffness, mimicking ECM architecture and mechanical environment respectively. Experiments show that T cells with higher contractility tend to invade in the grooves (similar to pseudopodia, more amoeboid like) whereas cells with relatively lower contractility tend to be less invasive and spread more on the ridges (more mesenchymal-like). With the increase in rigidity of the substrate, the amoeboid invasiveness of the T cells goes down. Cells with higher contractility show strong contact guidance with persistent directional migration. This is regulated by microtubule dynamics where microtubule de-stabilization leads to increase invasiveness. This is corroborated with the findings that microtubule destabilization leads to an increase in contractility by releasing GEF-H1 (Rho-GEF) that activates RhoA pathway. This was shown to be analogous with human CD4+ T cells and cytotoxic mouse T cells migrating in a more complex 3D micro-environment. GEF-H1 knock-out in the presence of microtubule destabilization leads to a decrease in motility suggesting the role of GEF-H1 in regulating the contractility axis and thus T cell motility.

What’s next and my questions to the authors:

Immunotherapy with targeted T cells has to overcome the challenges of complex micro-environment like low pH, lack of nutrients along with the physical barriers, and heterogeneity in the solid tumors. This work focusses on tackling the complexity of ECM architecture and mechanics by perturbing the microtubule-contractility axis and modulating RhoA activity. Microtubule destabilization leads to an increase in the contractility and authors show that this is via GEF-H1, however, GEF-H1 knockdown leads to an increase in the motility of T cells. This seems a little surprising since GEF-H1 knockdown would decrease contractility, I wonder if authors have thoughts about it? Plasticity in the modes of migration is based on the balance between contractility and adhesion, do the authors think one important feature to consider along with the ECM architecture and mechanics would be the availability of adhesive ligands? Do microtubules impact cortical tension and would impact the invasiveness?

References:

Best, S.L., Liu, Y., Keikhosravi, A., Drifka, C.R., Woo, K.M., Mehta, G.S., Altwegg, M., Thimm, T.N., Houlihan, M., Bredfeldt, J.S., et al. (2019). Collagen organization of renal cell carcinoma differs between low and high grade tumors. BMC Cancer 19, 490.

Provenzano, P.P., Eliceiri, K.W., Campbell, J.M., Inman, D.R., White, J.G., and Keely, P.J. (2006). Collagen reorganization at the tumor-stromal interface facilitates local invasion. BMC Med. 4, 38.

Provenzano, P.P., Inman, D.R., Eliceiri, K.W., Trier, S.M., and Keely, P.J. (2008). Contact guidance mediated three-dimensional cell migration is regulated by Rho/ROCK-dependent matrix reorganization. Biophys. J. 95, 5374–5384.

Tabdanov, E.D., Puram, V.V., Win, Z. et al. Bimodal sensing of guidance cues in mechanically distinct microenvironments. Nat Commun 9, 4891 (2018)

Tabdanov ED, Puram V, Zhovmer A, Provenzano PP. Microtubule-Actomyosin Mechanical Cooperation during Contact Guidance Sensing. Cell Rep. 2018;25(2):328‐338.e5.

Tags: cell biology, cell migration, immune, immunotherapy, microtubules

Posted on: 3rd June 2020 , updated on: 4th June 2020

doi: https://doi.org/10.1242/prelights.21633

Read preprint (No Ratings Yet)




  • Author's response

    Erdem Tabdanov shared

    Thank you, Ankita! We are very glad that our study interested the scientific community, and in particularly the cell biology auditorium. We are grateful for highlighting our preprint for a wider attention across many fields in biology and biophysics.

    Indeed, the principles of 3D cell motility are becoming the next frontier towards understanding the very principles of multicellular organisms organization. More importantly, at this stage, these study inform us more on how immune cells navigate and survey for the pathogen and cancer cells. A deeper, mechanistic understanding will enable us to engineer immune cells with biophysical properties, better suited to target solid tumors, currently impenetrable for the T and NK cells to eliminate the malignant cells.

    We hope that this study will become a step towards the novel engineering principles of 3D cell motility.

    Have your say

    Your email address will not be published. Required fields are marked *

    This site uses Akismet to reduce spam. Learn how your comment data is processed.

    Sign up to customise the site to your preferences and to receive alerts

    Register here

    Also in the cell biology category:

    FENS 2020

    A collection of preprints presented during the virtual meeting of the Federation of European Neuroscience Societies (FENS) in 2020

     



    List by Ana Dorrego-Rivas

    Planar Cell Polarity – PCP

    This preList contains preprints about the latest findings on Planar Cell Polarity (PCP) in various model organisms at the molecular, cellular and tissue levels.

     



    List by Ana Dorrego-Rivas

    BioMalPar XVI: Biology and Pathology of the Malaria Parasite

    [under construction] Preprints presented at the (fully virtual) EMBL BioMalPar XVI, 17-18 May 2020 #emblmalaria

     



    List by Gautam Dey, Samantha Seah

    1

    Cell Polarity

    Recent research from the field of cell polarity is summarized in this list of preprints. It comprises of studies focusing on various forms of cell polarity ranging from epithelial polarity, planar cell polarity to front-to-rear polarity.

     



    List by Yamini Ravichandran

    TAGC 2020

    Preprints recently presented at the virtual Allied Genetics Conference, April 22-26, 2020. #TAGC20

     



    List by Maiko Kitaoka, Madhuja Samaddar, Miguel V. Almeida, Sejal Davla, Jennifer Ann Black, Gautam Dey

    3D Gastruloids

    A curated list of preprints related to Gastruloids (in vitro models of early development obtained by 3D aggregation of embryonic cells)

     



    List by Paul Gerald L. Sanchez and Stefano Vianello

    ECFG15 – Fungal biology

    Preprints presented at 15th European Conference on Fungal Genetics 17-20 February 2020 Rome

     



    List by Hiral Shah

    ASCB EMBO Annual Meeting 2019

    A collection of preprints presented at the 2019 ASCB EMBO Meeting in Washington, DC (December 7-11)

     



    List by Madhuja Samaddar, Ramona Jühlen, Amanda Haage, Laura McCormick, Maiko Kitaoka

    EMBL Seeing is Believing – Imaging the Molecular Processes of Life

    Preprints discussed at the 2019 edition of Seeing is Believing, at EMBL Heidelberg from the 9th-12th October 2019

     



    List by Gautam Dey

    Autophagy

    Preprints on autophagy and lysosomal degradation and its role in neurodegeneration and disease. Includes molecular mechanisms, upstream signalling and regulation as well as studies on pharmaceutical interventions to upregulate the process.

     



    List by Sandra Malmgren Hill

    Lung Disease and Regeneration

    This preprint list compiles highlights from the field of lung biology.

     



    List by Rob Hynds

    Cellular metabolism

    A curated list of preprints related to cellular metabolism at Biorxiv by Pablo Ranea Robles from the Prelights community. Special interest on lipid metabolism, peroxisomes and mitochondria.

     



    List by Pablo Ranea Robles

    BSCB/BSDB Annual Meeting 2019

    Preprints presented at the BSCB/BSDB Annual Meeting 2019

     



    List by Gautam Dey

    MitoList

    This list of preprints is focused on work expanding our knowledge on mitochondria in any organism, tissue or cell type, from the normal biology to the pathology.

     



    List by Sandra Franco Iborra

    ASCB/EMBO Annual Meeting 2018

    This list relates to preprints that were discussed at the recent ASCB conference.

     



    List by Gautam Dey, Amanda Haage
    Close