Aashrith Koundinya Saraswathibhatla

All Publications

• Cell volume expansion and local contractility drive collective invasion of the basement membrane in breast cancer. Nature materials Chang, J., Saraswathibhatla, A., Song, Z., Varma, S., Sanchez, C., Alyafei, N. H., Indana, D., Slyman, R., Srivastava, S., Liu, K., Bassik, M. C., Marinkovich, M. P., Hodgson, L., Shenoy, V., West, R. B., Chaudhuri, O. 2023

  Abstract

  Breast cancer becomes invasive when carcinoma cells invade through the basement membrane (BM)-a nanoporous layer of matrix that physically separates the primary tumour from the stroma. Single cells can invade through nanoporous three-dimensional matrices due to protease-mediated degradation or force-mediated widening of pores via invadopodial protrusions. However, how multiple cells collectively invade through the physiological BM, as they do during breast cancer progression, remains unclear. Here we developed a three-dimensional in vitro model of collective invasion of the BM during breast cancer. We show that cells utilize both proteases and forces-but not invadopodia-to breach the BM. Forces are generated from a combination of global cell volume expansion, which stretches the BM, and local contractile forces that act in the plane of the BM to breach it, allowing invasion. These results uncover a mechanism by which cells collectively interact to overcome a critical barrier to metastasis.

  View details for DOI 10.1038/s41563-023-01716-9

  View details for PubMedID 37957268

• Cell-extracellular matrix mechanotransduction in 3D. Nature reviews. Molecular cell biology Saraswathibhatla, A., Indana, D., Chaudhuri, O. 2023

  Abstract

  Mechanical properties of extracellular matrices (ECMs) regulate essential cell behaviours, including differentiation, migration and proliferation, through mechanotransduction. Studies of cell-ECM mechanotransduction have largely focused on cells cultured in 2D, on top of elastic substrates with a range of stiffnesses. However, cells often interact with ECMs in vivo in a 3D context, and cell-ECM interactions and mechanisms of mechanotransduction in 3D can differ from those in 2D. The ECM exhibits various structural features as well as complex mechanical properties. In 3D, mechanical confinement by the surrounding ECM restricts changes in cell volume and cell shape but allows cells to generate force on the matrix by extending protrusions and regulating cell volume as well as through actomyosin-based contractility. Furthermore, cell-matrix interactions are dynamic owing to matrix remodelling. Accordingly, ECM stiffness, viscoelasticity and degradability often play a critical role in regulating cell behaviours in 3D. Mechanisms of 3D mechanotransduction include traditional integrin-mediated pathways that sense mechanical properties and more recently described mechanosensitive ion channel-mediated pathways that sense 3D confinement, with both converging on the nucleus for downstream control of transcription and phenotype. Mechanotransduction is involved in tissues from development to cancer and is being increasingly harnessed towards mechanotherapy. Here we discuss recent progress in our understanding of cell-ECM mechanotransduction in 3D.

  View details for DOI 10.1038/s41580-023-00583-1

  View details for PubMedID 36849594

  View details for PubMedCentralID 3976548

• Nanoscale Tracking Combined with Cell-Scale Microrheology Reveals Stepwise Increases in Force Generated by Cancer Cell Protrusions. Nano letters Sikic, L., Schulman, E., Kosklin, A., Saraswathibhatla, A., Chaudhuri, O., Pokki, J. 2022

  Abstract

  In early breast cancer progression, cancer cells invade through a nanoporous basement membrane (BM) as a first key step toward metastasis. This invasion is thought to be mediated by a combination of proteases, which biochemically degrade BM matrix, and physical forces, which mechanically open up holes in the matrix. To date, techniques that quantify cellular forces of BM invasion in 3D culture have been unavailable. Here, we developed cellular-force measurements for breast cancer cell invasion in 3D culture that combine multiple-particle tracking of force-induced BM-matrix displacements at the nanoscale, and magnetic microrheometry of localized matrix mechanics. We find that cancer-cell protrusions exert forces from picoNewtons up to nanoNewtons during invasion. Strikingly, the protrusions extension involves stepwise increases in force, in steps of 0.2 to 0.5 nN exerted from every 30 s to 6 min. Thus, this technique reveals previously unreported dynamics of force generation by invasive protrusions in cancer cells.

  View details for DOI 10.1021/acs.nanolett.2c01327

  View details for PubMedID 35950832