Bi Research group - Physics of Cancer

The Physics of Cancer

Our research on the physics of cancer focuses on understanding the mechanical interactions and heterogeneity that drive cancer progression and epithelial defense mechanisms. We investigate how mechanical imbalances between normal and transformed cells enable epithelial tissues to target and eliminate cancerous cells. Additionally, we explore the mechanical heterogeneity within tumors, revealing that while tumors are rigid overall, they contain softer, motile cancer cells that contribute to metastasis. Our studies also highlight the role of compressive stress and cell adhesion in driving unjamming transitions, which facilitate cancer cell migration without triggering traditional markers of metastasis like the epithelial-mesenchymal transition.

Mechanical imbalance between normal and cancer cells drives epithelial defense against cancer

(In collaboration with the group of Prof. Tamal Das)

Cell competition in epithelial tissues helps maintain homeostasis by eliminating transformed cells that express cancer-promoting oncoproteins. Although this process is known to involve mechanical forces, the specifics were unclear. Our research used advanced stress measurement techniques and theoretical modeling to reveal a mechanical imbalance between normal and transformed cells that drives this competition. We found that transformed cells experience compressive stress, making them more compact during competition. This stress arises from their higher collective compressibility compared to normal cells, due to weaker cell-cell adhesions and reduced E-cadherin. These findings provide new insights into how epithelial tissues defend against cancer by mechanically targeting abnormal cells.

Related Publication(s):

Gupta, Praver, et al. "Mechanical imbalance between normal and cancer cells drives epithelial defense against cancer." bioRxiv (2023). https://doi.org/10.1101/2023.09.27.559723

Rigid tumors contain soft cancer cells

(In collaboration with the group of Prof. Josef Käs)

Palpation relies on the fact that solid breast tumors are stiffer than surrounding tissue, yet cancer cells themselves often soften, which might help them move through dense tissue. This raises two possibilities: either cancer cells soften as they adapt to their environment, or soft cancer cells already exist within a rigid tumor, enabling their mobility. Our research on primary tumor samples from breast and cervix cancer patients reveals that tumors are mechanically heterogeneous, with a wide range of stiffness from very rigid to softer than healthy tissue. We found that stiff cell clusters are surrounded by softer cells, and both jammed (immobile) and unjammed (motile) areas coexist within the tumors. Despite this variability, cancer cell clusters maintain a solid-like structure with a finite elastic modulus, providing mechanical stability. These findings help explain how tumors can be both rigid and contain motile cancer cells, contributing to our understanding of cancer progression.

Related Publication(s):

Fuhs, Thomas, et al. "Rigid tumours contain soft cancer cells." Nature Physics 18.12 (2022): 1510-1519. https://doi.org/10.1038/s41567-022-01755-0
Xie, Xiaofan, et al. "Effect of non-linear strain stiffening in eDAH and unjamming." Soft Matter 20.9 (2024): 1996-2007. https://doi.org/10.1039/D3SM00630A

Compressive Stress and Matrix Modulation: Key Factors in Cancer Unjamming and Invasion

(In collaboration with the group of Prof. Allen Liu)

In cancer, the rapid proliferation of cells within confined spaces generates mechanical compressive stress, but the role of this stress in driving unjamming transitions has been unclear. Recent research explores this by examining a dense, mechanically stressed monolayer, revealing that long-term compression leads to cell arrest in benign cells and enhances cancer cell migration, particularly in correlation with changes in cell shape.

The study identifies cadherin-mediated cell-cell adhesion as a critical factor in how cells respond to compressive stress, driving unjamming in stressed monolayers. Notably, this stress-induced unjamming does not trigger the epithelial-mesenchymal transition (EMT), a process often linked to increased cell motility and metastasis. This indicates that other mechanisms, specifically related to cell adhesion and mechanical stress, are at play in these unjamming transitions.

Furthermore, traction force microscopy shows that compressive stress reduces traction forces within the bulk of the monolayer, regardless of cell type. However, cancer cells at the leading edge maintain traction under compression, suggesting a nuanced balance between intercellular adhesion and traction forces. These findings provide new insights into how compressive stress influences cellular behavior, with potential implications for understanding tumor development and breast cancer progression.

Related Publication(s):

Cai, Grace, et al. "Compressive stress drives adhesion-dependent unjamming transitions in breast cancer cell migration." Frontiers in Cell and Developmental Biology 10 (2022): 933042. https://doi.org/10.3389/fcell.2022.933042
Cai, Grace, et al. "Matrix confinement modulates 3D spheroid sorting and burst-like collective migration." Acta Biomaterialia 179 (2024): 192-206. https://doi.org/10.1016/j.actbio.2024.03.007

Glassy Behavior, Intermittency, and Cell Streaming in Epithelial Tissues

(In collaboration with the group of Profs. Srikanth Sastry)

Embryonic development, tissue repair, and cancer progression all rely on neighboring cells rearranging themselves in biological tissue. One basic unit of such movement of cells in close-packed tissues is the T1 transition, where two cells swap positions. Because of the time required to remodel complex structures at junctions between cells, T1 transition cannot occur instantaneously. How this biological constraint affects collective behaviors among cells inside tissues is not known. Using theoretical modeling and simulations, we demonstrate that cell-level control of the time it takes to complete a T1 transition has unique consequences that change the ways cells mechanically interact, collectively organize, and migrate.

Related Publication(s):

A. Das, S. Sastry & D. Bi. “Controlled neighbor exchanges drive glassy behavior, intermittency and cell streaming in epithelial tissues” Phys. Rev. X 11, 041037 (2021)
SZ Lin, WY Zhang, D. Bi, B Li, XQ Feng “Energetics of mesoscale cell turbulence in two-dimensional monolayers” Communications Physics 4 (1) (2021), 1-9

Unjamming transition vs. the Epithelial-to-Mesenchymal transition in epithelial tissues

(In collaboration with the groups of Profs. Jin-Ah Park and Jeff Fredberg)

The epithelial-to-mesenchymal transition (EMT) and the unjamming transition (UJT) each comprises a gateway to cellular migration, plasticity and remodeling, but the extent to which these core programs are distinct, overlapping, or identical has remained undefined. Here, we triggered partial EMT (pEMT) or UJT in differentiated primary human bronchial epithelial cells. After triggering UJT, cell-cell junctions, apico-basal polarity, and barrier function remain intact, cells elongate and align into cooperative migratory packs, and mesenchymal markers of EMT remain unapparent. After triggering pEMT these and other metrics of UJT versus pEMT diverge. A computational model attributes effects of pEMT mainly to diminished junctional tension but attributes those of UJT mainly to augmented cellular propulsion. Through the actions of UJT and pEMT working independently, sequentially, or interactively, those tissues that are subject to development, injury, or disease become endowed with rich mechanisms for cellular migration, plasticity, self-repair, and regeneration.

Related Publication(s):

J.A. Mitchel, A. Das, M. O’Sullivan, I. Stancil, S. DeCamp, S. Koehler, J.J. Fredberg, J. Drazen, J. P Butler, A. Nieto, D. Bi and J.-A. Park, “The unjamming transition is distinct from the epithelial-to-mesenchymal transition”, Nature Communications 11 5053 (2020)
J.-H. Kim et al “Unjamming and collective migration in MCF10A breast cancer cell lines." Biochemical and Biophysical Research Communications 521 3 (2020)
M. J. O'Sullivan, J. A. Mitchel, A. Das, S. Koehler, H. Levine, D. Bi., Z. D. Nagel, & J.-A Park. “Collective migration of non-cancerous, well-differentiated human airway epithelial cells by ionizing radiation", Frontiers in Cell and Developmental Biology 8 (2020)

Effect of mechanical heterogeneity in epithelial layers

Heterogeneity amongst cells in a tumor has been recognized as one of the hallmarks of cancer. This so-called intratumor heterogeneity is thought to facilitate metastasis by allowing a cellular community the flexibility and efficiency to adapt to new environments. It is also largely responsible for therapeutic resistance. Cellular differences within a tumor result from an interplay of both genetic and extrinsic influences. Whereas fitness or genotypic heterogeneity has been studied extensively, the role of mechanical heterogeneity in a tumor or cellular collective is still not well understood.

Related Publication(s):

X. Li, A. Das, & D. Bi “Mechanical Heterogeneity in Tissues Promotes Rigidity and Controls Cellular Invasion", Physical Review Letters 123, 058101 (2019) https://doi.org/10.1103/PhysRevLett.123.058101