Prospective Outlook of Mechanics in Oncology

Executive Summary

PS-ON within the NCI Division of Cancer Biology (DCB) aims to enrich our current understanding of cancer by facilitating the formation of teams of physical scientists and cancer researchers who work together to bring a novel “physical sciences perspective” to cancer biology.

On September 11-12, 2014, DCB convened a Strategic Workshop: Prospective Outlook of Mechanics in Oncology to provide a status update of the field of cell and tissue mechanics in cancer biology and to address the prospect of using mechanical measurements as physical biomarkers for disease progression or treatment response.

The response of cancer cells and tissues to physical forces, pressures, or molecular tensions in the stromal microenvironment is a function of their inherent architectural and structural properties. Cell and tissue mechanics is defined as the physical properties, the strength of mechanical forces, and the resultant cell and tissue functional response.

Mounting evidence suggests cell and tissue mechanics are significant contributors to the initiation and progression of cancer. The propagation of mechanical forces at cellular and tissue scales has been associated with numerous cell processes, including differentiation, migration, and proliferation. Changes to the physical properties of cells, extracellular matrix, or tissue during cancer progression perturb these mechanical forces and subsequently affect downstream cellular processes. Therefore, knowledge of the mechanisms involved in mechanical feedback loops and application of appropriate mechanical measurement tools may lead to new potential drug targets, diagnostic tools, and risk indicators in oncology.

This workshop was designed to explore the latest research in the field of cell and tissue mechanics in cancer biology and identify opportunities as next steps for the field.

Workshop discussions centered around findings pertaining to the mechanical measurements of single cells, mechanical forces between neighboring cells, as well as between cells and their surrounding matrix. Presentations highlighted the effects of mechanical forces on cancer progression, correlations between cell mechanical properties and molecular expression pathways, and assessments of how changes in the extracellular matrix structure and physical properties and may correlate with tumor progression.

Two broad topics were identified as emerging areas for more development:

1. Interplay between mechanical forces and biological pathways
   • Induction of mechanical pressure in vivo activates oncogenic signaling pathways in mouse models of cancer
   • Mechanical stress in fibronectin induces expression of soluble factors that promote angiogenesis and tumor formation
   • Pro-inflammatory pathways modulate matrix stiffness and drive tumor progression
   • Dynamic shear forces and cellular crowding influence adhesion molecule-mediated migration of metastatic tumor cells in a 3D context
   • Matrix stiffness affects the viscosity and elasticity of the cell nucleus, which leads to susceptibility of cells to DNA damage and activation of oncogenic signaling pathways
2. Biophysical markers for tumor progression signatures and diagnostics
   • Mechanophenotyping of circulating tumor cells (i.e., cell size, contractility, deformability, morphology, adhesiveness) enables more sensitive, objective, and efficient diagnosis of tumor cell malignancy
   • Mechanical waves in magnetic resonance elastography image tissue stiffness in vivo (human and mouse) and determine distinct tumor types based on tissue stiffness signatures
   • Biomechanical measurements distinguish between cancerous and normal tissue by quantifying cell-cell adhesion/surface tension and cell stiffness from the single-cell scale to tissue scale
   • Cell-matrix traction forces and adhesion strength measurements define adhesive force signatures that are unique to distinct cancer cell types (e.g., tumor-initiating cells, cancer stem cells, cell subpopulations within a heterogeneous tumor)
   • Collagen remodeling signatures defined by structural properties are potential prognostic indicators in cancer (i.e., higher degree of collagen fiber alignment perpendicular to the tumor boundary is indicative of tumor progression)

Next steps to advance the field of cell and tissue mechanics:

• Increased collaboration between the mechanics/mechanobiology and oncology communities in order to better identify immediate clinical needs as well as developing better methods for incorporating cell and tissue mechanical measurements into clinical practice
• Development of standardized cell lines and standardized synthetic matrix analogs with precise control over biophysical and biochemical properties to improve studies of cell-cell and cell-matrix mechanics in 3D cultures
• Development of more robust technologies to better understand the connection between mechanical forces and cellular processes such as molecular pathways and regulation, transcription, translation, genome editing, and phenotype
• Integration of measurements taken at different time- and length-scales into more comprehensive datasets and incorporating them with mathematical approaches; and the use of mathematical modeling to better understand the feedback loop of mechanical and biological information
• Better understanding of the effect of anti-cancer drugs, chemotherapy and radiation on the physical properties of the stroma
• Identification of new biomechanical markers that have prognostic value
• Addressing the dynamic complexity of cancer (e.g., tumor heterogeneity, etc.) when developing new cell and tissue mechanics models
• Development of clinically relevant animal models for studying cell and tissue mechanics in vivo
• Incorporating physical factors in addition to stiffness, such as topology and spatial features within tumor tissues, to better understand the specific physical parameters and how they affect cancer biology.

Agenda

Prospective Outlook of Mechanics in Oncology
NCI Division of Cancer Biology Strategic Workshop

September 11-12, 2014

National Cancer Institute Shady Grove Campus
Rockville, Maryland

Participant List