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Prospective Outlook of Mechanics in Oncology

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
  • 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

Thursday, September 11, 2014
3:30 p.m. - 3:35 p.m. Welcome and Introductions
Larry A. Nagahara, Ph.D., NCI
3:35 p.m. - 3:45 p.m. Workshop Goals
Nicole M. Moore, D.Sc., NCI
3:45 p.m. - 6:30 p.m. Session I: Quantifying Mechanical Forces
Moderator: Jennifer Couch, PhD, NCI
3:45 p.m. - 6:30 p.m. Session I: Quantifying Mechanical Forces
Moderator: Jennifer Couch, Ph.D., NCI
3:45 – 4:10 pm Cell and Tissue Mechanics
Josef Käs, PhD, University of Leipzig
4:10 – 4:35 pm Fluid Stresses Govern 3D Cell Migration
Roger D. Kamm, PhD, Massachusetts Institute of Technology
4:35 – 5:00 pm ECM Tension and Topology
Delphine Gourdon, PhD, Cornell University
5:00 – 5:25 pm Integrin Tension and Cell Adhesion
Andrés Garcia, PhD, Georgia Institute of Technology
5:25 – 6:30 pm Group Discussion
Friday, September 12, 2014
8:15 a.m. - 8:20 a.m. Day 2 Opening Remarks
Nastaran Z. Kuhn, PhD, NCI
8:20 a.m. - 9:15 a.m. Session 2: Standardizing Mechanics Measurements
Moderator: Nicole M. Moore, DSc, NCI
8:20 – 8:45 am Summary of the UN of Cell Modulus Project
Denis Wirtz, PhD, Johns Hopkins
8:45 – 9:15 am Group Discussion
9:15 – 11:40 am Session 3: Biological Responses to Mechanical Forces
Moderator: Suresh Mohla, PhD, NCI
9:15 – 9:45 am Force Driven Tumorigenesis
Michael Shuler, PhD, INSERM, and Emmanuel Farge, PhD, Institute Curie
9:40 – 10:05 am Biological Response to ECM Stiffness
Patricia Keely, PhD, University of Wisconsin - Madison
10:05 – 10:20 am Break
10:20 – 10:45 am Mechanically Coupled Systems of Mammary Acini
Jan Liphardt, PhD, Stanford University
10:45 – 11:10 am Nuclear Mechanics and DNA Stability
Dennis Discher, PhD, University of Pennsylvania
11:10 – 11:40 am Group Discussion
11:40 am - 1:00 pm Lunch and Poster Viewing
Dexamethasone Increases Tissue Surface Tension and Reduces Dispersal of Primary Glioblastoma Cells
Ramsey Foty, PhD, Rutgers University

Mechanobiology of the Cellular Glycocalyx
Matthew Paszek, PhD, Cornell University

Screening Cancer Cell Mechanotype by Parallel Microfiltration
Amy Rowat, PhD, University of California, Los Angeles

Biomaterials Based Adaptive Tumor microenvironments for Lymphoma
Ankur Singh, PhD, Cornell University

Extracting Quantitative Data from AFM Indentations on Soft, Heterogeneous Biomaterials
J. Rory Staunton, Arizona State University

MDA-MB-231 Cells Stiffen During Invasion into 3D Collagen I Matrices
J. Rory Staunton, Arizona State University
1:00 p.m. - 2:45 p.m. Session 4: Translational Potential of Mechanics in Oncology
Moderator: Jerry S.H. Lee, PhD, NCI
1:00 – 1:25 pm Mechanical Drug Targets and Prognostic Indicators
Valerie Weaver, PhD, University of California, San Francisco
1:25 – 1:50 pm Diagnosis of Malignant Pleural Effusions by Single-Cell Mechanophenotyping
Dino DiCarlo, PhD, University of California, Los Angeles
1:50 – 2:15 pm Magnetic Resonance Elastography
Richard Ehman, MD, Mayo Clinic
2:15 – 2:45 pm Group Discussion
2:45 – 2:55 pm Break
2:55 p.m. - 3:30 p.m. Overview and Future Directions
Nicole M. Moore, DSc, NCI
Nastaran Z. Kuhn, PhD, NCI

Participant List

First Name Last Name Degree Institution
Lokesh Agrawal PhD NCI
Atef Asnacios PhD University of Paris, Diderot
Greg Baxter PhD CCS Associates
Michelle Berny-Lang PhD NCI
Clara Bodelon PhD NCI
Lingfeng Chen PhD NICHD
Marshall Colville BS Cornell University
Donald Coppock PhD NCI
Jennifer Couch PhD NCI
Howland Crosswell MD KIYATEC, Inc.
Dino Dicarlo PhD University of California, Los Angeles
Tony Dickherber PhD NCI
Dennis E. Discher PhD University of Pennsylvania
Brian DuChez PhD NIDCR
Pauline Durand MS University of Paris, Diderot
Richard L. Ehman MD Mayo Clinic
Andrew Ekpenyong PhD Creighton University
Emmanuel Farge PhD Institute Curie
Claudia Fischbach-Teschl PhD Cornell University
Ramsey Foty PhD Rutgers-Robert Wood Johnson Medical School
Dan Gallahan PhD NCI
Andres Garcia PhD Georgia Institute of Technology
Gretchen L. Gierach PhD, MPH NCI
Emily Greenspan PhD NCI
Delphine Gourdon PhD Cornell University
Todd Haim PhD NCI
Bumsoo Han PhD Purdue University
Toby Hecht PhD NCI
Stephen M. Hewitt MD, PhD NCI
Roger Kamm PhD Massachusetts Institute of Technology
Josef Käs PhD University of Leipzig
Susan Keating PhD CCS Associates
Patricia Keely PhD University of Wisconsin-Madison
Chris Kelley PhD NIBIB
Warren Kibbe PhD NCI
Randy Knowlton PhD NCI
Nastaran Z. Kuhn PhD NCI
Philip R. LeDuc PhD Carnegie Mellon University
Jerry Lee PhD NCI
Jan Liphardt PhD Stanford University
Gregory Longmore PhD Washington University School of Medicine
Wolfgang Losert PhD University of Maryland
Shadi Mamaghani PhD NIBIB
Susan McCarthy PhD NCI
Suresh Mohla PhD NCI
Nicole Moore ScD NCI
Mahua Mukhopadhyay PhD NICHD
Maeve Mullooly PhD NCI
Larry Nagahara PhD NCI
Thomas Neumann MD Nortis, Inc.
Carole A. Parent PhD NCI
Catherine Park PhD University of California, San Francisco
Matthew J. Paszek PhD Cornell University
Yeh-Chuin Poh PhD Massachusetts Institute of Technology
Robert Ros PhD Arizona State University
Amy Rowat PhD University of California, Los Angeles
Mathias Sander BS Saarland University
Teresa Schuessler MS NCI
Victoria Seewaldt MD Duke University
Caroline Sigman PhD CCS Associates
Dinah Singer PhD NCI
Ankur Singh PhD Cornell University
Igor Sokolov PhD Tufts University
Brian Sorg PhD NCI
Jack 'Rory' Staunton MS Arizona State University
Kandice Tanner PhD NCI
Katrina Theisz PhD NCI
Andreea Trache PhD Texas A&M University
Jim Tricoli PhD NCI
Jessica Tucker PhD NIBIB
Valerie M. Weaver PhD University of California, San Francisco
Denis Wirtz PhD Johns Hopkins University
Keren Witkin PhD NCI
Elisa Woodhouse PhD NCI

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