Mapping Mechanical Properties of the Tumor Microenvironment by Laser Speckle Rheological Microscopy

Z. Hajjarian, E.F. Brachtel, D.M. Tshikudi, S.K. Nadkarni*

*Corresponding author for this work

Research output: Contribution to journalArticleAcademicpeer-review

Abstract

Altered mechanical properties of the tumor matrix have emerged as both the cause and consequence of breast carcinogenesis. Increased tumor stiffness has traditionally provided a viable metric to screen for malignancies via palpation or imaging. Previous studies have demonstrated that the microscale mechanical properties of the cell substrate influence tumor proliferation and invasive migration in vitro. Nevertheless, the association of the mechanical microenvironment with clinical hallmarks of aggressiveness in human breast tumors, including histopathological subtype, grade, receptor expression status, and lymph node involvement is poorly understood. This is largely due to the lack of tools for mapping tumor viscoelastic properties in clinical specimens with high spatial resolution over a large field of view (FoV). Here we introduce laser Speckle rHEologicAl micRoscopy (SHEAR) that for the first time enables mapping the magnitude viscoelastic or shear modulus, vertical bar G*(x,y,omega)vertical bar, over a range of frequencies (omega = 1-250 rad/second) in excised tumors within minutes with a spatial resolution of approximately 50 mm, over multiple cm2 FoV. Application of SHEAR in a cohort of 251 breast cancer specimens from 148 patients demonstrated that vertical bar G* (x,y,omega)vertical bar (omega = 2p rad/second) closely corresponds with histological features of the tumor, and that the spatial gradient of the shear modulus, vertical bar del vertical bar G* (x,y,omega)vertical bar vertical bar, is elevated at the tumor invasive front. Multivariate analyses established that the metrics, (vertical bar G*vertical bar) and (vertical bar del vertical bar G*vertical bar vertical bar|), measured by SHEAR are associated with prognosis. These findings implicate the viscoelastic properties of the tumor microenvironment in breast cancer prognosis and likely pave the path for identifying new modifiable targets for treatment.Significance: Laser speckle rheological microscopy establishes the links between microscale heterogeneities of viscoelasticity and histopathological subtype, tumor grade, receptor expression, as well as lymph node status in breast carcinoma.
Original languageEnglish
Pages (from-to)4874-4885
Number of pages12
JournalCancer Research
Volume81
Issue number18
DOIs
Publication statusPublished - 1 Sep 2021

Keywords

  • BREAST-CANCER
  • EXTRACELLULAR-MATRIX
  • ELASTOGRAPHY
  • METASTASIS
  • SIGNATURE
  • CARCINOMA
  • MIGRATION
  • COLLAGEN
  • IMPACT

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