In vivo compression and imaging in the brain to measure the effects of solid stress

Brain tumors store and exert solid mechanical forces both internally and on the surrounding brain tissue. Here we sought to answer the question: can we decouple the physical effects from the biological effects of a brain tumor?

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In the lab of Professor Rakesh K. Jain at Massachusetts General Hospital/Harvard Medical School, we have identified “mechanopathology” as a new hallmark of cancer biology. Indeed, abnormal biomechanical properties (e.g., increased tissue stiffness) and forces (e.g., increased fluid pressure) are increasingly being recognized for their ability to drive tumorigenesis, metastasis, and treatment resistance. Our lab discovered that tumors exert solid stress: a mechanical force arising from the solid components in the tumor microenvironment, including cells and extracellular matrix, that is distinguished from stiffness and fluid pressure [1]. Solid stress promotes tumor progression and compromises anti-cancer therapy by compressing blood and lymphatic vessels and inducing hypoxia [2]. We recently established three robust new techniques to measure and map solid stress in both human and mouse tumors [3, 4]. Our lab has further shown that targeting solid stress can enhance drug delivery and efficacy in mice and patients [5-7].

Mechanical forces are of particular importance in the brain, where physical confinement by the skull can amplify detrimental effects and debilitating symptoms. Clinicians have long been familiar with the qualitative “mass effect” of brain tumors on neurological function and treatment outcome in patients. We have found that brain tumor solid stress – such as in primary glioblastoma and metastatic breast cancer – is  exerted outward on the surrounding brain tissue, leading to blood flow loss and neuronal cell death [8]. To differentiate whether these effects were the direct result of mechanical forces rather than the pathophysiological impact of cancer cell biology, we designed a new device for in vivo mechanistic studies in mice.  

We adapted standard transparent cranial windows, commonly used for intravital imaging in mice, by adding a tunable screw for controlled mechanical force application on the brain. This compressive cranial window (cCW) allows for simultaneous i) acute or chronic compression and decompression, ii) live imaging for real-time dynamic visualization of the brain, and iii) behavioral tests for neurological functional analyses (Fig. 1). Utilizing the cCW in combination with intravital imaging and cellular and molecular analyses, we confirmed that mechanical forces directly impact the surrounding tissue, and that decompression (simulating brain tumor surgical removal) improves vascular, neuronal, and functional activity in the surrounding brain [8].

The cCW can also be used in applications beyond cancer, including other diseases that present with brain masses, such as cysts and benign tumors. In future studies, we hope that the cCW will be able to reveal new insights into mechanical abnormalities in brain tumors that can be targeted to enhance therapeutic outcomes. We recently established solid stress as a biomarker of neurological dysfunction in patients [8], underlining the need for biomechanical studies that may identify new and better predictive/prognostic biomarkers of patient outcomes. Most importantly, this study highlights the importance of multidisciplinary approaches in cancer research, as the cCW design was the result of a rich collaboration between neuro-, tumor, and vascular biologists, oncologists, radiologists, neurosurgeons, and engineers.

Figure 1. (A) The compressive cranial window in mice allows for (B) controlled and chronic mechanical forces to be applied to the brain cortex coupled to (C) longitudinal intravital imaging.

References:

  1. Helmlinger, G., et al., Solid stress inhibits the growth of multicellular tumor spheroids. Nat Biotechnol, 1997. 15(8): p. 778-83.
  2. Padera, T.P., et al., Pathology: cancer cells compress intratumour vessels. Nature, 2004. 427(6976): p. 695.
  3. Nia, H.T., et al., Quantifying solid stress and elastic energy from excised or in situ tumors. Nat Protoc, 2018. 13(5): p. 1091-1105.
  4. Nia, H.T., et al., Solid stress and elastic energy as measures of tumour mechanopathology. Nat Biomed Eng, 2016. 1(1): p. 1-11.
  5. Chauhan, V.P., et al., Reprogramming the microenvironment with tumor-selective angiotensin blockers enhances cancer immunotherapy. Proc Natl Acad Sci U S A, 2019. 116(22): p. 10674-10680.
  6. Chauhan, V.P., et al., Angiotensin inhibition enhances drug delivery and potentiates chemotherapy by decompressing tumour blood vessels. Nat Commun, 2013. 4: p. 2516.
  7. Murphy, J.E., et al., Total Neoadjuvant Therapy With FOLFIRINOX in Combination With Losartan Followed by Chemoradiotherapy for Locally Advanced Pancreatic Cancer: A Phase 2 Clinical Trial.JAMA Oncol, 2019. 5(7): p. 1020-1027.
  8. Seano, G., et al., Solid stress in brain tumours causes neuronal loss and neurological dysfunction and can be reversed by lithium. Nat Biomed Eng, 2019. 3(3): p. 230-245.
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Meenal Datta

Postdoctoral Fellow, Massachusetts General Hospital/Harvard Medical School

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