An estimated 700,000 people are living with a primary brain tumor in the United States and the amount of cancer cases that metastasize to the brain is progressively growing. More than any other cancer, brain tumors can have permanent and life-changing physical and cognitive impacts on a patient’s life. Brain tumors have very poor prognoses and are associated with significant morbidity due to progressive neurological dysfunction. Although huge efforts have been employed to stop brain tumor growth, little is known about the reasons for neuronal loss in the surrounding brain tissue, which is the ultimate cause of significant neurological dysfunction, loss of quality of life and death. One of the possible causes of neuronal loss is the tumor-generated mechanical force exerted on the surrounding brain tissue. While much focus has been given to fluid pressure and edema in brain tumors, little is known about how solid stress – i.e., mechanical forces exerted by the solid components of the tissue – affects the tissue surrounding the tumor, thus potentially impairing neurological function.

In our paper, we investigate the extent of pathological solid stress from brain tumors and the biological consequences on the surrounding brain tissue. We show that nodular tumors – with well-defined margins, as opposed to more infiltrative tumors – exert compressive solid stress on the surrounding brain tissue, reducing peritumoral vascular perfusion and inducing neuronal loss (Figure 1). Notably, alleviating solid stress restores vascular perfusion in the surrounding tissue, and pharmacologic neuroprotective treatments, such as with lithium, strongly attenuate compression-induced neuronal damage (explicative video). Clinically, these results allowed us to design a stratification method for glioblastoma and brain metastases patients using perfusion magnetic resonance imaging, which allow for the identification of patients experiencing solid stress-mediated neurological impairment.

This was a highly multidisciplinary study at the interface of tumor biology, biomechanics, and clinical neuro-oncology, in which multiple techniques were utilized, including several orthotopic mouse models of primary and secondary brain tumors, a novel in vivo compression apparatus, neurological/behavior tests, mathematical modeling, and intravital microscopy, as well as extensive analyses of magnetic resonance imaging of large cohorts of patients with glioblastoma and brain metastases from breast cancer.

• This study revealed that nodular tumors exerts more mechanical stress on the brain tissue than infiltrative tumors, and a new patient stratification method allowed us to identify which patients may experience solid stress-mediated neurological impairment.
• For the first time, we directly and mechanistically demonstrated that chronic and gradual solid stress applied to the brain causes neurological impairment, and we identified biological consequences of aberrant tumor mechanics on the brain, such as vessel compression and neuronal damage. 
• Finally, we demonstrated the potential of lithium treatment as a neuroprotection strategy to abrogate mechanical damage to neurons.  

Preservation of quality of life and neurological function is increasingly being taken into consideration in current clinical practice for brain tumor patients. Our results identify solid stress as one of the causes of brain tumor-induced loss of neurological function. Thus, our preclinical findings provide evidence for the translation of the concept of pharmacological neuroprotection in a specific subclass of patients with nodular brain tumors who experience neurological defects due to compression of the surrounding brain tissue. 

Solid stress in brain tumours causes neuronal loss and neurological dysfunction and can be reversed by lithium. Seano G*, Nia HT*, Emblem KE*, Datta M, Ren J, Krishnan S, Kloepper J, Pinho M, Ho WW, Ghosh M, Askoxylakis V, Ferraro GB, Riedemann L, Gerstner ER, Batchelor TT, Wen PY, Lin NU, Grodzinsky AJ, Fukumura D, Huang P, Baish JW, Padera TP, Munn LL, Jain RK. 
Nature Biomedical Engineering. 2019