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Extracellular matrix biophysical cues in dormancy and bone metastasis

Subject Area Orthopaedics, Traumatology, Reconstructive Surgery
General and Visceral Surgery
Medical Physics, Biomedical Technology
Term from 2017 to 2022
Project identifier Deutsche Forschungsgemeinschaft (DFG) - Project number 362625353
 
Final Report Year 2023

Final Report Abstract

Breast cancer (BC) is one of the leading causes of cancer-associated deaths among women worldwide. BC cells often metastasize to bone. However, metastatic outgrowth might not occur instantly, with time periods for cancer recurrence ranging from years to decades. This indicates that some cells can survive dormant for years. It has been accepted that soluble biochemical signals might orchestrate such events. Nonetheless, increasing evidence also points towards the biophysical microenvironment. Our overall goal in the DFG Emmy Noether project is to elucidate the role of biophysical mechanisms in controlling breast cancer dormancy in the bone marrow, and reactivation leading to bone metastasis. Building on engineering approaches, my group has developed in vitro models to investigate the role of ECM biophysical cues in cancer dormancy. Using hydrogels and microfluidics, we can control mechanical 3D confinement, osmotic pressure and fluid flow, and monitor the effect on cell cycle of BC cells modified with the fluorescence ubiquitination cell cycle indicator-2 (FUCCI2). Our work shows that 3D confinement in elastic gels induces reversible growth arrest of BC cells. As mechanism, we identify the mechanosensitive and drug protective FHL2-p21 signaling: high matrix stiffness induces nuclear localization of FHL2 protein, high p21 nuclear expression, cell growth arrest and drug resistance. Silencing FHL2 leads to cytoplasmic p21 and drug sensitization. By developing a FUCCItrack all-in-one open software, my group has also shown that osmotic pressure and fluid flow modulate BC cycle dynamics, migration, cellular and nuclear morphological changes. We have demonstrated that under hyperosmotic stress, distinct cell subpopulations emerge with impaired nuclear growth, delayed or growth arrested cell cycle and reduced migration; this state is reversible for mild hyperosmotic stress. Using microfluidic chips, we have isolated single BC cells under controlled fluid flow mimicking capillaries and have quantified in 2D/3D single cell cycle dynamics, motility, volume and shape changes. We show that it is feasible to use biophysical principles to control BC growth, independent of nichespecific cellular and molecular mechanisms. Engineered cell microenvironments obtain inspiration from in vivo mouse models of breast cancer bone metastasis. Breast cancer often metastasizes to bone causing osteolytic lesions. ECM structural and biophysical changes at metastatic sites are rarely studied, but are hypothesized to influence metastatic progression. My group has established a mouse model of BC bone metastasis and advanced 3D imaging to quantify dynamic bone structural changes. Using tissue clearing and 3D light sheet fluorescence microscopy (LSFM), we show for the first-time GFP+ cancer cells and small clusters (diameter ranging between 10-60 um) in intact 3D mineralized bones, with and without bone lesions. Further, we detect early bone lesions using time-lapse in vivo microCT and reveal altered bone remodeling in absence of detectable bone lesions, suggesting an early systemic effect of BC cells in the bone. With a newly developed microCT image analysis open tool, we can detect and track early bone lesion growth over time. This combination of in vivo longitudinal imaging and ex vivo multiscale characterization provides novel insight of homing of cancer cells in the bone marrow, their microenvironment and onset of early bone metastatic lesions.

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