Reduction of Liver Metastasis Stiffness Improves Response to Bevacizumab in Metastatic Colorectal Cancer

Ying, Shao‐Yao; Wang, Xiaohong; Lu, Junyan; Salfenmoser, Martin; Wirsik, Naita Maren; Schleußner, Nikolai; Imle, Andrea; Valls, Aïda; Radhakrishnan, P.; Liang, Jie; Wang, Guoliang; Muley, Thomas; Schneider, Martin; Almodóvar, Carmen Ruiz de; Diz-Muñoz, Alba; Schmidt, Thomas

doi:10.1016/j.ccell.2020.05.005

Cited by 216 publications

(176 citation statements)

References 100 publications

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“…Flow-independent biomechanical cues might also be elemental to the endothelial response during metastatic progression. It was recently demonstrated that stiffness reduction in liver metastasis induced a higher therapeutic response to bevacizumab (Shen et al, 2020), similarly to our observations pointing at a crosstalk between VEGFR-mediated endothelial response and external biomechanical cues. More work is needed to identify additional signaling pathways, and more specific molecules, to efficiently counteract this new mechanism of metastatic extravasation.…”

Section: R a F Tsupporting

confidence: 91%

Impairing flow-mediated endothelial remodeling reduces extravasation of tumor cells

Follain

Osmani

Mercier

et al. 2020

Preprint

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Tumor progression and metastatic dissemination are driven by cell-intrinsic and biomechanical cues that favor the growth of life-threatening secondary tumors. We recently identified prometastatic vascular regions with blood flow profiles that are permissive for the arrest of circulating tumor cells. We have further established that such flow profiles also control endothelial remodeling, which favors extravasation of arrested CTCs. Yet, how shear forces control endothelial remodeling is unknown. In the present work, we aimed at dissecting the cellular and molecular mechanisms driving blood flow-dependent endothelial remodeling. Transcriptomic analysis revealed that blood flow modulated several signaling pathways in endothelial cells. More specifically, we observed that VEGFR signaling was significantly enhanced. Using a combination of in vitro microfluidics and intravital imaging in zebrafish embryos, we now demonstrate that the early flow-driven endothelial response can be prevented with sunitinib, a pan-inhibitor of VEGFR signaling. Embryos treated with sunitinib displayed reduced endothelial remodeling and subsequent metastatic extravasation. These results confirm the importance of endothelial remodeling as a driving force of CTC extravasation and metastatic dissemination. Furthermore, the present work suggests that therapies targeting endothelial remodeling might be a relevant clinical strategy in order to impede metastatic progression.Highlights-Flow profiles that are permissive for metastasis stimulate the VEGFR pathway-Flow-dependent VEGFR signaling favors extravasation of CTCs through endothelial remodeling-Inhibition of VEGFR signaling suppresses early flow-driven endothelial response

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Section: R a F Tsupporting

confidence: 91%

Impairing flow-mediated endothelial remodeling reduces extravasation of tumor cells

Follain

Osmani

Mercier

et al. 2020

Preprint

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“…A well-established concept is that a deposition and cross-linking of ECM components such as collagen 1 lead to increased matrix stiffness, which in turn reduces perfusion with antineoplastic agents. These mechanisms can be therapeutically addressed by molecules that target the renin–angiotensin system [ 18 , 73 , 74 ]. COL1A1 and COL1A2 were significantly overexpressed in MuEp and SaDu.…”

Section: Discussionmentioning

confidence: 99%

Expression Profiling of Extracellular Matrix Genes Reveals Global and Entity-Specific Characteristics in Adenoid Cystic, Mucoepidermoid and Salivary Duct Carcinomas

Arolt

Meyer

Hoffmann

et al. 2020

Cancers

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The composition of the extracellular matrix (ECM) plays a pivotal role in tumour initiation, metastasis and therapy resistance. Until now, the ECM composition of salivary gland carcinomas (SGC) has not been studied. We quantitatively analysed the mRNA of 28 ECM-related genes of 34 adenoid cystic (AdCy; n = 11), mucoepidermoid (MuEp; n = 14) and salivary duct carcinomas (SaDu; n = 9). An incremental overexpression of six collagens (including COL11A1) and four glycoproteins from MuEp and SaDu suggested a common ECM alteration. Conversely, AdCy and MuEp displayed a distinct overexpression of COL27A1 and LAMB3, respectively. Nonhierarchical clustering and principal component analysis revealed a more specific pattern for AdCy with low expression of the common gene signature. In situ studies at the RNA and protein level confirmed these results and indicated that, in contrast to MuEp and SaDu, ECM production in AdCy results from tumour cells and not from cancer-associated fibroblasts (CAFs). Our findings reveal different modes of ECM production leading to common and distinct RNA signatures in SGC. Of note, an overexpression of COL27A1, as in AdCy, has not been linked to any other neoplasm so far. Here, we contribute to the dissection of the ECM composition in SGC and identified a panel of deferentially expressed genes, which could be putative targets for SGC therapy and overcoming therapeutic resistance.

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“…Overall, the modeling framework presented here provides a platform to explore the mechanobiological conditions that lead to metastatic seeding, dormancy, and growth in liver tissue [76,77]. Model explorations generate predictions (hypotheses) that we can presently assess qualitatively against known clinical and experimental observations.…”

Section: Discussionmentioning

confidence: 99%

Impact of tumor-parenchyma biomechanics on liver metastatic progression: a multi-model approach

Brodin

Nishii

Frieboes

et al. 2020

Preprint

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Colorectal carcinoma (CRC) and other cancers often metastasize to the liver in later stages of the disease, contributing significantly to patient death. While the biomechanical properties of the liver parenchyma (normal liver tissue) are known to affect primary and metastatic tumor growth in liver tissues, the role of these properties in driving or inhibiting metastatic inception remains poorly understood. This study uses a multi-model approach to study the effect of tumor-parenchyma biomechanical interactions on metastatic seeding and growth; the framework also allows investigating the impact of changing tissue biomechanics on tumor dormancy and "reawakening." We employ a detailed poroviscoelastic (PVE) model to study how tumor metastases deform the surrounding tissue, induce pressure increases, and alter interstitial fluid flow in and near the metastases. Results from these short-time simulations in detailed single hepatic lobules motivate constitutive relations and biological hypotheses for use in an agent-based model of metastatic seeding and growth in centimeter-scale tissue over months-long time scales. We find that biomechanical tumor-parenchyma interactions on shorter time scales (adhesion, repulsion, and elastic tissue deformation over minutes) and longer time scales (plastic tissue relaxation over hours) may play a key role in tumor cell seeding and growth within liver tissue. These interactions may arrest the growth of micrometastases in a dormant state and can prevent newly arriving cancer cells from establishing successful metastatic foci. Moreover, the simulations indicate ways in which dormant tumors can "reawaken" after changes in parenchymal tissue mechanical properties, as may arise during aging or following acute liver illness or injury. We conclude that the proposed modeling approach can yield insight into the role of tumor-parenchyma biomechanics in promoting liver metastatic growth, with the longer term goal of identifying conditions to clinically arrest and reverse the course of late-stage cancer. 4/25

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Reduction of Liver Metastasis Stiffness Improves Response to Bevacizumab in Metastatic Colorectal Cancer

Cited by 216 publications

References 100 publications

Impairing flow-mediated endothelial remodeling reduces extravasation of tumor cells

Impairing flow-mediated endothelial remodeling reduces extravasation of tumor cells

Expression Profiling of Extracellular Matrix Genes Reveals Global and Entity-Specific Characteristics in Adenoid Cystic, Mucoepidermoid and Salivary Duct Carcinomas

Impact of tumor-parenchyma biomechanics on liver metastatic progression: a multi-model approach

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