The Different Routes to Metastasis via Hypoxia-Regulated Programs

Nobre, Ana Rita; Entenberg, David; Wang, Yarong; Condeelis, John S.; Aguirre‐Ghiso, Julio A.

doi:10.1016/j.tcb.2018.06.008

Cited by 93 publications

(84 citation statements)

References 152 publications

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“…Hypoxia is a strong inducer of metastatic activity, 58 and calpain-2 activation predicts disease progression and poor prognosis in epithelial cancer. 47 To investigate whether hypoxia-induced metastasis depends on calpain, 4T1 cells were maintained in hypoxic or normoxic two-day culture in vitro in the absence or presence of calpain inhibitor PD150606, injected into the tail vein of nude mice, and analyzed for lung metastasis after 14 days ( Supplementary Fig.…”

Section: Calpain Activity Amoeboid Conversion and Relevance For Metamentioning

confidence: 99%

Calpain-2 regulates hypoxia/HIF-induced amoeboid reprogramming and metastasis

Boekhorst

Jiang

Mählen

et al. 2020

Preprint

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Hypoxia, through hypoxia inducible factor (HIF), drives cancer cell invasion and metastatic progression in various cancer types, leading to poor prognosis. In epithelial cancer, hypoxia further induces the transition to amoeboid cancer cell dissemination, yet the molecular mechanisms, relevance for metastasis, and effective interventions to combat hypoxia-induced amoeboid reprogramming remain unclear. Here, we identify calpain-2 as key regulator and anti-metastasis target of hypoxia-induced transition from collective to amoeboid dissemination of breast and head and neck (HN) carcinoma cells. Hypoxia-induced amoeboid dissemination occurred through low ECM-adhesive, bleb-based amoeboid movement, which effectively invaded into 3D collagen with low-oxidative and -glycolytic energy metabolism, revealing an microenvironmentally-induced, energy-conserving dissemination route in epithelial cancers. Hypoxia-induced calpain-2 mediated amoeboid conversion by deactivating beta1 integrins, through enzymatic cleavage of the focal adhesion adaptor protein talin-1.Consequently, targeted downregulation of calpain-2 or pharmacological intervention restored talin-1 integrity, beta1 integrin engagement and reverted blebbing-amoeboid to elongated phenotypes under hypoxia. Calpain-2 activity was required for hypoxia-induced blebbing-amoeboid conversion in the orthotopic mouse dermis, and upregulated in invasive HN tumor xenografts in vivo, and attenuation of calpain activity prevented hypoxia-induced metastasis to the lungs. This identifies the calpain-2/talin-1/beta1 integrin axis as mechanosignaling program and promising intervention target of plasticity of cancer cell invasion and metastasis formation in epithelial cancers under hypoxia. IntroductionCancer cell invasion initiates a multistep cascade to metastasis, which converts local neoplasia into a life-threatening systemic disease. 1-3 Invading cancer cells migrate away from the primary tumor and penetrate blood and lymph vessels, followed by systemic spreading and metastatic colonization of distant organs. 1,3 For tissue invasion, cancer cells deploy a range of collective and individual cell 3 migration strategies. Collective invasion of multicellular groups occurs when cells are held together by cell-cell adhesion, whereas single-cell migration lacks cell-cell cohesion and connectivity. 4 Mesenchymal single-cell migration depends on effective integrin-mediated adhesion to the extracellular matrix (ECM), which supports spindle-like cell elongation and directs matrix metalloproteases (MMPs) for ECM remodeling and path generation. 5 Amoeboid movement of roundish or ellipsoid cells engages only weak adhesion to the ECM, lacks ECM remodeling and, instead deploys kinetic deformation of the cell body for passage through 3D tissue. 6 Besides the cell shape and the strength of ECM interactions, protrusion types differ between amoeboid migration modes. Amoeboid-moving leukocytes and cancer cells develop actin-rich pseudopodia and filopodia at the leading edge, which generate protrusive...

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Section: Calpain Activity Amoeboid Conversion and Relevance For Metamentioning

confidence: 99%

Calpain-2 regulates hypoxia/HIF-induced amoeboid reprogramming and metastasis

Boekhorst

Jiang

Mählen

et al. 2020

Preprint

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“…For example, hypoxia is known to contribute to hypoxic secretome (10) and activate several transcription factors (1) and epigenetic modifications (11). These can further induce cell phenotype changes such as conventional or partial epithelial-to-mesenchymal transition (EMT) that contributes to drug resistance and possibly, to tumor migration and metastasis (3,(11)(12)(13)(14)(15)(16)(17). However, hypoxia-targeted therapies combined with current standard-of-care therapies (e.g., chemotherapy or radiotherapy) showed mixed outcomes in several clinical trials (18)(19)(20).…”

Section: Introductionmentioning

confidence: 99%

“…Traditional two-dimensional (2D) cell culture-based assays are unable to capture the constantly evolving dynamic in vivo microenvironment and are likely poor surrogates for studying emergence of migratory phenotypes (see recent review in ref. 13). Typical in vitro three-dimensional (3D) cultures such as spinner flasks (22-24) generate a broad size distribution of multicellular aggregates (microtumors), which present a technical difficulty for systematically studying the effect of tumor sizeinduced hypoxic microenvironment.…”

Section: Introductionmentioning

confidence: 99%

Targeting the Temporal Dynamics of Hypoxia-Induced Tumor-Secreted Factors Halts Tumor Migration

et al. 2019

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Targeting microenvironmental factors that foster migratory cell phenotypes is a promising strategy for halting tumor migration. However, lack of mechanistic understanding of the emergence of migratory phenotypes impedes pharmaceutical drug development. Using our three-dimensional microtumor model with tight control over tumor size, we recapitulated the tumor size-induced hypoxic microenvironment and emergence of migratory phenotypes in microtumors from epithelial breast cells and patientderived primary metastatic breast cancer cells, mesothelioma cells, and lung cancer xenograft cells. The microtumor models from various patient-derived tumor cells and patient-derived xenograft cells revealed upregulation of tumor-secreted factors, including matrix metalloproteinase-9 (MMP9), fibronectin (FN), and soluble E-cadherin, consistent with clinically reported elevated levels of FN and MMP9 in patient breast tumors compared with healthy mammary glands. Secreted factors in the conditioned media of large microtumors induced a migratory phenotype in nonhypoxic, nonmigratory small microtumors. Subsequent mathematical analyses identified a two-stage microtumor progression and migration mechanism whereby hypoxia induces a migratory phenotype in the initialization stage, which then becomes self-sustained through a positive feedback loop established among the tumor-secreted factors. Computational and experimental studies showed that inhibition of tumor-secreted factors effectively halts microtumor migration despite tumor-to-tumor variation in migration kinetics, while inhibition of hypoxia is effective only within a time window and is compromised by tumor-to-tumor variation, supporting our notion that hypoxia initiates migratory phenotypes but does not sustain it. In summary, we show that targeting temporal dynamics of evolving microenvironments, especially tumor-secreted factors during tumor progression, can halt tumor migration.Significance: This study uses state-of-the-art three-dimensional microtumor models and computational approaches to highlight the temporal dynamics of tumor-secreted microenvironmental factors in inducing tumor migration.

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“…Hypoxia is a crucial microenvironmental factor that induces cancer metastasis . Hypoxia/hypoxia‐inducible factor‐1α (HIF‐1α) regulates many critical steps of the metastatic processes .…”

Section: Introductionmentioning

confidence: 99%

Identification of new hypoxia‐regulated epithelial‐mesenchymal transition marker genes labeled by H3K4 acetylation

Wang

Yan

Wang

et al. 2019

Genes Chromosomes & Cancer

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Hypoxia‐induced epithelial‐mesenchymal transition (EMT) involves the interplay between chromatin modifiers histone deacetylase 3 (HDAC3) and WDR5. The histone mark histone 3 lysine 4 acetylation (H3K4Ac) is observed in the promoter regions of various EMT marker genes (eg, CDH1 and VIM). To further define the genome‐wide location of H3K4Ac, a chromatin immunoprecipitation followed by massively parallel DNA sequencing (ChIP‐seq) analysis was performed using a head and neck squamous cell carcinoma (HNSCC) FaDu cell line under normoxia and hypoxia. H3K4Ac was found to be located mainly around the transcription start site. Coupled with analysis of gene expression by RNA sequencing and using a HDAC3 knockdown cell line, 10 new genes (BMI1, GLI1, SMO, FOXF1, SIRT2, etc) that were labeled by H3K4Ac and regulated by HDAC3 were identified. Overexpression or knockdown of GLI1/SMO increased or repressed the in vitro migration and invasion activity in OECM‐1/FaDu cells, respectively. In HNSCC patients, coexpression of GLI1 and SMO in primary tumors correlated with metastasis. Our results identify new EMT marker genes that may play a significant role in hypoxia‐induced EMT and metastasis and further provide diagnostic and prognostic implications.

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The Different Routes to Metastasis via Hypoxia-Regulated Programs

Cited by 93 publications

References 152 publications

Calpain-2 regulates hypoxia/HIF-induced amoeboid reprogramming and metastasis

Calpain-2 regulates hypoxia/HIF-induced amoeboid reprogramming and metastasis

Targeting the Temporal Dynamics of Hypoxia-Induced Tumor-Secreted Factors Halts Tumor Migration

Identification of new hypoxia‐regulated epithelial‐mesenchymal transition marker genes labeled by H3K4 acetylation

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