Deregulation of the Hippo pathway in soft-tissue sarcoma promotes FOXM1 expression and tumorigenesis

Eisinger-Mathason, T.S. Karin; Mucaj, Vera; Biju, Kevin; Nakazawa, Michael S.; Gohil, Mercy; Cash, Timothy P.; Yoon, Sam S.; Skuli, Nicolas; Park, Kyung Min; Gerecht, Sharon; Simon, M. Celeste

doi:10.1073/pnas.1420005112

Cited by 92 publications

(104 citation statements)

References 49 publications

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“…3A). Notably, by day 7 in culture, O 2 levels have decreased to ∼0.5%, likely to due to expansion of the cell number over the longer culture period and the associated cellular O 2 consumption (18). An important feature of this culture system is the ability to maintain the hypoxic gradient environment without exposure to high O 2 levels, thus minimizing the introduction of ROS.…”

Section: Resultsmentioning

confidence: 99%

Intratumoral oxygen gradients mediate sarcoma cell invasion

Lewis

Park

Tang

et al. 2016

Proc. Natl. Acad. Sci. U.S.A.

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104

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Hypoxia is a critical factor in the progression and metastasis of many cancers, including soft tissue sarcomas. Frequently, oxygen (O 2 ) gradients develop in tumors as they grow beyond their vascular supply, leading to heterogeneous areas of O 2 depletion. Here, we report the impact of hypoxic O 2 gradients on sarcoma cell invasion and migration. O 2 gradient measurements showed that large sarcoma mouse tumors (>300 mm 3 ) contain a severely hypoxic core [≤0.1% partial pressure of O 2 (pO 2 )] whereas smaller tumors possessed hypoxic gradients throughout the tumor mass (0.1-6% pO 2 ). To analyze tumor invasion, we used O 2 -controllable hydrogels to recreate the physiopathological O 2 levels in vitro. Small tumor grafts encapsulated in the hydrogels revealed increased invasion that was both faster and extended over a longer distance in the hypoxic hydrogels compared with nonhypoxic hydrogels. To model the effect of the O 2 gradient accurately, we examined individual sarcoma cells embedded in the O 2 -controllable hydrogel. We observed that hypoxic gradients guide sarcoma cell motility and matrix remodeling through hypoxia-inducible factor-1α (HIF-1α) activation. We further found that in the hypoxic gradient, individual cells migrate more quickly, across longer distances, and in the direction of increasing O 2 tension. Treatment with minoxidil, an inhibitor of hypoxia-induced sarcoma metastasis, abrogated cell migration and matrix remodeling in the hypoxic gradient. Overall, we show that O 2 acts as a 3D physicotactic agent during sarcoma tumor invasion and propose the O 2 -controllable hydrogels as a predictive system to study early stages of the metastatic process and therapeutic targets.hydrogel | sarcoma | hypoxia | gradients | migration S oft tissue sarcomas are a heterogeneous group of malignant cancers derived from transformed cells of mesenchymal origin (1, 2). Approximately 13,000 new cases per year are diagnosed in the United States alone, with 25-50% of patients developing recurrent and metastatic disease (3-5). Current clinical data suggest that undifferentiated pleomorphic sarcoma (UPS) is one of the most aggressive sarcoma subtypes, which frequently results in lethal pulmonary metastases that are insensitive to radio/chemotherapy. It has recently become apparent that sarcoma progression and metastasis are regulated by microenvironmental cues, such as extracellular matrix (ECM) remodeling, stiffness modulation, cellto-cell/matrix interactions, signaling factors, and spatial gradients (6-8). Of all these factors, low intratumoral oxygen (O 2 ; hypoxia) is most dramatically associated with pulmonary metastasis and poor clinical outcomes (9, 10).Intratumoral hypoxia occurs when the partial pressure of O 2 (pO 2 ) falls below 5%, and it is a commonly observed feature of many sarcomas. Regional hypoxia develops as rapidly growing tumors outstrip their blood supply and as a consequence of aberrant tumor angiogenesis. As a result, O 2 gradients develop throughout the growing tumor. Tumor hypoxia promotes c...

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Section: Resultsmentioning

confidence: 99%

Intratumoral oxygen gradients mediate sarcoma cell invasion

Lewis

Park

Tang

et al. 2016

Proc. Natl. Acad. Sci. U.S.A.

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104

117

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“…It is a diagnosis of exclusion as these tumors defy lineage assignment. This postulate is partly substantiated by recent experimental evidence in which deregulated Hippo pathway signaling in soft-tissue sarcomas was found to promote FOXM1 expression and tumorigenesis in undifferentiated pleomorphic sarcoma, fibrosarcoma and liposarcoma [31]. Most soft-tissue sarcomas arise from tissues derived from the mesodermal or ectodermal germ layers, however some such as angiosarcomas have an endodermal origin.…”

Section: Foxm1 and Mesenchymal Tumorsmentioning

confidence: 88%

“…In a general perspective SOX2 has been found to antagonize the Hippo pathway to maintain ‘stemness’ in cancer cells [58]. Evidence also exists that Yes-Associated Protein (YAP), the effector molecule which is inhibited by the Hippo signaling pathway cascade of cytoplasmic kinases, is increased in a subset of soft tissue sarcoma [31]. In these sarcomas i.e.…”

Section: Foxm1 and Expression Of Pluripotency Genementioning

confidence: 99%

FOXM1 in sarcoma: role in cell cycle, pluripotency genes and stem cell pathways

Kelleher

O’Sullivan

2016

Oncotarget

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FOXM1 is a pro-proliferative transcription factor that promotes cell cycle progression at the G1-S, and G2-M transitions. It is activated by phosphorylation usually mediated by successive cyclin – cyclin dependent kinase complexes, and is highly expressed in sarcoma. p53 down regulates FOXM1 and FOXM1 inhibition is also partly dependent on Rb and p21. Abnormalities of p53 or Rb are frequent in sporadic sarcomas with bone or soft tissue sarcoma, accounting for 36% of index cancers in the high penetrance TP53 germline disorder, Li-Fraumeni syndrome.FOXM1 stimulates transcription of pluripotency related genes including SOX2, KLF4, OCT4, and NANOG many of which are important in sarcoma, a disorder of mesenchymal stem cell/ partially committed progenitor cells. In a selected specific, SOX2 is uniformly expressed in synovial sarcoma. Embryonic pathways preferentially used in stem cell such as Hippo, Hedgehog, and Wnt dominate in FOXM1 stoichiometry to alter rates of FOXM1 production or degradation. In undifferentiated pleomorphic sarcoma, liposarcoma, and fibrosarcoma, dysregulation of the Hippo pathway increases expression of the effector co-transcriptional activator Yes-Associated Protein (YAP). A complex involving YAP and the transcription factor TEAD elevates FOXM1 in these sarcoma subtypes. In another scenario 80% of desmoid tumors have nuclear localization of β-catenin, the Wnt pathway effector molecule. Thiazole antibiotics inhibit FOXM1 and because they have an auto-regulator loop FOXM1 expression is also inhibited. Current systemic treatment of sarcoma is of limited efficacy and inhibiting FOXM1 represents a potential new strategy.

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“…30 Thus, it is understandable that dysregulations of the Hippo pathway occur in many bone and soft tissue sarcomas. 31,32 However, only a few oncogenic mutations are found in the Hippo pathway that result in its dysregulation. Instead, the most likely cause of perturbed Hippo signaling in sarcoma is the cross-talk with commonly mutated cancer genes such as KRAS, PIK3CA, CTNNB1, or FBXW7.…”

Section: Rhabdomyosarcomamentioning

confidence: 99%

YAP and the Hippo pathway in pediatric cancer

Ahmed

Mohamed

Gener

et al. 2017

Molecular & Cellular Oncology

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The Hippo pathway is an important signaling pathway that controls cell proliferation and apoptosis. It is evolutionarily conserved in mammals and is stimulated by cell-cell contact, inhibiting cell proliferation in response to increased cell density. During early embryonic development, the Hippo signaling pathway regulates organ development and size, and its functions result in the coordinated balance between proliferation, apoptosis, and differentiation. Its principal effectors, YAP and TAZ, regulate signaling by the embryonic stem cells and determine cell fate and histogenesis. Dysfunction of this pathway contributes to cancer development in adults and children. Emerging studies have shed light on the upregulation of Hippo pathway members in several pediatric cancers and may offer prognostic information on rhabdomyosarcoma, osteosarcoma, Wilms tumor, neuroblastoma, medulloblastoma, and other brain gliomas. We review the results of such published studies and highlight the potential clinical application of this pathway in pediatric oncologic and pathologic studies. These studies support targeting this pathway as a novel treatment strategy.

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Deregulation of the Hippo pathway in soft-tissue sarcoma promotes FOXM1 expression and tumorigenesis

Cited by 92 publications

References 49 publications

Intratumoral oxygen gradients mediate sarcoma cell invasion

Intratumoral oxygen gradients mediate sarcoma cell invasion

FOXM1 in sarcoma: role in cell cycle, pluripotency genes and stem cell pathways

YAP and the Hippo pathway in pediatric cancer

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