Invadopodia: a new therapeutic target to block cancer metastasis

Stoletov, Konstantin; Lewis, John D.

doi:10.1586/14737140.2015.1058711

Cited by 30 publications

(27 citation statements)

References 12 publications

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“…Mounting evidence suggests a direct correlation between the propensity of cancer cells to form invadopodia and poor prognosis in breast cancer patients. Consequently, these structures are emerging as a promising target to impair metastasis formation232435. Our data implicate LPP as regulator of invadopodia formation and function, performing critical roles during breast cancer cell intravasation and extravasation during the metastatic process.…”

Section: Discussionmentioning

confidence: 73%

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LPP is a Src substrate required for invadopodia formation and efficient breast cancer lung metastasis

et al. 2017

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We have previously shown that lipoma preferred partner (LPP) mediates TGFβ-induced breast cancer cell migration and invasion. Herein, we demonstrate that diminished LPP expression reduces circulating tumour cell numbers, impairs cancer cell extravasation and diminishes lung metastasis. LPP localizes to invadopodia, along with Tks5/actin, at sites of matrix degradation and at the tips of extravasating breast cancer cells as revealed by intravital imaging of the chick chorioallantoic membrane (CAM). Invadopodia formation, breast cancer cell extravasation and metastasis require an intact LPP LIM domain and the ability of LPP to interact with α-actinin. Finally, we show that Src-mediated LPP phosphorylation at specific tyrosine residues (Y245/301/302) is critical for invadopodia formation, breast cancer cell invasion and metastasis. Together, these data define a previously unknown function for LPP in the formation of invadopodia and reveal a requirement for LPP in mediating the metastatic ability of breast cancer cells.

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Section: Discussionmentioning

confidence: 73%

“…Invadopodia are specialized degradative structures that facilitate tumour cell intravasation and efficient metastasis101323. Given the importance of LPP in mediating these processes, we investigated whether LPP also plays a role in invadopodia formation and ECM degradation.…”

Section: Resultsmentioning

confidence: 99%

LPP is a Src substrate required for invadopodia formation and efficient breast cancer lung metastasis

et al. 2017

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“…Recently invadopodia became a very interesting therapeutic target for aggressive cancer because their inhibition is effective to limit invasion, extravasation and subsequent metastasis (Stoletov and Lewis, 2015). Since EP4 has been proposed as potential anti-cancer treatments (Kundu et al, 2014; Majumder et al, 2014) (Kundu et al, 2014; Majumder et al, 2014), further investigation of EP4 targeting to restrict invadopodia formation and cancer cell invasion is warranted.…”

Section: Discussionmentioning

confidence: 99%

EP4 receptor promotes invadopodia and invasion in human breast cancer

Tönisen

Perrin

Bayarmagnai

et al. 2017

European Journal of Cell Biology

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The production of Prostaglandin E2 (PGE2) is elevated in human breast cancer cells. The abnormal expression of COX-2, which is involved in the synthesis of PGE2, was recently reported as a critical determinant for invasiveness of human breast cancer cells. Autocrine and paracrine PGE2-mediated stimulation of the PGE2 receptor EP4 transduces multiple signaling pathways leading to diverse patho-physiological effects, including tumor cell invasion and metastasis. It is known that PGE2-induced EP4 activation can transactivate the intracellular signaling pathway of the epidermal growth factor receptor (EGFR). In malignant cancer cells, EGFR pathway activation promotes invadopodia protrusions, which further leads to degradation of the surrounding extracellular matrix (ECM). Despite the known influence of EP4 on the EGFR signaling pathway, the effect of EP4 stimulation on invadopodia formation in human breast cancer was never tested directly. Here we demonstrate the involvement of EP4 in invasion and its effect on invadopodia in breast cancer MDA-MB-231 cells using 2D invadopodia and 3D invasion in vitro assays as well as intravital microscopy. The results show that stimulation with the selective EP4 agonist CAY10598 or PGE2 promotes invadopodia-mediated degradation of the ECM, as well as the invasion of breast cancer cells in in vitro models. The effect on matrix degradation can be abrogated via direct inhibition of EP4 signaling as well as via inhibition of EGFR tyrosine kinase, indicating that EP4-mediated effects on invadopodia-driven degradation are EGFR dependent. Finally, using xenograft mouse models, we show that short-term systemic treatment with CAY10598 results in a >9-fold increase in the number of invadopodia. These findings highlight the importance of further investigation on the role of EP4-EGFR crosstalk in invadopodia formation.

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“…Often these factors dramatically influence the prognosis for the affected individual. For invasion and metastasis neoplastic cells need the ability to migrate through the adjacent extracellular matrix, which is commonly mediated by the formation of invadopodia [35]. Therefore inhibition of invadopodia formation with consecutive reduction of tumour cell migration represents an exciting new possibility for improving prognosis and survival time.…”

Section: Discussionmentioning

confidence: 99%

Persistent Morbillivirus Infection Leads to Altered Cortactin Distribution in Histiocytic Sarcoma Cells with Decreased Cellular Migration Capacity

Pfankuche¹,

Sayed-Ahmed²,

Contioso³

et al. 2016

PLoS ONE

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Histiocytic sarcomas represent rare but fatal neoplasms in humans. Based on the absence of a commercially available human histiocytic sarcoma cell line the frequently affected dog displays a suitable translational model. Canine distemper virus, closely related to measles virus, is a highly promising candidate for oncolytic virotherapy. Therapeutic failures in patients are mostly associated with tumour invasion and metastasis often induced by misdirected cytoskeletal protein activities. Thus, the impact of persistent canine distemper virus infection on the cytoskeletal protein cortactin, which is frequently overexpressed in human cancers with poor prognosis, was investigated in vitro in a canine histiocytic sarcoma cell line (DH82). Though phagocytic activity, proliferation and apoptotic rate were unaltered, a significantly reduced migration activity compared to controls (6 hours and 1 day after seeding) accompanied by a decreased number of cortactin mRNA transcripts (1 day) was detected. Furthermore, persistently canine distemper virus infected DH82 cells showed a predominant diffuse intracytoplasmic cortactin distribution at 6 hours and 1 day compared to controls with a prominent membranous expression pattern (p ≤ 0.05). Summarized, persistent canine distemper virus infection induces reduced tumour cell migration associated with an altered intracellular cortactin distribution, indicating cytoskeletal changes as one of the major pathways of virus-associated inhibition of tumour spread.

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Invadopodia: a new therapeutic target to block cancer metastasis

Cited by 30 publications

References 12 publications

LPP is a Src substrate required for invadopodia formation and efficient breast cancer lung metastasis

LPP is a Src substrate required for invadopodia formation and efficient breast cancer lung metastasis

EP4 receptor promotes invadopodia and invasion in human breast cancer

Persistent Morbillivirus Infection Leads to Altered Cortactin Distribution in Histiocytic Sarcoma Cells with Decreased Cellular Migration Capacity

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