The CD44s splice isoform is a central mediator for invadopodia activity

Zhao, Pu; Xu, Yilin; Wei, Yong; Qiu, Qiong; Chew, Teng Leong; Kang, Yibin; Cheng, Chonghui

doi:10.1242/jcs.171959

Cited by 57 publications

(69 citation statements)

References 45 publications

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“…CD44 is a commonly used cancer stem cell marker which is associated with the subpopulation of invadopodium containing migrating and disseminating tumor cells in breast tumors [5, 51, 52]. CD44 enables invasive tumor cells to produce functional invadopodia in response to metastasis-promoting microenvironments [52, 53].…”

Section: Diverse Stimuli Initiate Invadopodium Formation In Diverse Mmentioning

confidence: 99%

“…CD44 enables invasive tumor cells to produce functional invadopodia in response to metastasis-promoting microenvironments [52, 53]. Originally characterized as a hyaluronan receptor, CD44 is involved in the adhesion of tumor cells to collagen type-I and –IV, laminin and fibronectin [54].…”

Section: Diverse Stimuli Initiate Invadopodium Formation In Diverse Mmentioning

confidence: 99%

“…CD44 has been shown to be in complex with MMP9 at invadopodia in breast cancer cells, and is involved with MMP9 recruitment to the ventral cell surface of lymphoma cells [55]. Furthermore, a specific splice-isoform of CD44 associated with metastasis and necessary for EMT also enhances invadopodium maturation, increasing cortactin phosphorylation at Y421 and MT1-MMP recruitment to invadopodia [52] (Figure 2). …”

Section: Diverse Stimuli Initiate Invadopodium Formation In Diverse Mmentioning

confidence: 99%

See 2 more Smart Citations

Tumor Cell Invadopodia: Invasive Protrusions that Orchestrate Metastasis

Eddy

Weidmann

Sharma

et al. 2017

Trends in Cell Biology

315

354

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Invadopodia are a subset of invadosomes that are implicated in the integration of signals from the tumor microenvironment to support tumor cell invasion and dissemination. Recent progress has begun to define how tumor cells regulate the plasticity necessary for invadopodia to assemble and function efficiently in the different microenvironments encountered during dissemination in vivo. Exquisite mapping by many laboratories of the pathways involved in integrating diverse invadopodium initiation signals, from growth factors, extracellular matrix and cell-cell contact in the tumor microenvironment, has led to insight into the molecular basis of this plasticity. Here we integrate this new information to discuss how the invadopodium is an important conductor that orchestrates tumor cell dissemination during metastasis.

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Section: Diverse Stimuli Initiate Invadopodium Formation In Diverse Mmentioning

confidence: 99%

Section: Diverse Stimuli Initiate Invadopodium Formation In Diverse Mmentioning

confidence: 99%

Section: Diverse Stimuli Initiate Invadopodium Formation In Diverse Mmentioning

confidence: 99%

See 1 more Smart Citation

Tumor Cell Invadopodia: Invasive Protrusions that Orchestrate Metastasis

Eddy

Weidmann

Sharma

et al. 2017

Trends in Cell Biology

315

354

View full text Add to dashboard Cite

show abstract

“…The cell surface molecule CD44 has been regarded as a cancer stem cell marker in many types of cancers (1)(2)(3)(4)(5), and increasing evidence has suggested a role for CD44 in promoting cancer progression (6)(7)(8)(9)(10)(11)(12). CD44 was reported to act as a coreceptor for RTKs, including EGFR, and stimulates signaling downstream of RTKs (13)(14)(15).…”

mentioning

confidence: 99%

Internalized CD44s splice isoform attenuates EGFR degradation by targeting Rab7A

Wang

Zhang

Liu

et al. 2017

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

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CD44 has been postulated as a cell surface coreceptor for augmenting receptor tyrosine kinase (RTK) signaling. However, how exactly CD44 triggers RTK-dependent signaling remained largely unclear.Here we report an unexpected mechanism by which the CD44s splice isoform is internalized into endosomes to attenuate EGFR degradation. We identify a CD44s-interacting small GTPase, Rab7A, and show that CD44s inhibits Rab7A-mediated EGFR trafficking to lysosomes and subsequent degradation. Importantly, CD44s levels correlate with EGFR signature and predict poor prognosis in glioblastomas. Because Rab7A facilitates trafficking of many RTKs to lysosomes, our findings identify CD44s as a Rab7A regulator to attenuate RTK degradation.bnormal activation of receptor tyrosine kinase (RTK) and its downstream PI3K/Akt signaling is a common mechanism that drives cancer progression. The cell surface molecule CD44 has been regarded as a cancer stem cell marker in many types of cancers (1-5), and increasing evidence has suggested a role for CD44 in promoting cancer progression (6-12). CD44 was reported to act as a coreceptor for RTKs, including EGFR, and stimulates signaling downstream of RTKs (13-15). However, the mechanism by which CD44 triggers RTK-dependent signaling has remained unclear. Adding another layer of complexity, CD44 undergoes extensive alternative splicing, producing two families of isoforms, termed CD44v and CD44s. The CD44v splice isoforms contain at least one of its nine variable exons, whereas the CD44s isoform is devoid of all variable exons. The contribution of specific isoforms of CD44 in RTK signaling has been elusive.The majority of glioblastoma (GBM) displays hyperactivation of RTKs with greater than 45% of specimens harboring EGFR amplification or mutation (16). A challenge for treating GBM patients with RTK inhibitors (RTKIs) is the acquired drug resistance, due in part to the cross-activation of RTKs converging on PI3K-Akt (17, 18). Thus, proteins that promote the signaling of not only EGFR but also many other RTKs could be ideal targets for GBM.Here, we report an unexpected finding that the CD44s splice isoform attenuates endocytosis-mediated EGFR degradation, thus sustaining downstream Akt signaling. We identify the small GTPase, Rab7A, as a major downstream target for CD44s in mediating EGFR degradation. Because Rab7A promotes the trafficking of many RTKs to the lysosomal pathway, CD44s may serve as a potential therapeutic target not only by impairing the EGFR-signaling cascade but also possibly through elimination of cross-activated RTK signaling in response to therapeutic resistance in GBM. Results CD44s Inhibits Lysosome-Mediated EGFR Degradation and SustainsAKT Signaling. The CD44 gene produces CD44s and CD44v family of splice isoforms. To examine the effect of CD44 on EGFR signaling, we used the HT1080 and U87MG cancer cells that predominately express CD44s and the experimentally immortalized mammary epithelial HMLE cells, which express CD44v as the major isoform (SI Appendix, Fig. S1A). Silencing ...

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“…PDPN-CD44 interaction appears to promote directional migration in SCC cells [22] . Interestingly, CD44s has also been identified as a component of invadopodia [23] , where it plays an important role in the formation these structures and recruitment of MMP14 (MT1-MMP) metalloprotease. The implication of PDPN-CD44s interaction in invadopodia assembly and activity remains to be investigated.…”

mentioning

confidence: 99%

Podoplanin promotes malignancy through a diversity of strategies

2016

Cancer Cell Microenviron

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Podoplanin (PDPN) is a small mucin-like glycoprotein upregulated in a variety of cancers where it can be expressed in tumor as well as in stromal cells, such as cancer associated fibroblasts (CAFs). In most cancers, especially in squamous cell carcinomas (SCC) and glioblastomas, PDPN expression is associated with increased risk of metastasis to lymph nodes and reduced overall survival, although the opposite has been found in other tumor types. Studies from different laboratories, including our own, suggest that PDPN is involved in different steps of the metastatic cascade. Thus, PDPN, which is connected to the actin cytoskeleton through the binding to ezrin and/or moesin, stimulates collective tumor cell migration/invasion, and induces an epithelial-mesenchymal transition allowing a directional migration of individual cells through its interaction with the hyaluronan receptor CD44. PDPN is a component of the invadopodium contributing to its stability and promoting an efficient invasion through the extracellular matrix. In addition, PDPN favors the survival of cancer cells in the bloodstream aiding to their metastatic dissemination by inducing platelet aggregation/activation through its binding to the platelet receptor CLEC-2. More recently, we have reported that PDPN is a component of microvesicles and exosomes released by tumor cells and that PDPN-containing exosomes enhance in vitro lymphangiogenesis. In this short review, we discuss the role of PDPN in all these processes that foster malignant progression.

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The CD44s splice isoform is a central mediator for invadopodia activity

Cited by 57 publications

References 45 publications

Tumor Cell Invadopodia: Invasive Protrusions that Orchestrate Metastasis

Tumor Cell Invadopodia: Invasive Protrusions that Orchestrate Metastasis

Internalized CD44s splice isoform attenuates EGFR degradation by targeting Rab7A

Podoplanin promotes malignancy through a diversity of strategies

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