<scp>SEMA</scp>
            3C drives cancer growth by transactivating multiple receptor tyrosine kinases via Plexin B1

Peacock, James W.; Takeuchi, Ario; Hayashi, Norihiro; Liu, Liangliang; Tam, Kevin J.; Nakouzi, Nader Al; Khazamipour, Nastaran; Tombe, Tabitha; Dejima, Takashi; Lee, Kevin C.K.; Shiota, Masaki; Thaper, Daksh; Lee, Wilson C.W.; Hui, Daniel; Kuruma, Hidetoshi; Ivanova, L.; Yenki, Parvin; Jiao, Ivy Z F; Khosravi, Shahram; Mui, Alice; Fazli, Ladan; Zoubeidi, Amina; Daugaard, Mads; Gleave, Martin; Ong, Christopher J.

doi:10.15252/emmm.201707689

Cited by 54 publications

(99 citation statements)

References 52 publications

(68 reference statements)

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“…Given that Sema domain is necessary for ligand docking and MET dimerization 16 , whereas the juxtamembrane domain regulates stability and nuclear trafficking of MET 25,26 , we postulated that the interaction with HER2 requires an intact Sema domain. On the basis that Sema-domain decoy proteins could suppress RTK activities 16,27 , we generated recombinant Sema proteins without the tyrosine kinase region-containing both the PSI domain and either WT (rSema wt ) or mutated (rSema N375S ) Sema sequences ( Supplementary Table 1)-as inhibitor proteins to competitively disrupt the interaction of MET with its binding partners. While both rSema proteins dose-dependently reduced the cell viability of MET wt-tGFP cells (Fig.…”

Section: Resultsmentioning

confidence: 99%

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A common MET polymorphism harnesses HER2 signaling to drive aggressive squamous cell carcinoma

et al. 2020

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MET receptors are activated in cancers through genomic events like tyrosine kinase domain mutations, juxtamembrane splicing mutation and amplified copy numbers, which can be inhibited by c-MET small molecule inhibitors. Here, we discover that the most common polymorphism known to affect MET gene (N375S), involving the semaphorin domain, confers exquisite binding affinity for HER2 and enables MET N375S to interact with HER2 in a ligandindependent fashion. The resultant MET N375S /HER2 dimer transduces potent proliferative, pro-invasive and pro-metastatic cues through the HER2 signaling axis to drive aggressive squamous cell carcinomas of the head and neck (HNSCC) and lung (LUSC), and is associated with poor prognosis. Accordingly, HER2 blockers, but not c-MET inhibitors, are paradoxically effective at restraining in vivo and in vitro models expressing MET N375S . These results establish MET N375S as a biologically distinct and clinically actionable molecular subset of SCCs that are uniquely amenable to HER2 blocking therapies.

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Section: Resultsmentioning

confidence: 99%

“…It is interesting to note that Sema proteins have been shown to act as oncogenic ligands in the activation of RTKs that include MET and HER2 27 . Based on molecular modeling and simulations, we postulate that the asparagine-to-serine substitution could induce significant localized conformational changes (Supplementary Fig.…”

Section: Discussionmentioning

confidence: 99%

A common MET polymorphism harnesses HER2 signaling to drive aggressive squamous cell carcinoma

et al. 2020

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“…PlexinB1 and its ligand Sema3C have been shown to promote resistance to androgen receptor pathway inhibition in prostate cancer treatment. Inhibition of either PlexinB1 or Sema3C significantly delays regrowth of prostate cancer xenografts in mice following castration or enzalutamide treatment [10]. In addition, overexpression of Sema3C increases the regrowth of prostate cancer xenografts following castration [10].…”

Section: Discussionmentioning

confidence: 99%

“…Inhibition of either PlexinB1 or Sema3C significantly delays regrowth of prostate cancer xenografts in mice following castration or enzalutamide treatment [10]. In addition, overexpression of Sema3C increases the regrowth of prostate cancer xenografts following castration [10]. In clinical prostate cancer, high Sema3C expression levels are associated with resistance to ADT in patient derived xenografts [39] and an increase in Sema3C is found in CRPC and bone metastases [10].…”

Section: Discussionmentioning

confidence: 99%

“…In addition, overexpression of Sema3C increases the regrowth of prostate cancer xenografts following castration [10]. In clinical prostate cancer, high Sema3C expression levels are associated with resistance to ADT in patient derived xenografts [39] and an increase in Sema3C is found in CRPC and bone metastases [10]. Upregulation of GR is also associated with resistance to ADT, probably due to GR activation of a subset of AR-regulated genes [3].…”

Section: Discussionmentioning

confidence: 99%

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PlexinB1 Promotes Nuclear Translocation of the Glucocorticoid Receptor

Williamson

Garg

Wells

2019

Cells

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Androgen receptor (AR) and glucocorticoid receptor (GR) are nuclear receptors whose function depends on their entry into the nucleus where they activate transcription of an overlapping set of genes. Both AR and GR have a role in resistance to androgen deprivation therapy (ADT), the mainstay of treatment for late stage prostate cancer. PlexinB1, a receptor for semaphorins, has been implicated in various cancers including prostate cancer and has a role in resistance to ADT. We show here that activation of PlexinB1 by Sema4D and Sema3C results in translocation of endogenous GR to the nucleus in prostate cancer cells, and that this effect is dependent on PlexinB1 expression. Sema4D/Sema3C promotes the translocation of GR-GFP to the nucleus and mutation of the nuclear localization sequence (NLS1) of GR abrogates this response. These findings implicate the importin α/β system in the Sema4D/Sema3C-mediated nuclear import of GR. Knockdown of PlexinB1 in prostate cancer cells decreases the levels of glucocorticoid-responsive gene products and antagonizes the decrease in cell motility and cell area of prostate cancer cells upon dexamethasone treatment, demonstrating the functional significance of these findings. These results show that PlexinB1 activation has a role in the trafficking and activation of the nuclear receptor GR and thus may have a role in resistance to androgen deprivation therapy in late stage prostate cancer.

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Single‐Nucleus RNA Sequencing and Spatial Transcriptomics Reveal the Immunological Microenvironment of Cervical Squamous Cell Carcinoma

Lin

Qiu

et al. 2022

Advanced Science

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The effective treatment of advanced cervical cancer remains challenging. Herein, single-nucleus RNA sequencing (snRNA-seq) and SpaTial enhanced resolution omics-sequencing (Stereo-seq) are used to investigate the immunological microenvironment of cervical squamous cell carcinoma (CSCC). The expression levels of most immune suppressive genes in the tumor and inflammation areas of CSCC are not significantly higher than those in the non-cancer samples, except for LGALS9 and IDO1. Stronger signals of CD56 + NK cells and immature dendritic cells are found in the hypermetabolic tumor areas, whereas more eosinophils, immature B cells, and Treg cells are found in the hypometabolic tumor areas. Moreover, a cluster of pro-tumorigenic cancer-associated myofibroblasts (myCAFs) are identified. The myCAFs may support the growth and metastasis of tumors by inhibiting lymphocyte infiltration and remodeling of the tumor extracellular matrix. Furthermore, these myCAFs are associated with poorer survival probability in patients with CSCC, predict resistance to immunotherapy, and might be present in a small fraction (< 30%) of patients with advanced cancer. Immunohistochemistry and multiplex immunofluorescence staining are conducted to validate the spatial distribution and potential function of myCAFs. Collectively, these findings enhance the understanding of the immunological microenvironment of CSCC and shed light on the treatment of advanced CSCC.

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SEMA 3C drives cancer growth by transactivating multiple receptor tyrosine kinases via Plexin B1

Cited by 54 publications

References 52 publications

A common MET polymorphism harnesses HER2 signaling to drive aggressive squamous cell carcinoma

A common MET polymorphism harnesses HER2 signaling to drive aggressive squamous cell carcinoma

PlexinB1 Promotes Nuclear Translocation of the Glucocorticoid Receptor

Single‐Nucleus RNA Sequencing and Spatial Transcriptomics Reveal the Immunological Microenvironment of Cervical Squamous Cell Carcinoma

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