DPYSL3 modulates mitosis, migration, and epithelial-to-mesenchymal transition in claudin-low breast cancer

Matsunuma, Ryoichi; Chan, Doug W.; Kim, Beom-Jun; Singh, Purba; Han, Airi; Saltzman, Alexander B.; Lei, Jonathan T.; Wang, Junkai; Silva, Leonardo Roberto da; Sahin, Ergün; Leng, Mei; Fan, Cheng; Perou, Charles M.; Malovannaya, Anna; Ellis, Matthew J.

doi:10.1073/pnas.1810598115

Cited by 49 publications

(37 citation statements)

References 46 publications

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“…DPYSL3 is also reported to play a role in cell migration and metastasis suppression in liver and prostate cancer [31][32][33]. In contrast, DPYSL3 is positively associated with metastasis and a poor outcome in breast cancer, renal cell carcinoma, gastric and pancreatic cancer [34][35][36][37]. Our study indicates that DPYSL3 acts as a promoter of cancer progression supported by the loss of DPYSL3 reduced cancer migration and EMT.…”

Section: Discussionmentioning

confidence: 52%

Upregulation of Thr/Tyr kinase Increases the Cancer Progression by Neurotensin and Dihydropyrimidinase-Like 3 in Lung Cancer

Tsai

Chang

et al. 2020

IJMS

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Lung cancer is one of the leading causes of cancer-related death globally, thus elucidation of its molecular pathology is highly highlighted. Aberrant alterations of the spindle assembly checkpoint (SAC) are implicated in the development of cancer due to abnormal cell division. TTK (Thr/Tyr kinase), a dual serine/threonine kinase, is considered to act as a cancer promoter by controlling SAC. However, the mechanistic details of how TTK-mediated signaling network supports cancer development is still a mystery. Here, we found that TTK was upregulated in the tumor tissue of patients with lung cancer, and enhanced tumor growth and metastasis in vitro and in vivo. Mechanistically, TTK exerted a significant enhancement in cancer growth by neurotensin (NTS) upregulation, and subsequently increased the expression of cyclin A and cdk2, which was resulting in the increase of DNA synthesis. In contrast, TTK increased cell migration and epithelial-to-mesenchymal transition (EMT) by enhancing the expression of dihydropyrimidinase-like 3 (DPYSL3) followed by the increase of snail-regulated EMT, thus reinforce metastatic potential and ultimately tumor metastasis. TTK and DPYSL3 upregulation was positively correlated with a poor clinical outcome in patients with lung cancer. Together, our findings revealed a novel mechanism underlying the oncogenic potential effect of TTK and clarified its downstream factors NTS and DPYSL3 might represent a novel, promising candidate oncogenes with potential therapeutic vulnerabilities in lung cancer.

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Section: Discussionmentioning

confidence: 52%

Upregulation of Thr/Tyr kinase Increases the Cancer Progression by Neurotensin and Dihydropyrimidinase-Like 3 in Lung Cancer

Tsai

Chang

et al. 2020

IJMS

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“…C ancer proteogenomics integrates data from cancer genomics and transcriptomics with cancer proteomics to provide deeper insights into cancer biology and therapeutic vulnerabilities. Both by improving the functional annotation of genomic aberrations and through insights into pathway activation, this multi-dimensional approach to the characterization of human tumors shows promise for application to precision oncology [1][2][3][4][5][6][7] Here we address tissue requirements for proteogenomics, which restricts translational research opportunities and applicability to cancer diagnostics. For example, the Clinical Proteomic Tumor Analysis Consortium (CPTAC) requires at least 100 mg of tumor tissue, which typically yields quantitative information on >10,000 proteins and >30,000 phosphosites per sample 8 .…”

mentioning

confidence: 99%

Microscaled proteogenomic methods for precision oncology

et al. 2020

Self Cite

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Cancer proteogenomics promises new insights into cancer biology and treatment efficacy by integrating genomics, transcriptomics and protein profiling including modifications by mass spectrometry (MS). A critical limitation is sample input requirements that exceed many sources of clinically important material. Here we report a proteogenomics approach for core biopsies using tissue-sparing specimen processing and microscaled proteomics. As a demonstration, we analyze core needle biopsies from ERBB2 positive breast cancers before and 48-72 h after initiating neoadjuvant trastuzumab-based chemotherapy. We show greater suppression of ERBB2 protein and both ERBB2 and mTOR target phosphosite levels in cases associated with pathological complete response, and identify potential causes of treatment resistance including the absence of ERBB2 amplification, insufficient ERBB2 activity for therapeutic sensitivity despite ERBB2 amplification, and candidate resistance mechanisms including androgen receptor signaling, mucin overexpression and an inactive immune microenvironment. The clinical utility and discovery potential of proteogenomics at biopsyscale warrants further investigation.

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“…Among these, CLBC share features with mammary stem cells, enhances the expression of epithelial-mesenchymal transition (EMT) and stem cell marker molecules, while the expression of tight junction proteins Claudins and E-cadherin is decreased. 5,6 Clinical data and genetically engineered mouse models have shown that CLBC is more resistant to chemotherapeutic agents and has a worse prognosis than BLBC. 7,8 However, no specific targeted treatment exists for CLBC.…”

Section: Introductionmentioning

confidence: 99%

<p>Targeting PIK3CG in Combination with Paclitaxel as a Potential Therapeutic Regimen in Claudin-Low Breast Cancer</p>

Chang¹,

Ling²,

Liu³

et al. 2020

CMAR

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Purpose: Molecular targeting is a powerful approach for aggressive claudin-low breast cancer (CLBC). Overexpression of PI3K catalytic subunit gamma (PIK3CG) in human CLBC is offering a promising opportunity for targeted therapies. We utilized a specific inhibitor of PIK3CG combined with paclitaxel (PTX) to treat CLBC cells in vitro and in vivo. Patients and Methods: The tumor cells growth and apoptosis in vitro were analyzed by CCK8, plate clone formation assay, tumorsphere assay, Hoechst staining and flow cytometry. The invasion and metastasis ability of tumor cells in vitro were investigated by wound healing and transwell experiments. Critical gene expression levels were checked by qRT-PCR and Western blot. Xenograft models with CLBC cell lines in SCID mice were established to investigate the effect of combined drugs in vivo. Results: We identified that PIK3CG was a potential therapeutic target for CLBC patients. Targeting PIK3CG potentiated CLBC cells growth inhibition in 2D and 3D cultures by PTX. Inhibition of PIK3CG activation could enhance CLBC cells apoptosis and migration suppression induced by PTX. Manipulating autophagy was a validated approach for the use of PIK3CG inhibitor. Using CLBC xenograft mice model, we found that CLBC tumors in vivo could be well treated by combined drugs of PIK3CG inhibitor and PTX. Conclusion: We demonstrated that PIK3CG was a potential target for the therapy of CLBC and inhibition of PIK3CG activation could reinforce the therapeutic effect of this aggressive disease by PTX. The combined use of PIK3CG inhibitor and PTX might be a potential regimen for treating this subtype of breast cancer.

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DPYSL3 modulates mitosis, migration, and epithelial-to-mesenchymal transition in claudin-low breast cancer

Cited by 49 publications

References 46 publications

Upregulation of Thr/Tyr kinase Increases the Cancer Progression by Neurotensin and Dihydropyrimidinase-Like 3 in Lung Cancer

Upregulation of Thr/Tyr kinase Increases the Cancer Progression by Neurotensin and Dihydropyrimidinase-Like 3 in Lung Cancer

Microscaled proteogenomic methods for precision oncology

<p>Targeting PIK3CG in Combination with Paclitaxel as a Potential Therapeutic Regimen in Claudin-Low Breast Cancer</p>

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