The CBM Complex Underwrites NF-κB Activation to Promote HER2-Associated Tumor Malignancy

Pan, Deng; Zhu, Yifan; Zhou, Zhicheng; Wang, Tingting; You, Harrison; Jiang, Changying; Lin, Xin

doi:10.1158/1541-7786.mcr-15-0229-t

Cited by 34 publications

(31 citation statements)

References 25 publications

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“…6E). Consistent with our observations in the K14 knockdown dataset, we observed that nine of these genes were previously reported in metastasis regulation, including in metastatic niche, vascular remodeling, and immunosurveillance, including Tnc, AdamTs1, Jag1, as well as Card10, Cav1, Ereg, Lgr5, Slpi, and Ptgs2 (29,(35)(36)(37)(38). Core genes showed evidence of multiple physical and genetic interactions and occurrence along common pathways (Fig.…”

Section: K14 Expression Is Required For Distant Metastasis and Regulasupporting

confidence: 90%

Polyclonal breast cancer metastases arise from collective dissemination of keratin 14-expressing tumor cell clusters

Cheung

Padmanaban

Silvestri

et al. 2016

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

639

701

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Recent genomic studies challenge the conventional model that each metastasis must arise from a single tumor cell and instead reveal that metastases can be composed of multiple genetically distinct clones. These intriguing observations raise the question: How do polyclonal metastases emerge from the primary tumor? In this study, we used multicolor lineage tracing to demonstrate that polyclonal seeding by cell clusters is a frequent mechanism in a common mouse model of breast cancer, accounting for >90% of metastases. We directly observed multicolored tumor cell clusters across major stages of metastasis, including collective invasion, local dissemination, intravascular emboli, circulating tumor cell clusters, and micrometastases. Experimentally aggregating tumor cells into clusters induced a >15-fold increase in colony formation ex vivo and a >100-fold increase in metastasis formation in vivo. Intriguingly, locally disseminated clusters, circulating tumor cell clusters, and lung micrometastases frequently expressed the epithelial cytoskeletal protein, keratin 14 (K14). RNA-seq analysis revealed that K14 + cells were enriched for desmosome and hemidesmosome adhesion complex genes, and were depleted for MHC class II genes. Depletion of K14 expression abrogated distant metastases and disrupted expression of multiple metastasis effectors, including Tenascin C (Tnc), Jagged1 (Jag1), and Epiregulin (Ereg). Taken together, our findings reveal K14 as a key regulator of metastasis and establish the concept that K14+ epithelial tumor cell clusters disseminate collectively to colonize distant organs.uring metastasis, cancer cells escape the primary tumor, travel through the circulation, and colonize distant organs. Conventional models of cancer progression propose that each metastasis arises from the clonal outgrowth of a single tumor cell and this conceptual framework is a foundation for models, such as epithelial-mesenchymal transition (EMT) and migratory cancer stem cells (1).Challenging the generality of the single-cell/single-metastasis model are long-standing clinical observations that tumor cell clusters (also termed "tumor clumps") are also observed across the stages of metastasis. Tumor cell clusters are detected in the bloodstream of cancer patients (2), clusters can efficiently seed metastases (3), and though rare, circulating tumor cell (CTC) clusters have prognostic significance (4, 5). Furthermore, metastases are composed of multiple genetically distinct tumor cell clones, in mouse models of breast, pancreas, and small cell carcinoma (5-7), and in human metastatic prostate cancer patients (8). Taken together, these observations provide accumulating evidence that tumor cell clusters contribute to metastasis. However, they leave unresolved two important questions: how do tumor cell clusters emerge from the primary tumor, and which molecular features identify cell clusters that metastasize?An important clinical observation is that cancer cells invade the surrounding stroma as cohesive clusters in the majority of ...

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Section: K14 Expression Is Required For Distant Metastasis and Regulasupporting

confidence: 90%

Polyclonal breast cancer metastases arise from collective dissemination of keratin 14-expressing tumor cell clusters

Cheung

Padmanaban

Silvestri

et al. 2016

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

639

701

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“…Finally, an increasing number of publications support a role for aberrant MALT1 signaling in the development of non-lymphoid cancers, such as glioblastoma (127), breast cancer (18, 128, 129), melanoma (130), lung cancer (18), and various other carcinomas (1, 131, 132). In these cancers, MALT1 seems to be activated by constitutive signaling from GPCRs or the EGFR via CARMA3 and/or by overexpression of MALT1 through various mechanisms.…”

Section: Malt1 Deregulation Is Associated With Allergy Inflammatory mentioning

confidence: 99%

“…For breast cancer, two different subtypes, which are HER2 or angiotensin II receptor (AGTR1) positive, have been described to be addicted to CBM signaling via CARMA3 (18, 128, 129). Interestingly, these two subsets show abnormal expressions of AGTR1 or HER2 in a mutually exclusive manner (128).…”

Section: Malt1 Deregulation Is Associated With Allergy Inflammatory mentioning

confidence: 99%

“…Interestingly, these two subsets show abnormal expressions of AGTR1 or HER2 in a mutually exclusive manner (128). In AGTR1 and HER2 positive breast cancer cell lines, NF-κB is activated upon stimulation with Angiotensin II or the HER2 ligand heregulin, respectively, in a CARMA3-dependent manner (18, 128, 129). Silencing of CBM components abrogates tumor cell growth, migration, and invasion (18, 128, 129) and affects the tumor microenvironment, since endothelial cell chemotaxis and angiogenesis are abolished (128).…”

Section: Malt1 Deregulation Is Associated With Allergy Inflammatory mentioning

confidence: 99%

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Holding All the CARDs: How MALT1 Controls CARMA/CARD-Dependent Signaling

Juilland

Thome

2018

Front. Immunol.

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The scaffold proteins CARMA1-3 (encoded by the genes CARD11, -14 and -10) and CARD9 play major roles in signaling downstream of receptors with immunoreceptor tyrosine activation motifs (ITAMs), G-protein coupled receptors (GPCR) and receptor tyrosine kinases (RTK). These receptors trigger the formation of oligomeric CARMA/CARD-BCL10-MALT1 (CBM) complexes via kinases of the PKC family. The CBM in turn regulates gene expression by the activation of NF-κB and AP-1 transcription factors and controls transcript stability. The paracaspase MALT1 is the only CBM component having an enzymatic (proteolytic) activity and has therefore recently gained attention as a potential drug target. Here we review recent advances in the understanding of the molecular function of the protease MALT1 and summarize how MALT1 scaffold and protease function contribute to the transmission of CBM signals. Finally, we will highlight how dysregulation of MALT1 function can cause pathologies such as immunodeficiency, autoimmunity, psoriasis, and cancer.

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“…CARD11 (CARMA1), expressed in lymphoid cells, is activated upon B-and T-cell receptor engagement, and gain-of-function (GoF) mutations in the genes encoding CARD11, Bcl10, and Malt1 have been associated with a number of lymphoid malignancies (Gaide, et al, 2002;Juilland and Thome, 2016;Pomerantz et al, 2002;Wang et al, 2002). Similarly, CARD10 (CARMA3), expressed in epithelial tissue and activated by G protein-coupled receptor stimulation, has been linked to the progression of various carcinomas Pan et al, 2016;Xia et al, 2016;Xie et al, 2014).…”

Section: Introductionmentioning

confidence: 99%

993 CARD14 gain-of-function mutation alone is sufficient to drive IL-23/IL-17-mediated psoriasiform skin inflammation in vivo

Mellett

Meier

Mohanan

et al. 2018

Journal of Investigative Dermatology

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Rare autosomal dominant mutations in the gene encoding the keratinocyte signaling molecule CARD14, have been associated with an increased susceptibility to psoriasis, but the physiological impact of CARD14 gain-offunction mutations remains to be fully determined in vivo. Here, we report that heterozygous mice harboring a CARD14 gain-of-function mutation (Card14DE138) spontaneously develop a chronic psoriatic phenotype with characteristic scaling skin lesions, epidermal thickening, keratinocyte hyperproliferation, hyperkeratosis, and immune cell infiltration. Affected skin of these mice is characterized by elevated expression of anti-microbial peptides, chemokines, and cytokines (including T helper type 17 cell-signature cytokines) and an immune infiltrate rich in neutrophils, myeloid cells, and T cells, reminiscent of human psoriatic skin. Disease pathogenesis was driven by the IL-23/IL-17 axis, and neutralization of IL-23p19, the key cytokine in maintaining T helper type 17 cell polarization, significantly reduced skin lesions and the expression of antimicrobial peptides and proinflammatory cytokines. Therefore, hyperactivation of CARD14 alone is sufficient to orchestrate the complex immunopathogenesis that drives T helper type 17-mediated psoriasis skin disease in vivo.

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The CBM Complex Underwrites NF-κB Activation to Promote HER2-Associated Tumor Malignancy

Cited by 34 publications

References 25 publications

Polyclonal breast cancer metastases arise from collective dissemination of keratin 14-expressing tumor cell clusters

Polyclonal breast cancer metastases arise from collective dissemination of keratin 14-expressing tumor cell clusters

Holding All the CARDs: How MALT1 Controls CARMA/CARD-Dependent Signaling

993 CARD14 gain-of-function mutation alone is sufficient to drive IL-23/IL-17-mediated psoriasiform skin inflammation in vivo

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