CDCP1 cleavage is necessary for homodimerization-induced migration of triple-negative breast cancer

Wright, Heather J.; Arulmoli, Janahan; Motazedi, M; Nelson, Luke; Heinemann, Frank; Flanagan, Lisa A.; Razorenova, Olga V.

doi:10.1038/onc.2016.7

Cited by 39 publications

(61 citation statements)

References 53 publications

(97 reference statements)

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“…Signal transduction events in synovial fibroblasts generated by cell-cell adhesion events that involve CD6 and CD318 are likely to be distinct from pathways activated by antiadhesive effects of the intracellular domain of CD318 that have been described in cancer cells (42). In cancer cells, CD318 is phosphorylated and can enhance downstream phosphorylation events, in part linked to signaling through the epidermal growth factor receptor (43,44). Moreover, cleavage of full-length 135-kDa CD318 by serine proteases creates a smaller membrane-retained 70-kDa form that either associates with membrane integrins or homodimerizes, and generates downstream signaling events that enhance cancer cell invasiveness and metastasis (16,44).…”

Section: Discussionmentioning

confidence: 99%

“…In cancer cells, CD318 is phosphorylated and can enhance downstream phosphorylation events, in part linked to signaling through the epidermal growth factor receptor (43,44). Moreover, cleavage of full-length 135-kDa CD318 by serine proteases creates a smaller membrane-retained 70-kDa form that either associates with membrane integrins or homodimerizes, and generates downstream signaling events that enhance cancer cell invasiveness and metastasis (16,44). Cleavage of CD318 can be blocked by dexamethasone (45).…”

Section: Discussionmentioning

confidence: 99%

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CD318 is a ligand for CD6

Enyindah-Asonye

Ruth

et al. 2017

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

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It has been proposed that CD6, an important regulator of T cells, functions by interacting with its currently identified ligand, CD166, but studies performed during the treatment of autoimmune conditions suggest that the CD6-CD166 interaction might not account for important functions of CD6 in autoimmune diseases. The antigen recognized by mAb 3A11 has been proposed as a new CD6 ligand distinct from CD166, yet the identity of it is hitherto unknown. We have identified this CD6 ligand as CD318, a cell surface protein previously found to be present on various epithelial cells and many tumor cells. We found that, like CD6 knockout (KO) mice, CD318 KO mice are also protected in experimental autoimmune encephalomyelitis. In humans, we found that CD318 is highly expressed in synovial tissues and participates in CD6-dependent adhesion of T cells to synovial fibroblasts. In addition, soluble CD318 is chemoattractive to T cells and levels of soluble CD318 are selectively and significantly elevated in the synovial fluid from patients with rheumatoid arthritis and juvenile inflammatory arthritis. These results establish CD318 as a ligand of CD6 and a potential target for the diagnosis and treatment of autoimmune diseases such as multiple sclerosis and inflammatory arthritis.C D6 is a marker of T cells and an important T-cell regulator (1). Recent genome-wide association studies also identified CD6 as a risk gene for multiple sclerosis (MS) (2-5), an autoimmune disease in which T cells play a vital role in the pathogenesis. CD6 is composed of three extracellular domains (domains 1, 2, and 3), and it functions by interacting with its ligand(s) (6). The domain 3 of CD6 has been shown to be the site that the identified CD6 ligand, CD166, also known as ALCAM (activated leukocyte cell adhesion molecule), binds to (7). However, anti-CD166 antibodies only partially blocked the binding of thymic epithelial cells to CD6-overexpressing COS cells, and mAbs blocking CD6-CD166 interactions do not abolish CD6 function (8, 9). Itolizumab, an anti-CD6 mAb developed in Cuba and approved in India for treating psoriasis, reduces pathogenic T-cell responses in patients with psoriasis, but this mAb binds to domain 1 of CD6 instead of domain 3, and it does not interfere with the CD6-CD166 interaction. Interestingly, UMCD6, a mouse antihuman CD6 mAb that we found highly effective in treating encephalomyelitis (EAE) in CD6 humanized mice, also fails to block the CD6-CD166 interaction. All these studies suggest the existence of an additional CD6 ligand, other than CD166, that binds to domain 1 of CD6, and could be critical for CD6 function in autoimmune conditions. Further studies using a CD6 fusion protein as a bait to pull down CD6-binding proteins from synovial fibroblast surface proteins showed the binding of three polypeptides (10). One of these polypeptides was identified as CD166, and the identities of the other two were unknown (11). A mAb termed 3A11 was developed, and the antigen recognized by this mAb was identified as the new ligand of ...

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Section: Discussionmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

CD318 is a ligand for CD6

Enyindah-Asonye

Ruth

et al. 2017

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

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“…CDCP1 | lipid droplets | FAO | metastasis | TNBC T he transmembrane glycoprotein, CUB-domain containing protein 1 (CDCP1), is a driver of migration and invasion in multiple forms of carcinoma, including renal (1, 2), ovarian (3,4), prostate (5), pancreatic (6,7), colon (8)(9)(10)(11)(12), and triple-negative breast (TNBC) (13,14) carcinomas, among others. Furthermore, CDCP1's role in tumor metastasis was confirmed in vivo in lung (15,16), ovarian (17), prostate (5), and colon (9) cancers.…”

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confidence: 99%

CDCP1 drives triple-negative breast cancer metastasis through reduction of lipid-droplet abundance and stimulation of fatty acid oxidation

Wright

Hou

et al. 2017

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

144

102

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Triple-negative breast cancer (TNBC) is notoriously aggressive with high metastatic potential, which has recently been linked to high rates of fatty acid oxidation (FAO). Here we report the mechanism of lipid metabolism dysregulation in TNBC through the prometastatic protein, CUB-domain containing protein 1 (CDCP1). We show that a "low-lipid" phenotype is characteristic of breast cancer cells compared with normal breast epithelial cells and negatively correlates with invasiveness in 3D culture. Using coherent anti-Stokes Raman scattering and two-photon excited fluorescence microscopy, we show that CDCP1 depletes lipids from cytoplasmic lipid droplets (LDs) through reduced acyl-CoA production and increased lipid utilization in the mitochondria through FAO, fueling oxidative phosphorylation. These findings are supported by CDCP1's interaction with and inhibition of acyl CoA-synthetase ligase (ACSL) activity. Importantly, CDCP1 knockdown increases LD abundance and reduces TNBC 2D migration in vitro, which can be partially rescued by the ACSL inhibitor, Triacsin C. Furthermore, CDCP1 knockdown reduced 3D invasion, which can be rescued by ACSL3 co-knockdown. In vivo, inhibiting CDCP1 activity with an engineered blocking fragment (extracellular portion of cleaved CDCP1) lead to increased LD abundance in primary tumors, decreased metastasis, and increased ACSL activity in two animal models of TNBC. Finally, TNBC lung metastases have lower LD abundance than their corresponding primary tumors, indicating that LD abundance in primary tumor might serve as a prognostic marker for metastatic potential. Our studies have important implications for the development of TNBC therapeutics to specifically block CDCP1-driven FAO and oxidative phosphorylation, which contribute to TNBC migration and metastasis.he transmembrane glycoprotein, CUB-domain containing protein 1 (CDCP1), is a driver of migration and invasion in multiple forms of carcinoma, including renal (1, 2), ovarian (3, 4), prostate (5), pancreatic (6, 7), colon (8-12), and triple-negative breast (TNBC) (13, 14) carcinomas, among others. Furthermore, CDCP1's role in tumor metastasis was confirmed in vivo in lung (15, 16), ovarian (17), prostate (5), and colon (9) cancers. Although CDCP1's role in TNBC metastasis has not been established to date, high CDCP1 expression has been validated as a prognostic marker of poor survival in TNBC when combined with positive node status (18).Our understanding of CDCP1's upstream regulators, its mechanism of activation, and downstream signaling continues to expand (recently reviewed in ref. 19). Studies by others (5) and our group (14) have demonstrated that CDCP1 cleavage is necessary for its activation, and recently, we have further shown that cleavage stimulates CDCP1 homodimerization (14). Homodimeric CDCP1 stimulates phosphorylation of protein kinase C δ (PKCδ) by Src kinase, leading to migration and invasion of TNBC cells in vitro (14). Adding to our knowledge of CDCP1's downstream signaling, we report that CDCP1 regulates lipid m...

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“…We have shown for the first time that the level of ShE-CDCP1 is significantly higher in serum of colorectal cancer patients compared with the serum of individuals with benign conditions, and that elevated levels may be indicative of cancer that has spread beyond the colonic mucosa. The use of anti-ShE-CDCP1 ELISAs may potentially be extended to other malignancies as CDCP1 is cleaved in a wide range of cancer cell lines [3,20], fragments of CDCP1 are present in the urine of prostate cancer patients at high risk of poor survival [21], and CDCP1 cleavage is necessary for triple negative breast cancer migration [23] and for vascular metastasis in animal models [15,16]. ) and (C) are mean ± SEM, aggregated from data from three assays that each included duplicate wells.…”

Section: Resultsmentioning

confidence: 99%

“…Also, there is indirect evidence from Western blot analyses of tissue lysates, that CDCP1 cleavage occurs in high grade serous ovarian carcinoma patients [22], and in many cell lines derived from epithelial tumors [3,20]. Although the functional importance of ShE-CDCP1 in cancer has not been directly addressed, recent studies indicate that CDCP1 cleavage is necessary for triple negative breast cancer migration [23] and for vascular metastasis in animal models [15,16].…”

Section: Introductionmentioning

confidence: 99%

Development of an enzyme-linked immunosorbent assay for detection of CDCP1 shed from the cell surface and present in colorectal cancer serum specimens

Chen

Harrington

Lau

et al. 2017

Journal of Pharmaceutical and Biomedical Analysis

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Development of an enzyme-linked immunosorbent assay for detection of CDCP1 shed from the cell surface and present in colorectal cancer serum specimens, Journal of Pharmaceutical and Biomedical Analysis http://dx.doi.org/10. 1016/j.jpba.2017.02.047 This is a PDF file of an unedited manuscript that has been accepted for publication. As a service to our customers we are providing this early version of the manuscript. The manuscript will undergo copyediting, typesetting, and review of the resulting proof before it is published in its final form. Please note that during the production process errors may be discovered which could affect the content, and all legal disclaimers that apply to the journal pertain. HIGHLIGHTS 1. First report of an enzyme-linked immunosorbent assay (ELISA) to detect fragments of the protein CDCP1 in human serum 2. The ELISA has a wide working range of 0.68 to 26.5 ng/ml, and a low limit of detection of 0.25 ng/ml 3. The ELISA has high intra-assay (repeatability) and high inter-assay (reproducibility) precision with all coefficients of variation ≤ 7% 4. The ELISA displays high accuracy detecting ShE-CDCP1 levels at ≥ 94.8% of actual concentration 5. Because CDCP1 has potential as a biomarker for colorectal, prostate, breast, kidney and ovarian cancer, the findings will be relevant to investigators interested in clinical applications as well as those interested in the functions of CDCP1.ABSTRACT CUB domain containing protein 1 (CDCP1) is a transmembrane protein involved in progression of several cancers. When located on the plasma membrane, full-length 135 kDa CDCP1 can undergo proteolysis mediated by serine proteases that cleave after two adjacent amino acids (arginine 368 and lysine 369). This releases from the cell surface two 65 kDa fragments, collectively termed ShE-CDCP1, that differ by one carboxyl terminal residue. To evaluate the function of CDCP1 and its potential utility as a cancer biomarker, in this study we developed an enzyme-linked immunosorbent assay (ELISA) to reliably and easily measure the concentration of ShE-CDCP1 in biological samples. Using a reference standard we demonstrate that the developed ELISA has a working range of 0.68 to 26.5 ng/ml, and the limit of detection is 0.25 ng/ml. It displays high intra-assay (repeatability) and high inter-assay (reproducibility) precision 2 with all coefficients of variation ≤ 7%. The ELISA also displays high accuracy detecting ShE-CDCP1 levels at ≥ 94.8% of actual concentration using quality control samples. We employed the ELISA to measure the concentration of ShE-CDCP1 in human serum samples with our results suggesting that levels are significantly higher in serum of colorectal cancer patients compared with serum from individuals with benign conditions (p < 0.05). Our data also suggest that colorectal cancer patients with stage II-IV disease have at least 50% higher serum levels of ShE-CDCP1 compared with stage I cases (p < 0.05). We conclude that the developed ELISA is a suitable method to quantify ShE-CDCP1 concentration in ...

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CDCP1 cleavage is necessary for homodimerization-induced migration of triple-negative breast cancer

Cited by 39 publications

References 53 publications

CD318 is a ligand for CD6

CD318 is a ligand for CD6

CDCP1 drives triple-negative breast cancer metastasis through reduction of lipid-droplet abundance and stimulation of fatty acid oxidation

Development of an enzyme-linked immunosorbent assay for detection of CDCP1 shed from the cell surface and present in colorectal cancer serum specimens

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