Cell line and patient-derived xenograft models reveal elevated CDCP1 as a target in high-grade serous ovarian cancer

Harrington, Brittney S.; He, Yaowu; Davies, Claire; Wallace, Sarah; Adams, Mark N.; Beaven, Elizabeth A.; Roche, Deborah; Kennedy, Catherine J.; Chetty, Naven; Crandon, Alexander J.; Flatley, Christopher; Oliveira, Niara; Shannon, Catherine; deFazio, Anna; Tinker, Anna V.; Gilks, C. Blake; Gabrielli, Brian; Brennan, Donal J.; Coward, Jermaine; Armes, Jane E.; Perrin, Lewis; Hooper, John D.

doi:10.1038/bjc.2015.471

Cited by 57 publications

(63 citation statements)

References 58 publications

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“…In this study, we found HAX1, RAB1B, PBX3, CDCP1 and PLAGL2 to be direct miR-654 targets, and their silencing revealed that the miR-654-related phenotype in OC is primarily caused by direct targeting of CDCP1 and PLAGL2 oncogenes. Furthermore, CDCP1 and PLAGL2 levels were found to be increased in ovarian tumors compared to normal samples, which has also been seen in leukemia [35] for PLAGL2, and in other malignancies including OC [36,37] for CDCP1, supporting their role in OC progression and turning them into attractive therapeutic targets.…”

Section: Discussionmentioning

confidence: 67%

MicroRNA-654-5p suppresses ovarian cancer development impacting on MYC, WNT and AKT pathways

et al. 2019

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Ovarian cancer is the most lethal gynecological malignancy due to the silent nature on its early onset and the rapid acquisition of drug resistance. Histologically heterogeneous, it includes several subtypes with different mutational landscapes, hampering the development of effective targeted therapies. Non-coding RNAs are emerging as potential new therapeutic targets in cancer. To search for a microRNA signature related to ovarian carcinomas and study its potential as effective targeted therapy, we examined the expression of 768 miRNA in a large collection of tumor samples and found miR-654-5p to be infraexpressed in ovarian serous carcinomas, the most common and aggressive type. Restoration of miR-654-5p levels reduced tumor cell viability in vitro and in vivo and impaired sphere formation capacity and viability of ovarian cancer patient-derived ascitic cells ex vivo. CDCP1 and PLAGL2 oncogenes were found to be the most relevant direct miR-654-5p targets and both genes convey in a molecular signature associated with key cancer pathways relevant to ovarian tumorigenesis, such as MYC, WNT and AKT pathways. Together, we unveiled the tumor suppressor function of miR-654-5p, suggesting that its restoration or co-targeting of CDCP1 and PLAGL2 may be an effective therapeutic approach for ovarian cancer.

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Section: Discussionmentioning

confidence: 67%

MicroRNA-654-5p suppresses ovarian cancer development impacting on MYC, WNT and AKT pathways

et al. 2019

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“…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).…”

mentioning

confidence: 87%

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.

135

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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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“…It is expressed by epithelial cells of most organs [1][2][3] and its over-expression is associated with poor survival of patients with renal cell carcinoma [4,5], colorectal [6], lung [7,8], pancreatic [9], and breast cancer [10], and clear cell ovarian carcinoma [11]. CDCP1 modulates adhesion and promotes motility of cells in vitro [2,9,[12][13][14], mediates metastasis in in vivo models [11,12,[14][15][16][17], and also contributes to in vitro and in vivo resistance of cancer to chemotherapy [11,17] and targeted agents [10,18,19].…”

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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Cell line and patient-derived xenograft models reveal elevated CDCP1 as a target in high-grade serous ovarian cancer

Cited by 57 publications

References 58 publications

MicroRNA-654-5p suppresses ovarian cancer development impacting on MYC, WNT and AKT pathways

MicroRNA-654-5p suppresses ovarian cancer development impacting on MYC, WNT and AKT pathways

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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