CDCP1 is a novel marker of the most aggressive human triple-negative breast cancers

Turdo, Federica; Bianchi, Francesca; Gasparini, Patrizia; Sandri, Marco; Sasso, Marianna; Cecco, Loris De; Forte, Luca; Casalini, Patrizia; Aiello, Piera; Sfondrini, Lucia; Agresti, Roberto; Carcangiu, Maria Luisa; Plantamura, Ilaria; Sozzi, Gabriella; Tagliabue, Elda; Campiglio, Manuela

doi:10.18632/oncotarget.11935

Cited by 29 publications

(33 citation statements)

References 49 publications

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“…Surgical excision of the primary tumor induces a wound healing response and inflammatory processes that alter the local environment and stimulate the growth kinetics of the remaining cancer foci, thereby potentially promoting metastasis [7][8][9]. Studies using global transcriptome analysis of a panel of triple-negative breast cancer (TNBC) cell lines have found that stimulation with surgical wound fluid (SWF) significantly increases the expression of genes related to wound response, cytokine activity, and locomotory characteristics [10]. Belletti et al [6] showed that IORT after BCS alters this effect, making the microenvironment less favorable for tumor cells.…”

Section: Introductionmentioning

confidence: 99%

Surgical Wound Fluids from Patients with Breast Cancer Reveal Similarities in the Biological Response Induced by Intraoperative Radiation Therapy and the Radiation-Induced Bystander Effect—Transcriptomic Approach

Kulcenty

Piotrowski

Ruciński

et al. 2020

IJMS

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In patients with breast cancer who undergo breast-conserving surgery (BCS), more than 90% of local recurrences occur in the same quadrant as the primary cancer. Surgical wound fluids (SWF) are believed to play a role in this process by inducing an inflammatory process in the scar tissue area. Despite strong clinical data demonstrating the benefits of intraoperative radiotherapy (IORT), the biological basis underlying this process remains poorly understood. Ionizing radiation (IR) directly affects cells by damaging DNA, thereby altering the cell phenotype. IR directly affects cancer cells and also influences unirradiated cells located nearby, a phenomenon known as the radiation-induced bystander effect (RIBE), significantly modifying the tumor microenvironment. We hypothesized that SWF obtained from patients after BCS and IORT would induce a radiobiological response (due to RIBE) in unirradiated cells, thereby modifying their phenotype. To confirm this hypothesis, breast cancer cells were incubated with SWF collected from patients after BCS: (1) without IORT (wound fluid (WF) group), (2) with IORT (radiotherapy wound fluid (RT-WF) group), and (3) WF with conditioned medium from irradiated cells (WF+RIBE group) and then subjected to microarray analysis. We performed gene set enrichment analysis to determine the biological processes present in these cells. This analysis showed that the RT-WF and WF+RIBE groups shared common biological processes, including the enhancement of processes involved in cell-cycle regulation, DNA repair, and oxidative phosphorylation. The WF group was characterized by overrepresentation of pathways involved in the INF-α and INF-γ response, inflammatory response, and the IL6 JAK/STAT3 signaling pathway. These findings show that MDA-MB-468 cells stimulated with surgical wound fluids obtained from patients who underwent BCS plus IORT and from cells stimulated with SWF plus RIBE share common biological processes. This confirms the role of the radiation-induced bystander effect in altering the biological properties of wound fluids.

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Section: Introductionmentioning

confidence: 99%

Surgical Wound Fluids from Patients with Breast Cancer Reveal Similarities in the Biological Response Induced by Intraoperative Radiation Therapy and the Radiation-Induced Bystander Effect—Transcriptomic Approach

Kulcenty

Piotrowski

Ruciński

et al. 2020

IJMS

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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).…”

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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.

148

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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“…Upregulation of CDCP1 has been implicated in tumor progression (Alajati et al, 2015;Awakura et al, 2008;Dong et al, 2012;Emerling et al, 2013;He et al, 2016;Hooper et al, 2003;Ikeda et al, 2009;Leroy et al, 2015;Miyazawa et al, 2010;Scherl-Mostageer et al, 2001;Turdo et al, 2016;Wright et al, 2016). In some cancer cells, upregulated CDCP1 promotes invasion, metastasis, and tumor growth (Alajati et al, 2015;Casar et al, 2012;Kollmorgen et al, 2013;Lin et al, 2014;Liu et al, 2011;Miyazawa et al, 2010;Turdo et al, 2016;Uekita et al, 2007), although the underlying mechanisms remain elusive. Our findings presented here suggest that CDCP1-mediated activation of the Src-STAT3 pathway contributes to malignant progression by inducing invasive and growth promoting phenotypes, even in cancer cells.…”

Section: Discussionmentioning

confidence: 99%

CUB domain-containing protein 1 controls HGF responses by integrating Src and Met–STAT3 signaling

Kajiwara

Aoki

Okuzaki

et al. 2019

Preprint

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Compensatory growth of organs after loss of mass and/or function is controlled by hepatocyte growth factor (HGF), but the underlying regulatory mechanisms remain elusive. Here, we show that the transmembrane glycoprotein CUB domain-containing protein 1 (CDCP1) controls compensatory renal growth by acting as a critical regulator of HGF signaling. In MDCK cysts, HGF induces the temporal upregulation of Src and its scaffold CDCP1, and the ablation of CDCP1 abrogates HGF-induced morphological change and cell growth. Mechanistically, upregulated CDCP1 recruits Src into lipid rafts to activate STAT3 associated with the HGF receptor Met, resulting in the upregulation of downstream factors required for HGF functions. In vivo, CDCP1 is upregulated in the renal tubules after unilateral nephrectomy, and the ablation of CDCP1 significantly suppresses compensatory renal growth by attenuating Met-STAT3 signaling. These findings demonstrate that CDCP1 controls HGFinduced compensatory renal growth by integrating Src and Met signaling, and provide new insights into the regulatory mechanisms underlying the multifaceted functions of HGF during regenerative growth of various organs.

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CDCP1 is a novel marker of the most aggressive human triple-negative breast cancers

Cited by 29 publications

References 49 publications

Surgical Wound Fluids from Patients with Breast Cancer Reveal Similarities in the Biological Response Induced by Intraoperative Radiation Therapy and the Radiation-Induced Bystander Effect—Transcriptomic Approach

Surgical Wound Fluids from Patients with Breast Cancer Reveal Similarities in the Biological Response Induced by Intraoperative Radiation Therapy and the Radiation-Induced Bystander Effect—Transcriptomic Approach

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

CUB domain-containing protein 1 controls HGF responses by integrating Src and Met–STAT3 signaling

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