CDCP1 overexpression drives prostate cancer progression and can be targeted in vivo

Alajati, Abdullah; ́Ambrosio, Mariantonietta D; Troiani, Martina; Mosoloe, Simone; Pellegrini, Laura; Chen, Jingjing; Rvandkar, Ajinkya; Bolis, Marco; Theurillat, Jean-Philippe; Guccini, Ilaria; Losa, Marco; Calcinotto, Arianna; Bernardis, Gaston De; Pasquini, Emiliano; D’Antuono, Rocco; Sharp, Adam; Figueiredo, Ines; Rodrigues, Daniel Nava; Welti, Jonathan; Gil, Veronica; Yuan, Wei; Vlajnic, Tatjana; Bubendorf, Lukas; Chiorino, Giovanna; Gnetti, Letizia; Torrano, Verónica; Carracedo, Arkaitz; Camplese, Laura; Hirabayashi, Susumu; Canato, Elena; Pasut, Gianfranco; Montopoli, Monica; Rüschoff, Jan H.; Wild, Peter J.; Moch, H.; Bono, Johann de; Alimonti, Andrea

doi:10.1172/jci131133

Cited by 31 publications

(42 citation statements)

References 57 publications

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“…Up-regulation of CDCP1 has been implicated in tumor progression (32,38,45,53,54,55,56,57,58,59,60,61,62). In some cancer cells, up-regulated CDCP1 promotes invasion, metastasis, and tumor growth (33,40,45,58,60,63,64,65), although the underlying mechanisms remain elusive.…”

Section: Discussionmentioning

confidence: 99%

CDCP1 promotes compensatory renal growth by integrating Src and Met signaling

et al. 2021

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Compensatory growth of organs after loss of their mass and/or function is controlled by hepatocyte growth factor (HGF), but the underlying regulatory mechanisms remain elusive. Here, we show that CUB domain-containing protein 1 (CDCP1) promotes HGF-induced compensatory renal growth. Using canine kidney cells as a model of renal tubules, we found that HGF-induced temporal up-regulation of Src activity and its scaffold protein, CDCP1, and that the ablation of CDCP1 robustly abrogated HGF-induced phenotypic changes, such as morphological changes and cell growth/proliferation. Mechanistic analyses revealed that up-regulated CDCP1 recruits Src into lipid rafts to activate STAT3 associated with the HGF receptor Met, and activated STAT3 induces the expression of matrix metalloproteinases and mitogenic factors. After unilateral nephrectomy in mice, the Met-STAT3 signaling is transiently up-regulated in the renal tubules of the remaining kidney, whereas CDCP1 ablation attenuates regenerative signaling and significantly suppresses compensatory growth. These findings demonstrate that CDCP1 plays a crucial role in controlling compensatory renal growth by focally and temporally integrating Src and Met signaling.

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Section: Discussionmentioning

confidence: 99%

CDCP1 promotes compensatory renal growth by integrating Src and Met signaling

et al. 2021

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“…A role for CDCP1 expression in prostate cancer has yet to be fully defined. Early functional data suggest CDCP1 may have oncogenic properties, especially in the context of PTEN loss, but the molecular details underpinning this observation require further elaboration (8). Our immunoblot data, combined with previous analyses in cell line models, do not appear to suggest that prostate cancer preferentially expresses the full length versus cleaved form of CDCP1.…”

Section: Discussionmentioning

confidence: 45%

“…We hypothesized that the single pass transmembrane protein CUB domain containing protein 1 (CDCP1) could be potential target for RLT that overcomes some of the abovementioned limitations. For example, after two reports between 2008-2015 showed CDCP1 overexpression in human prostate cancer cell lines and small cohorts of primary tumors, a recent study from Alimonti et al has more convincingly established that CDCP1 overexpression is a common feature of prostate cancer (8)(9)(10). Mining open access RNA-seq data from tumor biopsies, as well as determining protein expression in biopsies with immunohistochemistry showed that CDCP1 is overexpressed in ~50% of mCRPC biopsies and ~30% of primary tumors.…”

Section: Introductionmentioning

confidence: 99%

CUB domain containing protein 1 (CDPC1) is a target for radioligand therapy in castration resistant prostate cancer

Zhao

Trepka

Wang

et al. 2021

Preprint

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Purpose: Radioligand therapy (RLT) is relatively unexplored in metastatic castration resistant prostate cancer (mCRPC), with much of the focus having been on bone seeking radionuclides and PSMA-directed RLT. Herein, we evaluated if CUB domain containing protein 1 (CDCP1) can be exploited to treat mCRPC with RLT, particularly for subsets like small cell neuroendocrine prostate cancer (SCNC) that would not be expected to respond to current options. Experimental Design: CDCP1 mRNA levels were evaluated in the RNA-seq data from 119 recent mCRPC biopsies. Protein expression was assessed in twelve SCNC and adenocarcinoma patient derived xenografts. Saturation binding assays were performed with 4A06, a recombinant human antibody that targets the CDCP1 ectodomain. The feasibility of imaging and treating mCRPC in vivo was tested with 89Zr-4A06 and 177Lu-4A06. Results: CDCP1 mRNA expression was observed in over 90% of mCRPC biopsies, including SCNC and in adenocarcinoma with low FOLH1 (PSMA) levels. A modest anticorrelation was observed between CDCP1 and PTEN. Overall survival was not significantly different based on CDCP1 mRNA levels, regardless of PTEN status. Full length and/or cleaved CDCP1 was expressed in ten of twelve PDX samples . Bmax values of ~22,000 and ~6,200 fmol/mg were calculated for two human prostate cancer cell lines. Five prostate cancer models were readily detected in vivo with 89Zr-4A06. 177Lu-4A06 significantly suppressed the growth of DU145 tumors compared to control. Conclusions: The antitumor data and the overexpression of CDCP1 reported herein provide the first evidence promoting CDCP1 directed RLT as a treatment strategy for mCRPC.

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“…This is the case for the modification of Notch signaling, which was discussed earlier, and which induces notched wings or defects in the development of the wing vein. Another example related to prostate cancer is a recent study where the authors showed in mice that CDPC1 (CUB domain-containing protein 1), a transmembrane protein that is a substrate for SRC family kinase, can drive prostate cancer progression via activation of the MAPK signaling pathway [ 117 ]. In Drosophila , increased EGFR/Ras/MAPK signaling in wing imaginal discs induces the formation of bristles located on the dorsal part of the thorax, a tumor-like phenotype.…”

Section: Drosophila a Model For Human Pathologies And Prostate Cancermentioning

confidence: 99%

Drosophila Accessory Gland: A Complementary In Vivo Model to Bring New Insight to Prostate Cancer

Rambur

Vialat

Beaudoin

et al. 2021

Cells

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Prostate cancer is the most common cancer in aging men. Despite recent progress, there are still few effective treatments to cure its aggressive and metastatic stages. A better understanding of the molecular mechanisms driving disease initiation and progression appears essential to support the development of more efficient therapies and improve patient care. To do so, multiple research models, such as cell culture and mouse models, have been developed over the years and have improved our comprehension of the biology of the disease. Recently, a new model has been added with the use of the Drosophila accessory gland. With a high level of conservation of major signaling pathways implicated in human disease, this functional equivalent of the prostate represents a powerful, inexpensive, and rapid in vivo model to study epithelial carcinogenesis. The purpose of this review is to quickly overview the existing prostate cancer models, including their strengths and limitations. In particular, we discuss how the Drosophila accessory gland can be integrated as a convenient complementary model by bringing new understanding in the mechanisms driving prostate epithelial tumorigenesis, from initiation to metastatic formation.

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CDCP1 overexpression drives prostate cancer progression and can be targeted in vivo

Cited by 31 publications

References 57 publications

CDCP1 promotes compensatory renal growth by integrating Src and Met signaling

CDCP1 promotes compensatory renal growth by integrating Src and Met signaling

CUB domain containing protein 1 (CDPC1) is a target for radioligand therapy in castration resistant prostate cancer

Drosophila Accessory Gland: A Complementary In Vivo Model to Bring New Insight to Prostate Cancer

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