Publications of Benjamin KOOPMANSCH
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See detailMethylglyoxal Scavengers Resensitize KRAS-Mutated Colorectal Tumors to Cetuximab
Bellier, Justine ULiege; Nokin, Marie-Julie ULiege; Caprasse, Maurine ULiege et al

in Cell Reports (2020), 30(5), 1400-14166

The use of cetuximab anti-epidermal growth factor receptor (anti-EGFR) antibodies has opened the era of targeted and personalized therapy in colorectal cancer (CRC). Poor response rates have been ... [more ▼]

The use of cetuximab anti-epidermal growth factor receptor (anti-EGFR) antibodies has opened the era of targeted and personalized therapy in colorectal cancer (CRC). Poor response rates have been unequivocally shown in mutant KRAS and are even observed in a majority of wild-type KRAS tumors. Therefore, patient selection based on mutational profiling remains problematic. We previously identified methylglyoxal (MGO), a by-product of glycolysis, as a metabolite promoting tumor growth and metastasis. Mutant KRAS cells under MGO stress show AKT-dependent survival when compared with wild-type KRAS isogenic CRC cells. MGO induces AKT activation through phosphatidylinositol 3-kinase (PI3K)/mammalian target of rapamycin 2 (mTORC2) and Hsp27 regulation. Importantly, the sole induction of MGO stress in sensitive wild-type KRAS cells renders them resistant to cetuximab. MGO scavengers inhibit AKT and resensitize KRAS-mutated CRC cells to cetuximab in vivo. This study establishes a link between MGO and AKT activation and pinpoints this oncometabolite as a potential target to tackle EGFR-targeted therapy resistance in CRC. [less ▲]

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See detailInnovative methodology for the identification of soluble biomarkers in fresh tissues.
Costanza, Brunella ULiege; Turtoi, Andrei ULiege; Bellahcene, Akeila ULiege et al

in Oncotarget (2018), 9(12), 10665-10680

The identification of diagnostic and prognostic biomarkers from early lesions, measurable in liquid biopsies remains a major challenge, particularly in oncology. Fresh human material of high quality is ... [more ▼]

The identification of diagnostic and prognostic biomarkers from early lesions, measurable in liquid biopsies remains a major challenge, particularly in oncology. Fresh human material of high quality is required for biomarker discovery but is often not available when it is totally required for clinical pathology investigation. Hence, all OMICs studies are done on residual and less clinically relevant biological samples. Here after, we present an innovative, simple, and non-destructive, procedure named EXPEL that uses rapid, pressure-assisted, interstitial fluid extrusion, preserving the specimen for full routine clinical pathology investigation. In the meantime, the technique allows a comprehensive OMICs analysis (proteins, metabolites, miRNAs and DNA). As proof of concept, we have applied EXPEL on freshly collected human colorectal cancer and liver metastases tissues. We demonstrate that the procedure efficiently allows the extraction, within a few minutes, of a wide variety of biomolecules holding diagnostic and prognostic potential while keeping both tissue morphology and antigenicity unaltered. Our method enables, for the first time, both clinicians and scientists to explore identical clinical material regardless of its origin and size, which has a major positive impact on translation to the clinic. [less ▲]

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See detailTwo cases of atypical CALR mutations in MPN patients
SAGOT, Clémence ULiege; CHARLIER, Hélène ULiege; KOOPMANSCH, Benjamin ULiege et al

Poster (2016, January 29)

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See detailPHARMACOGENOMIQUE ET MEDECINE PERSONNALISEE : VERS UN SCREENING SYSTEMATIQUE DE LA POPULATION ?
DIDEBERG, Vinciane ULiege; SEGERS, Karin ULiege; KOOPMANSCH, Benjamin ULiege et al

in Revue Médicale de Liège (2015), 70(5-6), 251-6

Recent advances in medical genomics open new perspectives for personalized medicine through the identification of genetic variants that influence drug response and/or the risk of side effects. Today, the ... [more ▼]

Recent advances in medical genomics open new perspectives for personalized medicine through the identification of genetic variants that influence drug response and/or the risk of side effects. Today, the clinical applications of pharmacogenetics remain scarce as a consequence of the cost and turn-around-time of genetic tests. However, a few tests are recommended, for instance before the prescription of some anti-cancer agents or the anti-retroviral agent abacavir. In the future, we will probably move either towards rapid targeted tests or towards a large screening, before any diagnosis, of all the genetic factors influencing the therapeutic response. In that case, physicians will have to consult the patient genomic data before drug prescription in order to personalize the choice of the therapeutic agent or its dosage. However, such a genomic approach brings economical and ethical questions and will require further progress in our capacity to interpret and store the personal genomic data without compromising their confidentiality. [less ▲]

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See detailCancer du sein : de la thérapie ciblée à la médecine personnalisée
JERUSALEM, Guy ULiege; COLLIGNON, Joëlle ULiege; Josse, Claire ULiege et al

in Revue Médicale de Liège (2015), 70(5-6), 269-276

Dans cet article, les auteurs passent en revue les grands principes de prise en charge du traitement systémique du cancer du sein et posent la question suivante : jusqu'où réellement aujourd'hui ce ... [more ▼]

Dans cet article, les auteurs passent en revue les grands principes de prise en charge du traitement systémique du cancer du sein et posent la question suivante : jusqu'où réellement aujourd'hui ce traitement est-il individualisé ? Les nouvelles technologies permettent une analyse détaillée des anomalies génomiques au niveau des cellules cancéreuses. Malheureusement, nous n'avons pas encore compris comment utiliser au mieux ces données au bénéfice du patient. La majorité des modifications du génome sont des évènements relativement rares compliquant le développement de nouveaux médicaments dans le cadre d'une médecine de précision. De plus, les tumeurs présentent une grande hétérogénéité temporelle et spatiale dont il faudra tenir compte lors de ce développement. Une collaboration internationale intensive est en cours pour tenter de confirmer que la médecine de précision permet d'optimiser les résultats du traitement systémique dans le cancer du sein. [less ▲]

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See detailInterplay between KLF4 and ZEB2/SIP1 in the regulation of E-cadherin expression.
Koopmansch, Benjamin ULiege; Berx, Geert; Foidart, Jean-Michel ULiege et al

in Biochemical and Biophysical Research Communications (2013), 431(4), 652

E-cadherin expression is repressed by ZEB2/SIP1 while it is induced by KLF4. Independent data from the literature indicate that these two transcription factors could bind close to each other in the ... [more ▼]

E-cadherin expression is repressed by ZEB2/SIP1 while it is induced by KLF4. Independent data from the literature indicate that these two transcription factors could bind close to each other in the proximal region of the E-cadherin gene promoter. We have here explored a potential competition between ZEB2 and KLF4 for the binding to the E-cadherin promoter. We show an inverse correlation between ZEB2 expression levels and KLF4 recruitment on the E-cadherin promoter in three breast cancer cell lines and in A431/HA.ZEB2 cells in which ZEB2 expression is induced by doxycycline (DOX). We identified a region of the E-cadherin promoter bound by KLF4 which is necessary for the activation of the E-cadherin promoter activity after KLF4 overexpression. This region is localized between positions -28 and -10 and thus overlaps with one of the ZEB2 binding sites. Deleting the bipartite ZEB2 binding site results in increased KLF4 induced E-cadherin promoter activity. Taken together, our results suggest that E-cadherin expression in cancer cells is controlled by a balance between ZEB2 and KLF4 expression levels. [less ▲]

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See detailInteractions of KLF4 and SIP1 in the regulation of E-Cadherin expression
Koopmansch, Benjamin ULiege

Poster (2012, April 18)

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See detailKu proteins interact with activator protein-2 transcription factors and contribute to ERBB2 overexpression in breast cancer cell lines.
Nolens, Grégory ULiege; Pignon, Jean-Christophe ULiege; Koopmansch, Benjamin ULiege et al

in Breast Cancer Research (2009), 11(6),

INTRODUCTION: Activator protein-2 (AP-2) alpha and AP-2 gamma transcription factors contribute to ERBB2 gene overexpression in breast cancer. In order to understand the mechanism by which the ERBB2 gene ... [more ▼]

INTRODUCTION: Activator protein-2 (AP-2) alpha and AP-2 gamma transcription factors contribute to ERBB2 gene overexpression in breast cancer. In order to understand the mechanism by which the ERBB2 gene is overexpressed we searched for novel AP-2 interacting factors that contribute to its activity. METHODS: Ku proteins were identified as AP-2 alpha interacting proteins by glutathione serine transferase (GST)-pull down followed by mass spectrometry. Transfection of the cells with siRNA, expression vectors and reporter vectors as well as chromatin immunoprecipitation (ChIP) assay were used to ascertain the implication of Ku proteins on ERBB2 expression. RESULTS: Nuclear proteins from BT-474 cells overexpressing AP-2 alpha and AP-2 gamma were incubated with GST-AP2 or GST coated beads. Among the proteins retained specifically on GST-AP2 coated beads Ku70 and Ku80 proteins were identified by mass spectrometry. The contribution of Ku proteins to ERBB2 gene expression in BT-474 and SKBR3 cell lines was investigated by downregulating Ku proteins through the use of specific siRNAs. Depletion of Ku proteins led to downregulation of ERBB2 mRNA and protein levels. Furthermore, reduction of Ku80 in HCT116 cell line decreased the AP-2 alpha activity on a reporter vector containing an AP-2 binding site linked to the ERBB2 core promoter, and transfection of Ku80 increased the activity of AP-2 alpha on this promoter. Ku siRNAs also inhibited the activity of this reporter vector in BT-474 and SKBR3 cell lines and the activity of the ERBB2 promoter was further reduced by combining Ku siRNAs with AP-2 alpha and AP-2 gamma siRNAs. ChIP experiments with chromatin extracted from wild type or AP-2 alpha and AP-2 gamma or Ku70 siRNA transfected BT-474 cells demonstrated Ku70 recruitment to the ERBB2 proximal promoter in association with AP-2 alpha and AP-2 gamma. Moreover, Ku70 siRNA like AP-2 siRNAs, greatly reduced PolII recruitment to the ERBB2 proximal promoter. CONCLUSIONS: Ku proteins in interaction with AP-2 (alpha and gamma) contribute to increased ERBB2 mRNA and protein levels in breast cancer cells. [less ▲]

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See detailAndrogen receptor controls EGFR and ERBB2 gene expression at different levels in prostate cancer cell lines.
Pignon, Jean-Christophe ULiege; Koopmansch, Benjamin ULiege; Nolens, Grégory ULiege et al

in Cancer Research (2009), 69(7), 2941-2949

EGFR or ERBB2 contributes to prostate cancer (PCa) progression by activating the androgen receptor (AR) in hormone-poor conditions. Here, we investigated the mechanisms by which androgens regulate EGFR ... [more ▼]

EGFR or ERBB2 contributes to prostate cancer (PCa) progression by activating the androgen receptor (AR) in hormone-poor conditions. Here, we investigated the mechanisms by which androgens regulate EGFR and ERBB2 expression in PCa cells. In steroid-depleted medium (SDM), EGFR protein was less abundant in androgen-sensitive LNCaP than in androgen ablation-resistant 22Rv1 cells, whereas transcript levels were similar. Dihydrotestosterone (DHT) treatment increased both EGFR mRNA and protein levels and stimulated RNA polymerase II recruitment to the EGFR gene promoter, whereas it decreased ERBB2 transcript and protein levels in LNCaP cells. DHT altered neither EGFR or ERBB2 levels nor the abundance of prostate-specific antigen (PSA), TMEPA1, or TMPRSS2 mRNAs in 22Rv1 cells, which express the full-length and a shorter AR isoform deleted from the COOH-terminal domain (ARDeltaCTD). The contribution of both AR isoforms to the expression of these genes was assessed by small interfering RNAs targeting only the full-length or both AR isoforms. Silencing of both isoforms strongly reduced PSA, TMEPA1, and TMPRSS2 transcript levels. Inhibition of both AR isoforms did not affect EGFR and ERBB2 transcript levels but decreased EGFR and increased ERBB2 protein levels. Proliferation of 22Rv1 cells in SDM was inhibited in the absence of AR and ARDeltaCTD. A further decrease was obtained with PKI166, an EGFR/ERBB2 kinase inhibitor. Overall, we showed that ARDeltaCTD is responsible for constitutive EGFR expression and ERBB2 repression in 22Rv1 cells and that ARDeltaCTD and tyrosine kinase receptors are necessary for sustained 22Rv1 cell growth. [less ▲]

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