Publications of Pierre LOVINFOSSE
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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 detailObserver variability in the assessment of renal (18)F-FDG uptake in kidney transplant recipients.
JADOUL, Alexandre ULiege; LOVINFOSSE, Pierre ULiege; BOUQUEGNEAU, Antoine ULiege et al

in Scientific Reports (2020), 10(1), 4617

(18)F-FDG PET/CT imaging may help non-invasively disprove the diagnosis of acute kidney allograft rejection (AR) in kidney transplant recipients (KTR). The present study aims at evaluating the ... [more ▼]

(18)F-FDG PET/CT imaging may help non-invasively disprove the diagnosis of acute kidney allograft rejection (AR) in kidney transplant recipients (KTR). The present study aims at evaluating the repeatability and reproducibility of the quantification of renal (18)F-FDG uptake in KTR. We prospectively performed (18)F-FDG PET/CT in 95 adult KTR who underwent surveillance transplant biopsy between 3 to 6 months post transplantation. Images were obtained 180 minutes after injecting 3 MBq (18)F-FDG per kg body weight. Mean standard uptake value (SUVmean) of kidney cortex was independently measured by 2 experienced observers in 4 volumes of interest (VOI) distributed in the upper (n = 2) and lower (n = 2) poles. The first observer repeated SUV assessment in the uppermost VOI, blinded to the initial results. Intra-class correlation coefficients (ICC) and Bland-Altman plots were calculated. An ICC of 0.96 with 95%CI of [0.94; 0.97] was calculated for the intra-observer measurements. The ICC for inter-observer reproducibility for each VOI was 0.87 [0.81-0.91], 0.87 [0.81-0.91], 0.85 [0.78-0.89] and 0.83 [0.76-0.88] for the upper to the lower renal poles, respectively. The repeatability and reproducibility of the quantification of kidney allograft (18)F-FDG uptake are both consistent, which makes it transferrable to the clinical routine. [less ▲]

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See detailThe use of a visual 4-point scoring scale improves the yield of (18)F-FDG PET-CT imaging in the diagnosis of renal and hepatic cyst infection in patients with autosomal dominant polycystic kidney disease.
Neuville, Marie ULiege; LOVINFOSSE, Pierre ULiege; JADOUL, Alexandre ULiege et al

in European journal of nuclear medicine and molecular imaging (2020)

PURPOSE: [(18)F]FDG PET/CT (PET/CT) proved useful in the diagnosis of renal and hepatic cyst infection (CyI) in patients with autosomal dominant polycystic kidney disease (ADPKD). However, the definition ... [more ▼]

PURPOSE: [(18)F]FDG PET/CT (PET/CT) proved useful in the diagnosis of renal and hepatic cyst infection (CyI) in patients with autosomal dominant polycystic kidney disease (ADPKD). However, the definition of CyI by PET/CT is unclear. Here, we characterize the [(18)F]FDG uptake in CyI in order to infer a visual 4-point diagnostic scale. METHODS: All ADPKD patients hospitalized between 2007 and 2019 for suspected CyI and who underwent an [(18)F]FDG PET/CT scan were listed. CyI was defined by 5 concomitant criteria: fever ≥ 38 °C; abdominal pain; peak plasma CRP ≥ 70 mg/L; no other cause of inflammation; and favorable outcomes after antibiotics for ≥ 21 days. First, all PET/CT images were visually interpreted. Next, the [(18)F]FDG uptake around the suspected CyI was scored using a semiquantitative 4-point scale in comparison to blood and liver activities. RESULTS: Sixty [(18)F]FDG PET/CT scans were performed for suspected CyI in 38 ADPKD patients. Twenty-nine episodes met the gold-standard criteria for CyI. The visual assessment of PET/CT images reached a sensitivity of 73.1% and a specificity of 70.6%. Using the 4-point scale, an [(18)F]FDG score ≥ 3 (i.e., cyst uptake > liver) improved the specificity to 85.3%. CONCLUSION: [(18)F]FDG PET-CT is helpful in CyI diagnosis in ADPKD, and the use of a 4-point scoring of [(18)F]FDG uptake improves its diagnostic yield, with positive and negative predictive values of 78.3 and 78.4%, respectively. External validation is required. [less ▲]

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See detailInterobserver agreement of [(68)Ga]Ga-PSMA-11 PET/CT images interpretation in men with newly diagnosed prostate cancer.
Derwael, Celine ULiege; Lavergne, Olivier; LOVINFOSSE, Pierre ULiege et al

in EJNMMI Research (2020), 10(1), 15

BACKGROUND: Prostate-specific membrane antigen (PSMA) ligand PET/CT has already provided promising results in prostate cancer (PC) imaging, yet simple and reproductible reporting criteria are still ... [more ▼]

BACKGROUND: Prostate-specific membrane antigen (PSMA) ligand PET/CT has already provided promising results in prostate cancer (PC) imaging, yet simple and reproductible reporting criteria are still lacking. This study aimed at retrospectively evaluating interobserver agreement of [(68)Ga]Ga-PSMA-11 PET/CT images interpretation according to PC molecular imaging standardized evaluation (PROMISE) criteria and reproducibility of PSMA reporting and data systems (RADS). METHODS: Forty-three patients with newly diagnosed, histologically proven intermediate- or high-risk PC, eligible for radical prostatectomy and who underwent [(68)Ga]Ga-PSMA-11 PET/CT before surgery were retrospectively included. Three nuclear medicine physicians (2 experienced and 1 resident) independently reviewed PET/CT images. Interpretation of [(68)Ga]Ga-PSMA-11 PET/CT images was based on PROMISE criteria including miTNM staging and lesions miPSMA expression score visual estimation and PSMA-RADS version 1.0 for a given scan. Readers' agreement was measured using Krippendorff's coefficients RESULTS: Agreement between observers was almost perfect (coefficient >/= 0.81) for miM; it was substantial (coefficient >/= 0.61) for the following criteria: miT, miN, PSMA-RADS, and miPSMA expression score of primary PC lesion and metastases. However, agreement was moderate (coefficient = 0.41-0.60) for miPSMA score of positive lymph nodes and for detection of PC primary lesion. CONCLUSION: Visual interpretation of [(68)Ga]Ga-PSMA-11 PET/CT images in patients with newly diagnosed PC in a clinical setting leads to at least substantial agreement for PROMISE criteria and PSMA-RADS classification except for PC primary lesion detection and for miPSMA expression scoring of positive lymph nodes that might have been hampered by the interindividual variability of reference organs PSMA expression. [less ▲]

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See detailCOVID-19 dual energy CT scan for a double sided disease
DEPREZ, Louis ULiege; LOVINFOSSE, Pierre ULiege; Boulanger, Yves-Gauthier et al

in Thorax (2020)

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See detailStereotactic robotic body radiotherapy for patients with oligorecurrent pulmonary metastases.
Berkovic, Patrick; Gulyban, Akos; Defraene, Gilles et al

in BMC Cancer (2020), 20(1), 402

BACKGROUND: Our aim is to report treatment efficacy and toxicity of patients treated by robotic (Cyberknife®) stereotactic body radiotherapy (SBRT) for oligorecurrent lung metastases (ORLM). Additionally ... [more ▼]

BACKGROUND: Our aim is to report treatment efficacy and toxicity of patients treated by robotic (Cyberknife®) stereotactic body radiotherapy (SBRT) for oligorecurrent lung metastases (ORLM). Additionally we wanted to evaluate influence of tumor, patient and treatment related parameters on local control (LC), lung and distant progression free- (lung PFS/Di-PFS) and overall survival (OS). METHODS: Consecutive patients with up to 5 ORLM (confirmed by FDG PET/CT) were included in this study. Intended dose was 60Gy in 3 fractions (prescribed to the 80% isodose volume). Patients were followed at regular intervals and tumor control and toxicity was prospectively scored. Tumor, patient and treatment data were analysed using competing risk- and Cox regression. RESULTS: Between May 2010 and March 2016, 104 patients with 132 lesions were irradiated from primary lung carcinoma (47%), gastro-intestinal (34%) and mixed primary histologies (19%). The mean tumor volume was 7.9 cc. After a median follow up of 22 months, the 1, 2 and 3 year LC rate (per lesion) was 89.3, 80.0 and 77.8% respectively. The corresponding (per patient) 1, 2 and 3 years lung PFS were 66.3, 50.0, 42.6%, Di-PFS were 80.5, 64.4, 60.6% and OS rates were 92.2, 80.9 and 72.0% respectively. On univariable analysis, gastro-intestinal (GI) as primary tumor site showed a significant superior local control versus the other primary tumor sites. For OS, significant variables were primary histology and primary tumor site with a superior OS for patients with metastases of primary GI origin. LC was significantly affected by the tumor volume, physical and biologically effective dose coverage. Significant variables in multivariable analysis were BED prescription dose for LC and GI as primary site for OS. The vast majority of patients developed no toxicity or grade 1 acute and late toxicity. Acute and late grade 3 radiation pneumonitis (RP) was observed in 1 and 2 patients respectively. One patient with a centrally located lesion developed grade 4 RP and died due to possible RT-induced pulmonary hemorrhage. CONCLUSIONS: SBRT is a highly effective local therapy for oligorecurrent lung metastases and could achieve long term survival in patients with favourable prognostic features. [less ▲]

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See detailDevelopment and validation of an automated radiomic CT signature for detecting COVID-19
Vaidyantahan, Akshayaa; GUIOT, Julien ULiege; DEPREZ, Louis ULiege et al

in European Respiratory Journal (2020)

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See detailDevelopment of a Clinical Decision Support System for Severity Risk Prediction and Triage of COVID-19 Patients at Hospital Admission: an International Multicenter Study.
Wu, Guangyao; Yang, Pei; Xie, Yuanliang et al

in European Respiratory Journal (2020)

BACKGROUND: The outbreak of the coronavirus disease 2019 (COVID-19) has globally strained medical resources and caused significant mortality. OBJECTIVE: To develop and validate machine-learning model ... [more ▼]

BACKGROUND: The outbreak of the coronavirus disease 2019 (COVID-19) has globally strained medical resources and caused significant mortality. OBJECTIVE: To develop and validate machine-learning model based on clinical features for severity risk assessment and triage for COVID-19 patients at hospital admission. METHOD: 725 patients were used to train and validate the model including a retrospective cohort of 299 hospitalised COVID-19 patients at Wuhan, China, from December 23, 2019, to February 13, 2020, and five cohorts with 426 patients from eight centers in China, Italy, and Belgium, from February 20, 2020, to March 21, 2020. The main outcome was the onset of severe or critical illness during hospitalisation. Model performances were quantified using the area under the receiver operating characteristic curve (AUC) and metrics derived from the confusion-matrix. RESULTS: The median age was 50.0 years and 137 (45.8%) were men in the retrospective cohort. The median age was 62.0 years and 236 (55.4%) were men in five cohorts. The model was prospectively validated on five cohorts yielding AUCs ranging from 0.84 to 0.89, with accuracies ranging from 74.4% to 87.5%, sensitivities ranging from 75.0% to 96.9%, and specificities ranging from 57.5% to 88.0%, all of which performed better than the pneumonia severity index. The cut-off values of the low, medium, and high-risk probabilities were 0.21 and 0.80. The online-calculators can be found at www.covid19risk.ai. CONCLUSION: The machine-learning model, nomogram, and online-calculator might be useful to access the onset of severe and critical illness among COVID-19 patients and triage at hospital admission. [less ▲]

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See detailLa tomographie par emission de positons au 18F-FDG en pathologie renale non oncologique : indications actuelles et perspectives.
HANSSEN, Oriane ULiege; LOVINFOSSE, Pierre ULiege; WEEKERS, Laurent ULiege et al

in Nephrologie & therapeutique (2019)

Positron emission tomography combined with computed tomography (PET/CT) is a nuclear imaging technique which provides anatomical and functional information. PET/CT is increasingly used in non-oncological ... [more ▼]

Positron emission tomography combined with computed tomography (PET/CT) is a nuclear imaging technique which provides anatomical and functional information. PET/CT is increasingly used in non-oncological nephrology since conventional radiological approaches after injection of contrast agents are relatively contra-indicated in patients with chronic kidney disease (CKD). PET/CT after i.v. injection of (18)F-fluoro-deoxy-glucose (FDG) is not toxic and is characterized by a high sensitivity. The level of irradiation ( approximately 5mSv) is acceptable. CKD does not significantly influence tissue uptake of (18)F-FDG. The purpose of the present review aims at detailing the non-oncological indications of (18)F-FDG PET/CT in general nephrology and after kidney transplantation. Particularly, (18)F-FDG PET/CT appears useful in the diagnosis of cyst infection in patients with autosomal dominant polycystic kidney disease, as well as in the characterization of retroperitoneal fibrosis. In kidney transplant recipients, (18)F-FDG PET/CT may help in the diagnostic work-up of suspected acute rejection, thereby eventually avoiding unnecessary kidney transplant biopsy. Perspectives in (18)F-FDG PET/CT imaging are discussed, including innovative approaches of image analysis. [less ▲]

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See detailDiagnostic yield of (18) F-FDG PET/CT imaging and urinary CXCL9/creatinine levels in kidney allograft subclinical rejection.
Hanssen, Oriane ULiege; Weekers, Laurent ULiege; Lovinfosse, Pierre ULiege et al

in American journal of transplantation : official journal of the American Society of Transplantation and the American Society of Transplant Surgeons (2019)

Subclinical kidney allograft acute rejection (SCR) corresponds to "the unexpected histological evidence of acute rejection in a stable patient." SCR detection relies on surveillance biopsy. Noninvasive ... [more ▼]

Subclinical kidney allograft acute rejection (SCR) corresponds to "the unexpected histological evidence of acute rejection in a stable patient." SCR detection relies on surveillance biopsy. Noninvasive approaches may help avoid biopsy-associated complications. From November 2015 to January 2018, we prospectively performed positron emission tomography/computed tomography (PET/CT) after injection of F(18) -fluorodeoxyglucose ((18) F-FDG) in adult kidney transplant recipients with surveillance biopsy at ~3 months posttransplantation. The Banff-2017 classification was used. The ratio of the mean standard uptake value (mSUVR) between kidney cortex and psoas muscle was measured. Urinary levels of CXCL-9 were concomitantly quantified. Our 92-patient cohort was categorized upon histology: normal (n = 70), borderline (n = 16), and SCR (n = 6). No clinical or biological difference was observed between groups. The mSUVR reached 1.87 +/- 0.55, 1.94 +/- 0.35, and 2.41 +/- 0.54 in normal, borderline, and SCR groups, respectively. A significant difference in mSUVR was found among groups. Furthermore, mSUVR was significantly higher in the SCR vs normal group. The area under the receiver operating characteristic curve (AUC) was 0.79, with 83% sensitivity using an mSUVR threshold of 2.4. The AUC of urinary CXCL-9/creatinine ratios comparatively reached 0.79. The mSUVR positively correlated with ti and acute composite Banff scores. (18) F-FDG-PET/CT helps noninvasively exclude SCR, with a negative predictive value of 98%. External validations are required. [less ▲]

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See detailAdded value of para-aortic surgical staging compared to (18)F-FDG PET/CT on the external beam radiation field for patients with locally advanced cervical cancer: An ONCO-GF study.
DE CUYPERE, Marjolein ULiege; LOVINFOSSE, Pierre ULiege; GOFFIN, Frédéric ULiege et al

in European journal of surgical oncology : the journal of the European Society of Surgical Oncology and the British Association of Surgical Oncology (2019)

OBJECTIVE: Extended field chemoradiation is recommended for patients with locally advanced cervical cancer (LACC) and para-aortic lymph node (PALN) metastases. The radiation planning may be based on PET ... [more ▼]

OBJECTIVE: Extended field chemoradiation is recommended for patients with locally advanced cervical cancer (LACC) and para-aortic lymph node (PALN) metastases. The radiation planning may be based on PET/CT while others recommend to rely on surgical staging. We report the rate of patients for whom the radiation field defined on PET/CT was modified by the histological PALN status. METHODS: Between March 2010 and December 2016, 168 consecutive patients with LACC underwent a pre-therapeutic PET/CT and PALN dissection. The data were reviewed retrospectively. The diagnostic performance of the PET/CT for definition of PALN status was calculated. We determined the percentage of patients for whom PALN dissection altered the external beam radiotherapy (EBRT) field defined on the PET/CT basis. RESULTS: Of 151 patients with negative PALNs on PET/CT, 26 had histological PALN metastases. Of 17 patients with positive PALNs on PET/CT, 9 were negative on histology of which 7 were located in the common iliac region. Sensitivity, specificity, positive and negative predictive value of PET/CT were 23.5, 93.3, 47.1 and 82.8% respectively. In total, 35 out of 168 patients underwent EBRT - field adaptation (pelvic vs extended field). The rate of radiation field modification (27,7%) was particularly high in the subgroup of patients with metastatic pelvic lymph nodes (PLNs) on PET/CT. CONCLUSION: Para-aortic surgical staging contributes significantly to individualize the radiation treatment of patients with LACC, particularly for those with positive PLNs at PET/CT. Indication of surgical staging deserves particular attention when the PET/CT suggests positive LNs in the common iliac region. [less ▲]

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See detailDual time point [18F]FLT-PET for differentiating proliferating tissues vs non-proliferating tissues
LOVINFOSSE, Pierre ULiege; Rousseau, Caroline; Pierga, Jean-Yves et al

in EJNMMI Research (2019), 9(1),

Purpose: For differentiating tumor from inflammation and normal tissues, fluorodeoxyglucose ([18F]FDG) dual time point PET could be helpful. Albeit [18F]FLT is more specific for tumors than [18F]FDG; we ... [more ▼]

Purpose: For differentiating tumor from inflammation and normal tissues, fluorodeoxyglucose ([18F]FDG) dual time point PET could be helpful. Albeit [18F]FLT is more specific for tumors than [18F]FDG; we explored the role of dual time point [18F]FLT-PET for discriminating benign from malignant tissues. Methods: Before any treatment, 85 womens with de novo unifocal breast cancer underwent three PET acquisitions at 33.94 ± 8.01 min (PET30), 61.45 ± 8.30 min (PET60), and 81.06 ± 12.12 min (PET80) after [18F]FLT injection. Semiquantitative analyses of [18F]FLT uptake (SUV) were carried out on tumors, liver, bone marrow (4th thoracic vertebra (T4) and humeral head), descending thoracic aorta, muscle (deltoid), and contralateral normal breast. Repeated measures ANOVA tests and Tukey’s posttests were used to compare SUVmax of each site at the three time points. Results: There was a significant increase in SUVmax over time for breast lesions (5.58 ± 3.80; 5.97 ± 4.56; 6.19 ± 4.42; p < 0.0001) (m ± SD for PET30, PET60, and PET80, respectively), and bone marrow (for T4, 8.21 ± 3.17, 9.64 ± 3.66, 10.85 ± 3.63, p < 0.0001; for humeral head, 3.36 ± 1.79, 3.87 ± 1.89, 4.39 ± 2.00, p < 0.0001). A significant decrease in SUVmax over time was observed for liver (6.79 ± 2.03; 6.24 ± 1.99; 5.57 ± 1.74; p < 0.0001), muscle (0.95 ± 0.28; 0.93 ± 0.29; 0.86 ± 0.20; p < 0.027), and aorta (1.18 ± 0.34; 1.01 ± 0.32; 0.97 ± 0.30; p < 0.0001). No significant difference was observed for SUVmax in contralateral breast (0.8364 ± 0.40; 0.78 ± 0.38; 0.80 ± 0.35). Conclusion: [18F]FLT-SUVmax increased between 30 and 80 min only in proliferating tissues. This could be helpful for discriminating between residual tumor and scar tissue. © 2019, The Author(s). [less ▲]

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See detailHeterogeneity analysis of 18F‑FDG PET imaging in oncology: clinical indications and perspectives
LOVINFOSSE, Pierre ULiege; HATT, MATHIEU; VISIKIS, DIMITRI et al

in Clinical and Translational Imaging (2018)

Abstract Purpose : To evaluate the performances and perspectives of heterogeneity analysis of FDG PET imaging in oncology. Methods : We performed a review of the literature using PubMed/Medline and Google ... [more ▼]

Abstract Purpose : To evaluate the performances and perspectives of heterogeneity analysis of FDG PET imaging in oncology. Methods : We performed a review of the literature using PubMed/Medline and Google scholar, with multiple research keywords for each organ accompanying the terms ‘‘radiomics’’, ‘‘texture’’, ‘‘heterogeneity’’, ‘’FDG’’, ‘‘PET’’ and ‘‘PET/CT’’. The review considers shape, histogram and textural analysis of FDG PET. The references of the retrieved articles were also considered to identify additional articles. The search was limited to English language. Preoperative workup exploration, preclinical and animal studies were not included in the review. A total of 128 original articles were considered for the review. Results Many publications have explored the use of radiomics for multiple cancer sites, especially lung, head and neck, oesophageal and breast cancers. The results show variable levels of correlation with pathological characteristics and prediction of tumoral staging. Although initial results are promising, few studies have explored PET radiomics for delineating the radiotherapy target volume. Studies have predominantly investigated the prognostic value of radiomics for identifying failure of tumour response to treatment, high risk of recurrence and high mortality. Results are for the most part encouraging although rarely properly validated. The studies also exhibit a great methodological diversity for extracting and analysing features extraction, as various statistical approaches have been used, with the increasing help of machine learning tools. Conclusion PET radiomics show their potential to non-invasively improve tumoral characterisation and identification of aggressive pattern complementary to other omics. To be implemented in clinic, these promising results nevertheless need further validation, which must go through a standardisation of their extraction conditions. Machine learning, especially deep learning, could allow the empowerment of the selection of features and the creation of powerful prognostic models including clinical, pathological and iconographic parameters. [less ▲]

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See detailFDG PET radiomics: a review of the methodological aspects
LOVINFOSSE, Pierre ULiege; VISVIKIS, Dimitri; HUSTINX, Roland ULiege et al

in Clinical and Translational Imaging (2018)

Purpose To perform an updated review regarding the influence of methodological conditions on radiomics analyses of 18F-FDG PET imaging. Methods We performed a systematic review of the literature using ... [more ▼]

Purpose To perform an updated review regarding the influence of methodological conditions on radiomics analyses of 18F-FDG PET imaging. Methods We performed a systematic review of the literature using PubMed/Medline and Google scholars, with multiple research keywords for each organ accompanying the terms “radiomics”, “texture”, “heterogeneity”, “FDG”, “PET” and “PET/CT”. The review considers methodological studies for shape, histogram and textural features extracted from FDG PET imaging. The references cited in the retrieved articles were also explored to find additional studies. The search was limited to English language. Preclinical and animal studies were not included in the review. A total of 44 original articles were considered for the review. [less ▲]

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See detailMyoferlin controls mitochondrial structure and metabolism in pancreatic ductal adenocarcinoma, and affects tumor aggressiveness.
Rademaker, Gilles ULiege; Hennequière, Vincent ULiege; Brohée, Laura ULiege et al

Poster (2018, July 01)

Pancreatic ductal adenocarcinoma (PDAC) is the most common type of pancreatic cancer, and the third leading cause of cancer related death. Therapeutic options remain very limited and are still based on ... [more ▼]

Pancreatic ductal adenocarcinoma (PDAC) is the most common type of pancreatic cancer, and the third leading cause of cancer related death. Therapeutic options remain very limited and are still based on classical chemotherapies. Cell fraction can survive to the chemotherapy and is responsible for tumor relapse. It appears that these cells rely on oxydative phosphorylation (OXPHOS) for survival. Myoferlin, a membrane protein involved in cell fusion was recently shown by our laboratory to be overexpressed in pancreatic cancer. In the present study, we discovered that myoferlin was more expressed in cell lines undergoing (OXPHOS) than in glycolytic cell lines. In the former cell lines, we showed that myoferlin silencing reduced OXPHOS activity and forced cells to switch to glycolysis. The decrease in OXPHOS activity is associated with mitochondrial condensation and network disorganization. An increase of Dynamin-related protein (DRP)-1 phosphorylation in myoferlin-depleted cells led us to suggest mitochondrial fission, reducing cell proliferation, ATP production and inducing autophagy and ROS accumulation. Electron microscopy observation revealed mitophagy, suggesting mitochondrial alterations. To confirm the clinical importance of myoferlin in PDAC, we showed that low myoferlin expression was significantly correlated to high overall survival. Myoferlin staining of PDAC sections was negatively correlated with several 18FDG PET indices indicating that glycolytic lesions had less myoferlin. These observations are fully in accordance with our in vitro data. As the mitochondrial function was associated with cell chemoresistance, the metabolic switch induced by myoferlin silencing could open up a new perspective in the development of therapeutic strategies. Among them, targeting functional domains (C2, Dysf, …) of myoferlin should be a priority. [less ▲]

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See detailMyoferlin controls mitochondrial structure and activity in pancreatic ductal adenocarcinoma, and affects tumor aggressiveness
Rademaker, Gilles ULiege; Hennequière, Vincent ULiege; Nokin, Marie-Julie ULiege et al

in Oncogene (2018), 37((32)), 4398-4412

Pancreatic ductal adenocarcinoma (PDAC) is the third leading cause of cancer-related death. Therapeutic options remain very limited and are based on classical chemotherapies. Energy metabolism ... [more ▼]

Pancreatic ductal adenocarcinoma (PDAC) is the third leading cause of cancer-related death. Therapeutic options remain very limited and are based on classical chemotherapies. Energy metabolism reprogramming appears as an emerging hallmark of cancer and is considered a therapeutic target with considerable potential. Myoferlin, a ferlin family member protein overexpressed in PDAC, is involved in plasma membrane biology and has a tumor-promoting function. In the continuity of our previous studies, we investigated the role of myoferlin in the context of energy metabolism in PDAC. We used selected PDAC tumor samples and PDAC cell lines together with small interfering RNA technology to study the role of myoferlin in energetic metabolism. In PDAC patients, we showed that myoferlin expression is negatively correlated with overall survival and with glycolytic activity evaluated by 18F-deoxyglucose positron emission tomography. We found out that myoferlin is more abundant in lipogenic pancreatic cancer cell lines and is required to maintain a branched mitochondrial structure and a high oxidative phosphorylation activity. The observed mitochondrial fission induced by myoferlin depletion led to a decrease of cell proliferation, ATP production, and autophagy induction, thus indicating an essential role of myoferlin for PDAC cell fitness. The metabolic phenotype switch generated by myoferlin silencing could open up a new perspective in the development of therapeutic strategies, especially in the context of energy metabolism. [less ▲]

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See detailMurine stroma adopts a human-like metabolic phenotype in the PDX model of colorectal cancer and liver metastases
Blomme, Arnaud ULiege; van Simaeys, G.; Doumont, G. et al

in Oncogene (2018), 37(9), 1237-1250

Cancer research is increasingly dependent of patient-derived xenograft model (PDX). However, a major point of concern regarding the PDX model remains the replacement of the human stroma with murine ... [more ▼]

Cancer research is increasingly dependent of patient-derived xenograft model (PDX). However, a major point of concern regarding the PDX model remains the replacement of the human stroma with murine counterpart. In the present work we aimed at clarifying the significance of the human-to-murine stromal replacement for the fidelity of colorectal cancer (CRC) and liver metastasis (CRC-LM) PDX model. We have conducted a comparative metabolic analysis between 6 patient tumors and corresponding PDX across 4 generations. Metabolic signatures of cancer cells and stroma were measured separately by MALDI-imaging, while metabolite changes in entire tumors were quantified using mass spectrometry approach. Measurement of glucose metabolism was also conducted in vivo using [18F]-fluorodeoxyglucose (FDG) and positron emission tomography (PET). In CRC/CRC-LM PDX model, human stroma was entirely replaced at the second generation. Despite this change, MALDI-imaging demonstrated that the metabolic profiles of both stromal and cancer cells remained stable for at least four generations in comparison to the original patient material. On the tumor level, profiles of 86 water-soluble metabolites as well as 93 lipid mediators underlined the functional stability of the PDX model. In vivo PET measurement of glucose uptake (reflecting tumor glucose metabolism) supported the ex vivo observations. Our data show for the first time that CRC/CRC-LM PDX model maintains the functional stability at the metabolic level despite the early replacement of the human stroma by murine cells. The findings demonstrate that human cancer cells actively educate murine stromal cells during PDX development to adopt the human-like phenotype. © 2017 Macmillan Publishers Limited, part of Springer Nature [less ▲]

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