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See detailBlocking lipid synthesis overcomes tumor re-growth and metastasis after anti-angiogenic therapy withdrawal.
Sounni, Nor Eddine ULg; Cimino, Jonathan ULg; BLACHER, Silvia ULg et al

in Cell Metabolism (2014), 20(2), 280-94

The molecular mechanisms responsible for the failure of antiangiogenic therapies and how tumors adapt to these therapies are unclear. Here, we applied transcriptomic, proteomic, and metabolomic approaches ... [more ▼]

The molecular mechanisms responsible for the failure of antiangiogenic therapies and how tumors adapt to these therapies are unclear. Here, we applied transcriptomic, proteomic, and metabolomic approaches to preclinical models and provide evidence for tumor adaptation to vascular endothelial growth factor blockade through a metabolic shift toward carbohydrate and lipid metabolism in tumors. During sunitinib or sorafenib treatment, tumor growth was inhibited and tumors were hypoxic and glycolytic. In sharp contrast, treatment withdrawal led to tumor regrowth, angiogenesis restoration, moderate lactate production, and enhanced lipid synthesis. This metabolic shift was associated with a drastic increase in metastatic dissemination. Interestingly, pharmacological lipogenesis inhibition with orlistat or fatty acid synthase downregulation with shRNA inhibited tumor regrowth and metastases after sunitinib treatment withdrawal. Our data shed light on metabolic alterations that result in cancer adaptation to antiangiogenic treatments and identify key molecules involved in lipid metabolism as putative therapeutic targets. [less ▲]

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See detailTowards Lipidomics of Low-Abundant Species for Exploring Tumor Heterogeneity Guided by High-Resolution Mass Spectrometry Imaging
Cimino, Jonathan ULg; Calligaris, David; Far, Johann ULg et al

in International Journal of Molecular Sciences (2013), 14

Many studies have evidenced the main role of lipids in physiological and also pathological processes such as cancer, diabetes or neurodegenerative diseases. The identification and the in situ localization ... [more ▼]

Many studies have evidenced the main role of lipids in physiological and also pathological processes such as cancer, diabetes or neurodegenerative diseases. The identification and the in situ localization of specific low-abundant lipid species involved in cancer biology are still challenging for both fundamental studies and lipid marker discovery. In this paper, we report the identification and the localization of specific isobaric minor phospholipids in human breast cancer xenografts by FTICR MALDI imaging supported by histochemistry. These potential candidates can be further confirmed by liquid chromatography coupled with electrospray mass spectrometry (LC-ESI-MS) after extraction from the region of interest defined by MALDI imaging. Finally, this study highlights the importance of characterizing the heterogeneous distribution of low-abundant lipid species, relevant in complex histological samples for biological purposes. [less ▲]

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See detailSéminaire des chercheurs Télévie 2013
Cimino, Jonathan ULg; Sounni, Nor Eddine ULg; Calligaris, David ULg et al

Poster (2012, December 10)

Séminaire des chercheurs Télévie 2013

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See detailDetermination of the molecular players of adaptation to anti-angiogenic therapy in breast cancer by quantitative proteomic and high molecular MALDI Imaging.
Cimino, Jonathan ULg; Sounni, Nor Eddine ULg; Calligaris, David ULg et al

Poster (2012, October 13)

Breast carcinoma is the most common and second leading cause of cancer mortality in women. The recognition of the “angiogenic switch” as a rate-limiting secondary step in tumorigenesis led to extensive ... [more ▼]

Breast carcinoma is the most common and second leading cause of cancer mortality in women. The recognition of the “angiogenic switch” as a rate-limiting secondary step in tumorigenesis led to extensive pre-clinical researches on angiogenesis and finally the approval of VEGF-neutralizing antibodies (bevacizumab) and VEGF receptor tyrosine kinase inhibitors (RTKs:Sunitinib). The Sunitinib has been used clinically in patients with breast cancer refractory to other therapeutic agents. Unfortunately, like the cytotoxic therapies, these drugs do not produce lasting effects and resistance to treatment appeared clinically. Questions have emerged about the failure of anti-angiogenic therapy in clinic and the limitations of predictive preclinical models, and also about the molecular assessment of all stages of tumor adaptation and me<x>tastatic disease. To this end, we applied quantitative proteomics and imaging mass spectrometry tools to visualize and study the profiles of proteins and small molecules associated with tumor treated or not with Sunitinib using a novel preclinical model of breast carcinoma cells. In this project, we first developed a reproducible model of resistance to Sunitinib of human triple negative breast cancer MDA-MB-231 cells expressing luciferase gene. Cells were subcutaneously injected into mice RAG1-/- and divided into four experimental groups including, control mice treated with vehicle or Sunitinib for 30 days and sacrificed 1 days after treatment withdrawal or when tumor reached a volume of 300 mm3. In the second step. Tumors were analyzed using a nanoAcquity UPLC Synapt TM HDMS TM G1 (Waters, Manchester,UK) and Mass Spectrometry Imaging. For quantitative proteomic analyses of tumors, a bioinformatics analysis was used with the Protein lynx global server 2.2.5 software. Imaging mass spectrometry was performed on tissue sections of tumors and organs subsequently colonized by me<x>tastases. Matrix sublimation was used to coat tumor sections (14 µm-tick) with 1.5 Diaminonaphthalene for lipids analysis and Sinapinic acid for entire proteins analysis. Ion cartographies were recorded with a Solarix 9.4T FTMS instrument for lipids and with an Ultraflex II TOF-TOF instrument for entire proteins (Bruker Daltonics, Germany) with a spatial resolution of 100 µm. Global protemic revealed different protein profiles between tumor treated or not with Sunitinib. The Mass Spectrometry Imaging detected differences in intensity and location of some proteins and lipids are also associated with some histological features including inflammatory, necrotic and angiogenic areas. Bioinformatics analysis will be applied to ensure the integration of all data in order to provide the basis for identifying molecular pathways activated during the acquisition of refractoriness to drug treatments. [less ▲]

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See detailStudy  of  breast  cancer  adaptation  to  anti-­angiogenic  therapies  by   molecular  imaging  on  tissue  slides
Cimino, Jonathan ULg; Calligaris, David ULg; Debois, Delphine ULg et al

Conference (2012, September 04)

Breast   carcinoma   is   the   most   common   and   second   leading   cause   of   cancer   mortality   in   women1.   The   ␣␣␣␣␣␣␣␣␣␣␣␣ ␣␣␣ ␣␣␣␣ ␣␣␣␣␣␣␣␣␣␣␣␣ ␣␣␣␣␣␣␣␣ ␣␣␣ ␣␣ ␣␣␣␣-­‐limiting   ... [more ▼]

Breast   carcinoma   is   the   most   common   and   second   leading   cause   of   cancer   mortality   in   women1.   The   ␣␣␣␣␣␣␣␣␣␣␣␣ ␣␣␣ ␣␣␣␣ ␣␣␣␣␣␣␣␣␣␣␣␣ ␣␣␣␣␣␣␣␣ ␣␣␣ ␣␣ ␣␣␣␣-­‐limiting   secondary   step   in   tumorigenesis   led   to   extensive   pre-­‐clinical   researches   on   angiogenesis   and   finally   the   approval   of   VEGF-­‐neutralizing   antibodies   (bevacizumab)  and  VEGF  receptor  tyrosine  kinase  inhibitors  (RTKs:sunitinib).  The  Sunitinib  has  been  used   clinically   in   patients   with   breast   cancer   refractory   to   other   therapeutic   agents2.   Unfortunately,   like   the   cytotoxic   therapies,   these   drugs   do   not   produce   lasting   effects   and   resistance   to   treatment   appeared   clinically3.   Recently,   independent   laboratories   have   reported   experimental   data   demonstrating   that   anti-­‐ angiogenic   treatments   inhibit   tumor   growth,   but   also   stimulate   the   formation   of   lung   metastases   after   treatment   discontinuation4.   The   field   of   imaging   mass   spectrometry   provides   new   tools   to   visualize   and   study  the  profiles  of  proteins  and  small  molecules  associated  with  biomedical  problems5.   To  this  aim,  we  conducted  a  series  of  experiments  to  setup  a  reproductible  model  of  resistance  to  sunitinib.   The   cells   MDA-­‐MB-­‐231   triple   negative,   from   human   breast   cancer   and   expressing   luciferase   are   injected   subcutaneously  into  mice  RAG1-­‐/-­‐.  The  mice  were  divided  into  four  experimental  groups  including,  on  the   one  hand,  control  mice  treated  with  placebo  (Carboxymethyl  cellulose,  CMC)  sacrificed  on  day  30  (group  1)   or  when  the  tumor  reached  a  volume  of  300  mm3  (group  2).    On  the  other  hand,  Sunitinib-­‐treated  mice  (LC   Laboratories,   40mg/kg/day),   sacrificed   at   day   30   (group   3),   or   when   the   tumor   reached   a   volume   of   300   mm3  (group  4).  MALDI  mass  spectrometry  imaging  was  performed  on  tissue  sections  of  tumors  and  organs   subsequently   colonized   by   metastases.   Matrix   sublimation   was   used   to   coat   tumor   sections   (14   μm-­‐tick)   with   1.5   Diaminonaphthalene   (1.5   DAN)   for   lipids   analysis   and   Sinapinic   acid   (SA)   for   entire   proteins   analysis.   Ion   cartographies   were   recorded   with   a   Solarix9.4T   FTMS   instrument   for   lipids   and   with   an   Ultraflex   II   TOF-­‐TOF   instrument   for   entire   proteins   (BrukerDaltonics,   Bremen,   Germany)   with   a   spatial   resolution  of  100  μm.     The  analysis  of  differential  protein/lipid  profiles  with  high  mass  accuracy  and  broadband  resolution  allows   detection   of   intense   signals   from   lipid   families   such   as   Phosphatidylcholine   (PC),   Triglyceride   (TAG),   Sphingomyelin   (SM)   and   precise   lipid   droplets   or   tumor   cells   differentiated   location   in   the   Sunitinib   resistant   tumor   cells   compared   to   control   cells.The   protein   profiles   of   the   4   groups   of   mice   show   differences   in   intensity   and   location,   enabling   a   correlation   to   inflammatory   (highlighted   by   histological   staining)  and  angiogenic  phenomenon.   [less ▲]

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See detailMolecular imaging through in combinaison with quantitative proteomic approaches unraveling the molecular players of breast cancer adaptation to anti-angiogenic therapy.
Cimino, Jonathan ULg; Sounni, Nor Eddine ULg; Calligaris, David ULg et al

Poster (2012, June 22)

Breast carcinoma is the most common and second leading cause of cancer mortality in women. The recognition of the “angiogenic switch” as a rate-limiting secondary step in tumorigenesis led to extensive ... [more ▼]

Breast carcinoma is the most common and second leading cause of cancer mortality in women. The recognition of the “angiogenic switch” as a rate-limiting secondary step in tumorigenesis led to extensive pre-clinical researches on angiogenesis and finally the approval of VEGF-neutralizing antibodies (bevacizumab) and VEGF receptor tyrosine kinase inhibitors (RTKs:Sunitinib). The Sunitinib has been used clinically in patients with breast cancer refractory to other therapeutic agents. Unfortunately, like the cytotoxic therapies, these drugs do not produce lasting effects and resistance to treatment appeared clinically. Questions have emerged about the failure of anti-angiogenic therapy in clinic and the limitations of predictive preclinical models, and also about the molecular assessment of all stages of tumor adaptation and metastatic disease. To this end, we applied quantitative proteomics and imaging mass spectrometry tools to visualize and study the profiles of proteins and small molecules associated with tumor treated or not with Sunitinib using a novel preclinical model of breast carcinoma cells. In this project, we first developed a reproducible model of resistance to Sunitinib of human triple negative breast cancer MDA-MB-231 cells expressing luciferase gene. Cells were subcutaneously injected into mice RAG1-/- and divided into four experimental groups including, control mice treated with vehicle or Sunitinib for 30 days and sacrificed 1 days after treatment withdrawal or when tumor reached a volume of 300 mm3. In the second step. Tumors were analyzed using a nanoAcquity UPLC Synapt TM HDMS TM G1 (Waters, Manchester,UK) and Mass Spectrometry Imaging. For quantitative proteomic analyses of tumors, a bioinformatics analysis was used with the Protein lynx global server 2.2.5 software. Imaging mass spectrometry was performed on tissue sections of tumors and organs subsequently colonized by metastases. Matrix sublimation was used to coat tumor sections (14 µm-tick) with 1.5 Diaminonaphthalene for lipids analysis and Sinapinic acid for entire proteins analysis. Ion cartographies were recorded with a Solarix 9.4T FTMS instrument for lipids and with an Ultraflex II TOF-TOF instrument for entire proteins (Bruker Daltonics, Germany) with a spatial resolution of 100 µm. Global protemic revealed different protein profiles between tumor treated or not with Sunitinib. The Mass Spectrometry Imaging detected differences in intensity and location of some proteins and lipids are also associated with some histological features including inflammatory, necrotic and angiogenic areas. Bioinformatics analysis will be applied to ensure the integration of all data in order to provide the basis for identifying molecular pathways activated during the acquisition of refractoriness to drug treatments. [less ▲]

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See detailApplication of molecular imaging in combination with quantitative proteomic approaches to determine the molecular players of adaptation to anti-angiogenic therapy in breast cancer.
Cimino, Jonathan ULg; Sounni, Nor Eddine ULg; Calligaris, David ULg et al

Poster (2012, May 04)

The recognition of the “angiogenic switch” as a rate-limiting secondary step in tumorigenesis led to extensive pre-clinical researches on angiogenesis and finally the approval of VEGF-neutralizing ... [more ▼]

The recognition of the “angiogenic switch” as a rate-limiting secondary step in tumorigenesis led to extensive pre-clinical researches on angiogenesis and finally the approval of VEGF-neutralizing antibodies (bevacizumab) and VEGF receptor tyrosine kinase inhibitors (RTKs:Sunitinib). The Sunitinib has been used clinically in patients with breast cancer refractory to other therapeutic agents. Unfortunately, like the cytotoxic therapies, these drugs do not produce lasting effects and resistance to treatment appeared clinically. Questions have emerged about the failure of anti-angiogenic therapy in clinic and the limitations of predictive preclinical models, and also about the molecular assessment of all stages of tumor adaptation and metastatic disease. To this end, we applied a quantitative proteomics and imaging mass spectrometry tools to visualize and study the profiles of proteins and small molecules associated with tumor treated or not with Sunitinib using a novel preclinical model of breast carcinoma cells. [less ▲]

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See detailContribution of high mass resolution and accuracy of FTMS to molecular imaging
Debois, Delphine ULg; Calligaris, David ULg; Cimino, Jonathan ULg et al

Conference (2012, April 04)

Since its first implementation in 1997, MALDI Mass Spectrometry Imaging (MALDI MSI) has become an important tool in the proteomic arsenal, especially for biomarker hunting. First dedicated to high ... [more ▼]

Since its first implementation in 1997, MALDI Mass Spectrometry Imaging (MALDI MSI) has become an important tool in the proteomic arsenal, especially for biomarker hunting. First dedicated to high molecular weight, MALDI MSI is more and more used to map the distribution of small molecules too (lipids, drugs and metabolites,…). Last developments tend to improve the sample treatments to obtain the best spatial resolution as possible. From this perspective, great efforts have been made on the MALDI matrix deposition methods. Now, one of the remaining challenges for MALDI-MSI users consists of identification of detected molecules. For high molecular weight, methods inspired by classical proteomics techniques, are regularly used. Bottom-Up (PMF obtained after in situ trypsin digestion) and Top-Down (in situ In-Source Decay) approaches have been used directly from a tissue slice, leading to the identification of some of the most abundant proteins present at the surface of the tissue. When small molecules are analyzed, the identification is more straightforward. Indeed, tandem mass spectrometry can easily be used, leading to the fragmentation of the detected compounds which allows their unambiguous identification. This identification is even more reliable when high resolution exact mass measurements can be performed. In this talk, I will present how in our lab, we profit of the exceptional features of FT-ICR mass spectrometry for imaging and especially for identification purposes. The first example will deal with the benefit of high mass accuracy and high mass resolution for ISD-based protein identification. The mass accuracy and high mass resolution coupled with the use of a “cleaning” software allow unequivocal assignment of ISD fragments of proteins, in the low mass range (m/z between 300 and 900), whether from pure solutions or from tissue slices. The next examples will deal with the imaging of small molecules. The identification of drugs and their metabolites is facilitated with high mass accuracy. In our lab, we work on the localization of methadone and its first metabolite, EDDP in necrophagous fly larvae. In the mass range of these compounds (278-310 m/z), many matrix ion peaks are detected and the unique features of FT-ICR allows for unambiguous identification thanks to exact mass measurements. We also use MALDI Imaging to map the messenger molecules between plant roots and beneficial bacteria. The comparison of spectra recorded with a TOF/TOF instrument and with a FT-ICR demonstrates that high resolution allows for detecting molecules which could have been missed otherwise. It also allows to distinguish unknown compounds from alkali adducts of known molecules. [less ▲]

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