Laurène Froment
University of Bern
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Featured researches published by Laurène Froment.
BMC Cancer | 2014
Lourdes Cortes-Dericks; Laurène Froment; Ruben Boesch; Ralph A. Schmid; Golnaz Karoubi
BackgroundConventional chemotherapy in malignant pleural mesothelioma (MPM) has minimal impact on patient survival due to the supposed chemoresistance of cancer stem cells (CSCs). We sought to identify a sub-population of chemoresistant cells by using putative CSC markers, aldehyde dehydrogenase (ALDH) and CD44 in three MPM cell lines; H28, H2052 and Meso4.MethodsThe Aldefluor assay was used to measure ALDH activity and sort ALDHhigh and ALDHlow cells. Drug-resistance was evaluated by cell viability, anchorage-independent sphere formation, flow-cytometry and qRT-PCR analyses.ResultsThe ALDHhigh - and ALDHlow -sorted fractions were able to demonstrate phenotypic heterogeneity and generate spheres, the latter being less efficient, and both showed an association with CD44. Cis- diamminedichloroplatinum (II) (cisplatin) treatment failed to reduce ALDH activity and conferred only a short-term inhibition of sphere generation in both ALDHhigh and ALDHlow fractions of the three MPM cell lines. Induction of drug sensitivity by an ALDH inhibitor, diethylaminobenzaldehyde (DEAB) resulted in significant reductions in cell viability but not a complete elimination of the sphere-forming cells, suggestive of the presence of a drug-resistant subpopulation. At the transcript level, the cisplatin + DEAB-resistant cells showed upregulated mRNA expression levels for ALDH1A2, ALDH1A3 isozymes and CD44 indicating the involvement of these markers in conferring chemoresistance in both ALDHhigh and ALDHlow fractions of the three MPM cell lines.ConclusionsOur study shows that ALDHhigh CD44+ cells are implicated in conveying tolerance to cisplatin in the three MPM cell lines. The combined use of CD44 and ALDH widens the window for identification and targeting of a drug-resistant population which may improve the current treatment modalities in mesothelioma.
Cell Death and Disease | 2015
S-Q Liang; Thomas Marti; Patrick Dorn; Laurène Froment; Sean Hall; Sabina Anna Berezowska; Gregor J. Kocher; Ralph A. Schmid; R-W Peng
Anticancer therapies currently used in the clinic often can neither eradicate the tumor nor prevent disease recurrence due to tumor resistance. In this study, we showed that chemoresistance to pemetrexed, a multi-target anti-folate (MTA) chemotherapeutic agent for non-small cell lung cancer (NSCLC), is associated with a stem cell-like phenotype characterized by an enriched stem cell gene signature, augmented aldehyde dehydrogenase activity and greater clonogenic potential. Mechanistically, chemoresistance to MTA requires activation of epithelial-to-mesenchymal transition (EMT) pathway in that an experimentally induced EMT per se promotes chemoresistance in NSCLC and inhibition of EMT signaling by kaempferol renders the otherwise chemoresistant cancer cells susceptible to MTA. Relevant to the clinical setting, human primary NSCLC cells with an elevated EMT signaling feature a significantly enhanced potential to resist MTA, whereas concomitant administration of kaempferol abrogates MTA chemoresistance, regardless of whether it is due to an intrinsic or induced activation of the EMT pathway. Collectively, our findings reveal that a bona fide activation of EMT pathway is required and sufficient for chemoresistance to MTA and that kaempferol potently regresses this chemotherapy refractory phenotype, highlighting the potential of EMT pathway inhibition to enhance chemotherapeutic response of lung cancer.
Stem Cell Research & Therapy | 2016
Lourdes Cortes-Dericks; Laurène Froment; Gregor J. Kocher; Ralph A. Schmid
BackgroundThe soluble factors secreted by mesenchymal stem cells are thought to either support or inhibit tumor growth. Herein, we investigated whether the human lung-derived mesenchymal stem cell-conditioned medium (hlMSC-CM) exerts antitumor activity in malignant pleural mesothelioma cell lines H28, H2052 and Meso4.MethodshlMSC-CM was collected from the human lung-derived mesenchymal stem cells. Inhibition of tumor cell growth was based on the reduction of cell viability and inhibition of cell proliferation using the XTT and BrdU assays, respectively. Elimination of tumor spheroids was assessed by the anchorage-independent sphere formation assay. The cytokine profile of hlMSC-CM was determined by a chemiluminescence-based cytokine array.ResultsOur data showed that hlMSC-CM contains a broad range of soluble factors which include: cytokines, chemokines, hormones, growth and angiogenic factors, matrix metalloproteinases, metalloproteinase inhibitors and cell–cell mediator proteins. The 48- and 72-hour hlMSC-CM treatments of H28, H2052 and Meso4 cell lines elicited significant decreases in cell viability and inhibited cell proliferation. The 72-hour hlMSC-CM incubation of H28 cells completely eliminated the drug-resistant sphere-forming cells, which is more potent than twice the half maximal inhibitory concentration of cisplatin.ConclusionsOur findings indicate that the cell-free hlMSC-CM confers in vitro antitumor activities via soluble factors in the tested mesothelioma cells and, hence, may serve as a therapeutic tool to augment the current treatment strategies in malignant pleural mesothelioma.
Scientific Reports | 2017
Colette A. Bichsel; Limei Wang; Laurène Froment; Sabina Anna Berezowska; Stefan Jürg Müller; Patrick Dorn; Thomas Marti; Ren-Wang Peng; Thomas Geiser; Ralph A. Schmid; O. Guenat; Sean Hall
Pericytes represent important support cells surrounding microvessels found in solid organs. Emerging evidence points to their involvement in tumor progression and metastasis. Although reported to be present in the human lung, their specific presence and functional orientation within the tumor microenvironment in non-small cell lung cancer (NSCLC) has not yet been adequately studied. Using a multiparameter approach, we prospectively identified, sorted and expanded mesenchymal cells from human primary NSCLC samples based on co-expression of CD73 and CD90 while lacking hematopoietic and endothelial lineage markers (CD45, CD31, CD14 and Gly-A) and the epithelial marker EpCAM. Compared to their normal counterpart, tumor-derived Lineage-EpCAM-CD73+CD90+ cells showed enhanced expression of the immunosuppressive ligand PD-L1, a higher constitutive secretion of IL-6 and increased basal αSMA levels. In an in vitro model of 3D microvessels, both tumor-derived and matched normal Lineage-EpCAM-CD73+CD90+ cells supported the assembly of perfusable vessels. However, tumor-derived Lineage-EpCAM-CD73+CD90+ cells led to the formation of vessels with significantly increased permeability. Together, our data show that perivascular-like cells present in NSCLC retain functional abnormalities in vitro. Perivascular-like cells as an eventual target in NSCLC warrants further investigation.
Journal of Thoracic Oncology | 2016
Shun-Qing Liang; Thomas Marti; Patrick Dorn; Laurène Froment; Sean Hall; Sabina Anna Berezowska; Gregor J. Kocher; Ralph A. Schmid; Ren-Wang Peng
cells. Prognoscan assessment identified decrease SASH1 mRNA expression lead to a prognostic reduction in patient survival. The depletion of SASH1 in lung cells resulted in a significant increase in cellular proliferation in cancer lung cells. Connectivity mapping predicted the drug Chloropyramine would lead to an increase in SASH1 expression. We demonstrated that Chloropyramine upregulates SASH1 in malignant cell lines. In keeping with this we have demonstrated that Chloropyramine inhibited lung cancer proliferation in vitro. These novel observations support the tumour suppressive role of SASH1 in lung tumourgenesis. Further work is ongoing to understand the function of SASH1 in lung cancer growth. Conclusions: The upregulation of SASH1, either by chemical agents or gene therapy, is a potential novel approach to the management of lung cancer and other solid tumours. Legal entity responsible for the study: Queensland University of Technology Funding: Queensland Health Disclosure: All authors have declared no conflicts of interest.
Oncogene | 2018
Shun-Qing Liang; Elias D. Bührer; Sabina Anna Berezowska; Thomas Marti; Duo Xu; Laurène Froment; Haitang Yang; Sean Hall; Erik Vassella; Zhang Yang; Gregor J. Kocher; Michael A. Amrein; Carsten Riether; Adrian F. Ochsenbein; Ralph A. Schmid; Ren-Wang Peng
Oncogenic KRAS mutations comprise the largest subset of lung cancer defined by genetic alterations, but in the clinic no targeted therapies are available that effectively control mutational KRAS activation. Consequently, patients with KRAS-driven tumors are routinely treated with cytotoxic chemotherapy, which is often transiently effective owing to development of drug resistance. In this study, we show that hyperactivated mammalian target of rapamycin (mTOR) pathway is a characteristic hallmark of KRAS-mutant lung adenocarcinoma after chemotherapy treatment, and that KRAS-mutant lung cancer cells rely on persistent mTOR signaling to resist chemotherapeutic drugs. Coherently, mTOR inhibition circumvents the refractory phenotype and restores sensitivity of resistant KRAS-mutant lung cancer cells to chemotherapy. Importantly, drug combinations of clinically approved mTOR inhibitors and chemotherapy drugs synergize in inhibiting cell proliferation of KRAS-mutant cancer cells in vitro and in vivo, and the efficacy of this combination treatment correlates with the magnitude of mTOR activity induced by chemotherapy alone. These results pinpoint mTOR as a mechanism of resistance to chemotherapy in KRAS-mutant lung cancer and validate a rational and readily translatable strategy that combines mTOR inhibitors with standard chemotherapy to treat KRAS-mutant adenocarcinoma, the most common and deadliest lung cancer subset.
Journal of Thoracic Oncology | 2016
Thomas Marti; Colin Tièche; Ren-Wang Peng; Patrick Dorn; Laurène Froment; Ralph A. Schmid
were used. Pharmacological inhibition of HSP90 activity in these cell lines were achieved through geldanamycin and resorcinol derivatives. The response to these inhibitors at different time points was evaluated. Results: Westerns blots indicated that HSP70 and HSP90-a protein expression were increased after 17-AAG, IPI-504, STA9090 and AUY-922 treatments. EGFR, EML4-ALK and CDK4, the oncogenic client proteins studied, were depleted by the HSP90 inhibitors in the NSCLC cell lines. The strong relationship between client driver protein dependence on Hsp90 and the sensitivity to its inhibition was demonstrated in the HCC827 and H3122 cell lines. Conclusions: The reduction of oncogenic client proteins alongside HSP70 and HSP90-a induction could be used as a validated biomarker signature of HSP90 inhibition in the cell lines studied. Future study will be focused on understanding the biological basis for the differential response to these treatments. Legal entity responsible for the study: Instituo de Biomedicina de Sevilla (IBIS) (CSIC, HUVR, Universidad de Sevilla) Funding: Fundación para la Investigación de Sevilla (FISEVI) Disclosure: All authors have declared no conflicts of interest.
Journal of Thoracic Oncology | 2016
Thomas Marti; Patrick Dorn; Colin Tièche; Ren-Wang Peng; Laurène Froment; Ralph A. Schmid
pools could sensitize cancer cells to subsequent treatment with cisplatin. Methods: NSCLC A549 cells were treated with pemetrexed for 72 hours. In addition, 24 hours of cisplatin treatment was initiated at day 1, 2 or 3 resulting in either simultaneous pemetrexed application or pemetrexed pretreatment for 24 or 48 hours, respectively. Cell growth and colony formation as well as senescence induction were quantified after treatment. Cell cycle distribution and DNA damage induction was quantified by flow cytometry. Results: Extended pemetrexed pretreatment for 48 hours prior to cisplatin treatment maximally delayed long-term cell growth and significantly reduced the number of recovering clones. Moreover, apoptosis and senescence were augmented and recovery from treatment-induced DNA damage was delayed. Interestingly, a resistant cell population was identified that displayed an epithelialto-mesenchymal transition and which had a stem cell phenotype. Conclusions: Prolonged pemetrexed pretreatment optimizes the anticancer efficiency of pemetrexed–cisplatin combination therapy, therefore, this study warrants further investigations to elucidate whether such an adaptation could enhance the effectiveness of the standard clinical treatment regimen. In addition, a subpopulation of therapy resistant cells with EMT and cancer stem cell features was identified. Legal entity responsible for the study: N/A Funding: Supported by the Bernese Cancer League and the Swiss Cancer Research (KFS-3530–08–2014) to TMM Disclosure: All authors have declared no conflicts of interest.
Annals of Oncology | 2016
Sean Hall; Limei Wang; Thomas Marti; Ren-Wang Peng; Laurène Froment; Sabina Anna Berezowska; Gregor J. Kocher; Patrick Dorn; Ralph A. Schmid
Aim/Background: Solid tumors have been shown to evade host antitumor immunity through upregulation of the immune checkpoint PD-1/PD-L1 pathway. However, CD47, an antiphagocytic ligand expressed on tumor cells, represents another cell surface molecule promoting tumor immune evasion via targeting the innate immune system. We investigated whether PD-L1 and CD47 are co-expressed in early stage non-small cell lung cancer (NSCLC). Methods: Resected tumor and matched adjacent normal tissue from 84 stage I-III NSCLCs (42 adenocarcinomas [Adeno]; 42 squamous cell carcinomas [SqCC]) were processed to single cell suspensions, stained with a panel of antibodies (CD45, CD31, CD14, EpCAM, CD73, CD90, PD-L1, CD47) and subjected to multicolor flow cytometric analysis. In parallel, the phenotype of tumor infiltrating lymphocytes (TILs) was also performed using CD19, CD45RO, CD3, CD4, CD8, PD-1, CD127 and CD107a. In a subset of patients, expression of PD-L1 and CD47 was confirmed via immunohistochemistry. Results: PD-L1 expression on tumor epithelium (EpCAM+) was increased in both Adeno (p = 0.0295) and SqCC (p = 0.0016) patients. CD47 was also upregulated on the tumor EpCAM+ fraction in SqCC (p = 0.05) but not in Adeno patients (p = 0.124). An increase in the tumor mesenchymal fraction in both Adeno (p = 0.015) and SqCC (p = 0.027) patients was found that showed an enhanced expression of PD-L1 but not CD47. Immunohistochemical analysis confirmed coexpression of PD-L1 and CD47 in a subset of patients. Finally, there was an increase in CD4+PD-1hi TILs in Adeno patients, whereas a decrease in CD127 expression was found on CD8+ TILs (p < 0.0001) with a CD107aloPD1hi phenotype in both histological subtypes. Conclusions: We detected PD-L1 expression in different compartments in a subset of patients with early stage Adeno and SqCC, whereas CD47 expression was restricted to the tumor epithelial compartment in SqCC patients only. These differences may be related to the intragraft immune priming inside the tumor microenvironment. Further study is required to determine whether dual targeting of PD-L1 and CD47 in the perioperative setting represents a promising therapeutic strategy to reinvigorate TILs in affected patients. Legal entity responsible for the study: N/A Funding: Inselspital, University Hospital of Bern, Division of Thoracic Surgery Disclosure: All authors have declared no conflicts of interest.
BMC Cancer | 2016
Colin Tièche; Ren-Wang Peng; Patrick Dorn; Laurène Froment; Ralph A. Schmid; Thomas Marti