Detection and Outcome Markers . Metastasis . EMT . Aberrant Glycosylation, Drugs and Treatment . Therapeutic Targets

Ovarian Cancer Research

Ovarian cancer (OC) is the most lethal gynecological malignancy and the 5th leading cause of cancer death in women. OC is typically diagnosed at late stage, when the cancer has spread into the peritoneal cavity and complete surgical removal is difficult. The 5-year overall survival for patients diagnosed at this stage is 30%, in contrast to 90% 5-year survival for patients diagnosed at early stage. The disease recurrence is usually high due to insufficient therapies and risk to metastasis is considerable. Cancer screening and early detection have the potential to greatly decrease the mortality and morbidity from cancer, but currently available early detection markers like CA-125 or HE4 do not seem reliable enough.

The etiology of OC is until today not fully understood despite several decades of intensive research. Recent data suggest that OC arises from transformed epithelial cells in the fallopian tube rather than from the ovarian surface epithelium. At risk are women with germ line mutations in BRCA genes and somatic mutations in BRCA andTP53. Clinical management of patients with OC is by cytoreductive surgery and chemotherapy and rarely radiotherapy; immune therapeutic approaches are currently under clinical evaluation.

Metastasis is apart from therapy resistance a major obstacle and causative for OC-related death in OC treatment. OC preferably metastasizes (disseminates) into the peritoneal cavity and in particular to the omentum. The omentum is a layer of fatty tissue that covers and supports the intestines and organs in the lower abdominal area and that is lined by a monolayer of mesothelial cells. This may occur through different routes (lymphatic spread, hematogenous spread, and passive dissemination via ascites flow) and involves the shedding of tumor cells or clusters from the primary tumor and the colonization and establishment of secondary tumor (metastasis) at distant sites (e.g. omentum) via orchestrated processes including epithelial-to-mesenchymal transition.

The Ovarian Cancer Research (OCR) Group led by Prof. Viola Heinzelmann-Schwarz and her deputy Dr. Francis Jacob combines basic, translational, and clinical approaches to:

  • identify biomarkers and molecular signatures for early detection and prognostic outcome of OC (survival, therapy response, or relapse)
  • dissect the mechanisms of OC metastasis and identify potential routes of therapeutic Intervention
  • search for alternative and novel (precision medicine-driven) diagnostic and therapeutic approaches to the best benefit for OC patients
  • investigate biological roles of (aberrant) protein and lipid glycosylation in OC metastasis and resistance

 

Selected research projects

Key molecules in ovarian cancer dissemination

Peritoneal dissemination is a particular form ovarian cancer of metastasis which is the cause why the majority of patients are diagnosed at advanced FIGO stage accompanied with a poor patient’s outcome. Identification of the molecular players involved in ovarian cancer (OC) dissemination can offer an approach to develop treatment strategies to improve clinical prognosis.

We have identified several cell surface markers that may promote the spreading of ovarian cancer. Here, we describe integrina2 (ITGA2) as a key factor for cancer cell adhesion to extracellular matrix protein collagen that promotes metastasis to the omentum as demonstrated by in vitro assays in gene-edited cancer cell lines and ex vivo using patient-derived tumor cells. Moreover, we also demonstrate that ITGA2 promotes directed cell migration and mesothelial clearance in co-culture systems. Mechanistically, the oncogenic properties rely on ITGA2-dependent phosphorylation of focal adhesion kinase and activation mitogen-activated protein kinase pathways (Huang et al, 2020; Fig. 1). In a collaboration with Leonor David (University of Porto, Portugal) we show that mesothelin (MSLN), which is overexpressed in primary and matched peritoneal metastasis of high-grade serous carcinomas, promoted invasion of tumor cells through the mesothelial cell layer in vitro. Intraperitoneal xenografts established with MSLN-high OC cell lines showed enhanced tumor burden and spread within the peritoneal cavity. MSLN is hence suggested as key player in OC progression by triggering peritoneal dissemination (Coelho et al, 2020).

Epithelial-to-mesenchymal transition (EMT) and its reverse MET are suggested to be key features of OC metastasis and comprise cellular and molecular processes essential for local tumor growth, dissemination, and establishment of metastases at distant sites. We found that loss globoside glycosphingolipids (GSL) through genomic deletion of the key enzyme A4GALT induced EMT in OC cells, associated with loss of E-cadherin expression (through epigenetic silencing of CDH1) and cell-cell adhesion and increased chemoresistance (Jacob et al, 2018). Our current focus is to understand the role of GSL in MET, identify associated signaling pathways and study the expression of GSLs in patient-derived cells. In collaboration with Arun Everest-Dass and Mark von Itzstein (Institute for Glycomics, Griffith University, Australia), we have established MALDI imaging to study spatial distribution of GSLs in human samples.

 

New molecular signatures towards early detection, outcome prediction, and tailored management of ovarian cancer

The identification of markers (signatures) for early and accurate diagnosis and reliable outcome prediction are the key to optimal management of ovarian cancer. In the era of precision medicine, where we transition from organ-based diagnosis towards individual genetically-linked diseases, the tailoring of treatment in cancer becomes increasingly important. This is particularly true for high-grade advanced stage serous adenocarcinomas comprising malignant tumors of the ovary (OC), fallopian tube (TC) and peritoneum (PC). These diseases are which currently are managed similarly, but our study using transcriptomic and next-generation sequencing data and validation by immunohistochemistry in various patient cohorts indicate that OC and PC are epidemiologically and molecularly distinct diseases: PC relapsed earlier, had a distinctively different gene signature, and showed a different sensitivity to standard chemotherapy drugs compared to OC (Jacob et al, 2020). A preceding study characterized the N- and O-glycome of these two diseases using tissue glycomics and revealed also distinct glycomic signatures i.e. proteins are differently and uniquely glycosylated in OC versus PC (Anugraham et al, 2017).

Additional studies from our own group evaluated candidate ovarian cancer detection and outcome markers for HGSOC. Among them the expression of maternal embryonic leucine-zipper kinase (MELK) correlated with poor survival (Kohler et al, 2017), whereas LATS expression was not associated with outcome in ovarian cancer patients (Montavon et al, 2019).

 

Selected Publications (last 5 years)

Irmisch A, Bonilla X, Chevrier S, Lehmann KV, Singer F, Toussaint NC, Esposito C, Mena J, Milani ES, Casanova R, Stekhoven DJ, Wegmann R, Jacob F, Sobottka B, Goetze S, Kuipers J, Sarabia Del Castillo J, Prummer M, Tuncel MA, Menzel U, Jacobs A, Engler S, Sivapatham S, Frei AL, Gut G, Ficek J, Miglino N; Tumor Profiler Consortium, Aebersold R, Bacac M, Beerenwinkel N, Beisel C, Bodenmiller B, Dummer R, Heinzelmann-Schwarz V, Koelzer VH, Manz MG, Moch H, Pelkmans L, Snijder B, Theocharides APA, Tolnay M, Wicki A, Wollscheid B, Rätsch G, Levesque MP. The Tumor Profiler Study: integrated, multi-omic, functional tumor profiling for clinical decision support. Cancer Cell. 2021 Jan 20:S1535-6108(21)00048-9. doi: 10.1016/j.ccell.2021.01.004. (2021).

Stark SG, Ficek J, Locatello F, Bonilla X, Chevrier S, Singer F; Tumor Profiler Consortium, Rätsch G, Lehmann KV. SCIM: universal single-cell matching with unpaired feature sets. Bioinformatics. 2020 Dec 30;36(Supplement_2):i919-i927. (2021).

Cumin C, Huang YL, Everest-Dass A, Jacob F. Deciphering the Importance of Glycosphingolipids on Cellular and Molecular Mechanisms Associated with Epithelial-to-Mesenchymal Transition in Cancer. Biomolecules. 2021 Jan 6;11(1):62. doi: 10.3390/biom11010062. (2021).

Coelho R, Ricardo S, Amaral AL, Huang YL, Nunes M, Neves JP, Mendes N, López MN, Bartosch C, Ferreira V, Portugal R, Lopes JM, Almeida R, Heinzelmann-Schwarz V, Jacob F, David L. Regulation of invasion and peritoneal dissemination of ovarian cancer by mesothelin manipulation. Oncogenesis. 2020;9:61. (2021).

Estermann M, Huang YL, Septiadi D, Ritz D, Liang CY, Jacob F, Drasler B, Petri-Fink A, Heinzelmann-Schwarz V, Rothen-Rutishauser B. Patient-derived and artificial ascites have minor effects on MeT-5A mesothelial cells and do not facilitate ovarian cancer cell adhesion. PLoS One. 2020;15:e0241500. (2020).

Huang YL, Liang CY, Ritz D, Coelho R, Septiadi D, Estermann M, Cumin C, Rimmer N, Schötzau A, Núñez López M, Fedier A, Konantz M, Vlajnic T, Calabrese D, Lengerke C, David L, Rothen-Rutishauser B, Jacob F, Heinzelmann-Schwarz V. Collagen-rich omentum is a premetastatic niche for integrin α2-mediated peritoneal metastasis. Elife. 2020;9:e59442. (2020).

Jacob F, Marchetti RL, Kind AB, Russell K, Schoetzau A, Heinzelmann-Schwarz VA. High-grade serous peritoneal cancer follows a high stromal response signature and shows worse outcome than ovarian cancer. Mol Oncol. 2021;15:91-103. (2020).

Trüb M, Uhlenbrock F, Claus C, Herzig P, Thelen M, Karanikas V, Bacac M, Amann M, Albrecht R, Ferrara-Koller C, Thommen D, Rothschield S, Savic Prince S, Mertz KD, Cathomas G, Rosenberg R, Heinzelmann-Schwarz V, Wiese M, Lardinois D, Umana P, Klein C, Laubli H, Kashyap AS, Zippelius A. Fibroblast activation protein-targeted-4-1BB ligand agonist amplifies effector functions of intratumoral T cells in human cancer. J. Immunother Cancer. 2020 Jul;8(2):e000238. (2020).

Heinzelmann-Schwarz V, Kind AB, Vetter M, Russell K, Omar S, Schoetzau A, Hoeck K, Fink D, Friedlander ML, Hacker NF. Should MMMT still be treated with adjuvant taxane-based combination chemotherapy? J Cancer Res Clin Oncol. 2020 Jan 28. doi: 10.1007/s00432-019-03091-y. [Epub ahead of print]. (2020).

Terraneo N, Jacob F, Peitzsch C, Dubrovska A, Krudewig C, Huang YL, Heinzelmann-Schwarz V, Schibli R, Béhé M, Grünberg J. L1 Cell Adhesion Molecule Confers Radioresistance to Ovarian Cancer and Defines a New Cancer Stem Cell Population. Cancers (Basel). 2020 Jan 15;12(1). pii: E217. doi: 10.3390/cancers12010217. (2020).

Le Page C, Rahimi K, Rodrigues M, Heinzelmann-Schwarz V, Recio N, Tommasi S, Bataillon G, Portelance L, Golmard L, Meunier L, Tonin PN, Gotlieb W, Yasmeen A, Ray-Coquard I, Labidi-Galy SI, Provencher D, Mes-Masson AM. Clinicopathological features of women with epithelial ovarian cancer and double heterozygosity for BRCA1 and BRCA2: A systematic review and case report analysis. Gynecol Oncol. 2019 Nov 18. pii: S0090-8258(19)31670-1. doi: 10.1016/j.ygyno.2019.11.019. (2019).

Labidi-Galy SI, de La Motte Rouge T, Derbel O, Wolfer A, Kalbacher E, Olivier T, Combes JD, Heimgartner-Hu K, Tredan O, Guevara H, Heudel PE, Reverdy T, Bazan F, Heinzelmann-Schwarz V, Fehr M, de Castelbajac V, Vaflard P, Crivelli L, Bonadona V, Viassolo V, Buisson A, Golmard L, Rodrigues M, Ray-Coquard I. Clinical factors associated with prolonged response and survival under olaparib as maintenance therapy in BRCA mutated ovarian cancers. Gynecol Oncol. 2019 Nov;155(2):262-269. doi: 10.1016/j.ygyno.2019.09.008. Epub 2019 Oct 8. (2019).

Claus C, Ferrara C, Xu W, Sam J, Lang S, Uhlenbrock F, Albrecht R, Herter S, Schlenker R, Hüsser T, Diggelmann S, Challier J, Mössner E, Hosse RJ, Hofer T, Brünker P, Joseph C, Benz J, Ringler P, Stahlberg H, Lauer M, Perro M, Chen S, Küttel C, Bhavani Mohan PL, Nicolini V, Birk MC, Ongaro A, Prince C, Gianotti R, Dugan G, Whitlow CT, Solingapuram Sai KK, Caudell DL, Burgos-Rodriguez AG, Cline JM, Hettich M, Ceppi M, Giusti AM, Crameri F, Driessen W, Morcos PN, Freimoser-Grundschober A, Levitsky V, Amann M, Grau-Richards S, von Hirschheydt T, Tournaviti S, Mølhøj M, Fauti T, Heinzelmann-Schwarz V, Teichgräber V, Colombetti S, Bacac M, Zippelius A, Klein C, Umaña P. Tumor-targeted 4-1BB agonists for combination with T cell bispecific antibodies as off-the-shelf therapy. Sci Transl Med. 2019 Jun 12;11(496). pii: eaav5989. (2019).

Szczerba BM, Castro-Giner F, Vetter M, Krol I, Gkountela S, Landin J, Scheidmann MC, Donato C, Scherrer R, Singer J, Beisel C, Kurzeder C, Heinzelmann-Schwarz V, Rochlitz C, Weber WP, Beerenwinkel N, Aceto N. Neutrophils escort circulating tumour cells to enable cell cycle progression. Nature. Feb;566(7745):553-557. doi: 10.1038/s41586-019-0915-y. Epub 2019 Feb 6. (2019).

Gkountela S, Castro-Giner F, Szczerba BM, Vetter M, Landin J, Scherrer R, Krol I, Scheidmann MC, Beisel C, Stirnimann CU, Kurzeder C, Heinzelmann-Schwarz V, Rochlitz C, Weber WP, Aceto N. Circulating Tumor Cell Clustering Shapes DNA Methylation to Enable Metastasis Seeding. Cell. Jan 10;176(1-2):98-112.e14. doi: 10.1016/j.cell.2018.11.046. (2019).

Montavon C, Stricker GR, Schoetzau A, Heinzelmann-Schwarz V, Jacob F, Fedier A. Outcome in serous ovarian cancer is not associated with LATS expression. J Cancer Res Clin Oncol. 2019 Oct 4. doi: 10.1007/s00432-019-03037-4. (2019).

Jacob F, Alam S, Konantz M, Liang CY, Kohler RS, Everest-Dass AV, Huang YL, Rimmer N, Fedier A, Schötzau A, Lopez MN, Packer NH, Lengerke C, Heinzelmann-Schwarz V. Transition of Mesenchymal and Epithelial Cancer Cells Depends on α1-4 Galactosyltransferase-Mediated Glycosphingolipids. Cancer Res 78:2952-2965. (2018).

Heinzelmann-Schwarz V, Knipprath Mészaros A, Stadlmann S, Jacob F, Schoetzau A, Russell K, Friedlander M, Singer G, Vetter M. Letrozole may be a valuable maintenance treatment in high-grade serous ovarian cancer patients. Gynecol Oncol 148:79-85. (2018).

Anugraham M, Jacob F, Everest-Dass AV, Schoetzau A, Nixdorf S, Hacker NF, Fink D, Heinzelmann-Schwarz V, Packer NH. Tissue glycomics distinguish tumour sites in women with advanced serous adenocarcinoma. Mol Oncol 11:1595-1615. (2017).

Alam S, Anugraham M, Huang YL, Kohler RS, Hettich T, Winkelbach K, Grether Y, López MN, Khasbiullina N, Bovin NV, Schlotterbeck G, Jacob F. Altered (neo-) lacto series glycolipid biosynthesis impairs α2-6 sialylation on N-glycoproteins in ovarian cancer cells. Sci Rep 7:45367. (2017).

Kohler RS, Kettelhack H, Knipprath-Meszaros A, Fedier A, Schoetzau A, Jacob F, Heinzelmann-Schwarz V. MELK expression in ovarian cancer correlates with poor outcome and its inhibition by OTSSP167 abrogates proliferation and viability of ovarian cancer cells. Gynecol Oncol 145:159-166. (2017).

Kohler RS, Anugraham M, López MN, Xiao C, Schoetzau A, Hettich T, Schlotterbeck G, Fedier A, Jacob F, Heinzelmann-Schwarz V. Epigenetic activation of MGAT3 and corresponding bisecting GlcNAc shortens the survival of cancer patients. Oncotarget 7:51674-51686. (2016).

Manegold-Brauer G, Buechel J, Knipprath-Mészaros A, Schoetzau A, Hacker NF, Tercanli S, Lapaire O, Heinzelmann-Schwarz V. Improved Detection Rate of Ovarian Cancer Using a 2-Step Triage Model of the Risk of Malignancy Index and Expert Sonography in an Outpatient Screening Setting. Int J Gynecol Cancer 26:1062-1069. (2016).

Henry C, Llamosas E, Knipprath-Meszaros A, Schoetzau A, Obermann E, Fuenfschilling M, Caduff R, Fink D, Hacker N, Ward R, Heinzelmann-Schwarz V, Ford C. Targeting the ROR1 and ROR2 receptors in epithelial ovarian cancer inhibits cell migration and invasion. Oncotarget 6:40310-40326. (2015).

Anugraham M, Everest-Dass AV, Jacob F, Packer NH. A platform for the structural characterization of glycans enzymatically released from glycosphingolipids extracted from tissue and cells. Rapid Commun Mass Spectrom 29:545-561. (2015).

 

A full list can be found on (https://www.ncbi.nlm.nih.gov/pubmed/?term=Heinzelmann-Schwarz+V

 

 

 

Selected Collaborations/Network

Interdisciplinary project to establish 3D-reconstructed functional omentum model to study omental metastasis of ovarian cancer and the underlying mechanisms (Uwe Pieles, FHNW Muttenz; Barbara Rothen-Rutishauser, Institute Adolphe Merkle, Fribourg; Ivan Martin, DBM, USB, Basel)

Interdisciplinary and interinstitutional project aimed at the molecular dissection of melanoma, ovarian cancer, and AML in order to genetically and molecularly dissect the tumors on single-cell level and to support clinicians in the best choice of therapy (ETH Zurich, Roche AG Schweiz)

Zebrafish embryo tumor xenografts (Claudia Lengerke, DBM, USB, Basel)

Investigation of OC metastasis in mouse models and design of radionuclid- and drug-coupled antibodies (Paul Scherrer Institute PSI; Jürgen Grünberg, Villingen, Switzerland)

Single Cell Technologies (Christian Beisel, ETH Basel), Franziska Singer (NEXUS))Analysis of glycosylated key cell surface proteins in metastasis (Daniel Kolarich, Arun Everest-Dass, Mark von Itzstein, Griffith University, Gold Coast, Australia) Role of mesothelin in ovarian cancer progression and metastasis (Leonor David, Porto, Portugal)

A feasibility study for investigating circulating tumor DNA (ctDNA) exposure in peripheral blood using a novel process (Quantgene Inc., Delaware Corporation, Berkeley, CA, USA)

Ovarian cancer stem cell markers and relation with histopathological parameters and patients’ prognosis (Ugo Cavallaro, Milan, Italy)

The biology of E-cadherin glycosylation (Henrik Clausen, Adnan Halim, University of Copenhagen, Copenhagen, Denmark)

Impact of integrin glycosylation in mouse metastatic xenograft models (Tobias Lange, University Medical Center Hamburg-Eppendorf, Hamburg, Germany)

Elucidiate molecular mechanisms of ascites development (Jan Hengstler, Leibniz Research Centre for Working Environment and Human Factors, Dortmund)

 

Specilities and Ressources

We have a large biobank with blood, tissue (frozen and embedded, TMA, ascites, urine samples, and primary tumor cells (frozen) from over 3’000 patients of 3 different locations (Sydney AUS, Zurich and Basel), including matched and longitudinal samples.

Our research laboratory has methodological expertise in molecular and translational cancer biology, glycobiology, and drug resistance; and employs modern lab technologies including CRISPR-Cas9-genome editing (silencing, activation, knock-out, knock-in, and library screens), fluorescence and live cell imaging, cultivation of primary cultures, zebrafish embryo tumor xenografts, and standard technologies such as fluorescence activated cell sorting.

 

Current Grants and Support

  • Swiss GO Trial Group (2019-2024; MATAO trial; MAintenance Therapy with Aromatase inhibitor in epithelial Ovarian cancer: a Randomized Double-blinded Placebo-controlled Phase III Trial)
  • MATAO trial; MAintenance Therapy with Aromatase inhibitor in epithelial Ovarian cancer: a Randomized Double-blinded Placebo-controlled Phase III Trial (supported by a.o. Helsana Krankenkasse; Krebsforschung Schweiz, Anticancer Fund/Reliable Cancer Therapies, Belgium/Switzerland; AGO Deutschland; Stiftung Fürstlicher Kommerzienrat Giudo Feger, Liechtenstein)
  • PHRT ETH Pioneer Project Grant (2020-2021; dissect longitudinal evolutionary trajectories in ovarian cancer patients using integrated proteogenomics)
  • FreeNovation Novartis (2020-2021; An approach towards single cell glycomics)
  • Swiss National Science Foundation SNF (Sinergia CRSII5_171037-1, 2018-2021; the underestimated role of the human omentum in metastatic spread)
  • Krebsforschung Schweiz (2017-2021; functional characterization of bisecting GlcNAc-dependent signalling pathways for the intervention of serous ovarian cancer omental metastasis)
  • Wilhelm Sander-Stiftung (2019-2020; Der Einfluss von Glykosphingolipiden auf molekulare und zelluläre Wirkmechanismen beim metastasierenden Ovarialkarzinom)

 

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