Klaus Pantel. Institut für Tumorbiologie. Tumor cell dissemination, cancer dormancy, circulating tumor cells and metastasis
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1 Klaus Pantel Institut für Tumorbiologie Tumor cell dissemination, cancer dormancy, circulating tumor cells and metastasis
2 Tumor cell dissemination and cancer dormancy Cancer cells disseminate early into the bone marrow and pose a risk for subsequent relapse (Braun/Pantel et al., NEJM, 2005; Köllermann/Pantel et al., J Clin Oncol., 2008) VCAM1, Jagged-1 and tumor-induced osteoclast mirnas as regulators of progression from DTCs to bone metastases (Lu/Pantel/Kang et al Cancer Cell 2011; Ell/Pantel/Kang et al, Cancer Cell 2013; Bednarz- Knoll, Kang Pantel et al, Clin Chem 2016) Metabolic adaptation of DTCs is important for survival (LeBleu, Pantel, Kalluri et al, Nature Cell Biol. 2014) RAI2 as new metastasis-suppressor (Werner, Wikman, Wilmanns, Pantel et al, Cancer Discovery 2015) DTCs persist in the bone marrow through sustained activation of the unfolded protein response (Bartkowiak, Pantel et al., Cancer Res. 2015) Exosome-mediated homing of metastatic cells to specific distant sites (Hoshino, Pantel, Bissell, Peinado, Lyden et al., Nature, 2015) Blood Distant tissue (e.g. bone marrow) Primary tumor Recirculation Tumormass dormancy Micrometastasis Metastasis DTCs Escape Local relapse CTCs DTC Tumor cell dormancy NATURE REVIEWS CLINICAL ONCOLOGY VOLUME 6 JUNE
3 DTC in bone marrow of cancer patients Bone marrow aspirates taken from the upper iliac crest Bone marrow Ficoll gradient MNC Breast Cancer: 199/552 (36%) (Braun, Pantel et al. NEJM, 2000 & 2005) Prostate Cancer: 86/193 (44.6%) (Koellermann/Pantel et al. JCO 2008) Nonmalignant disease: 2/191 (1%) DTC detection correlates with metastatic AND locoregional relapse Most DTC are Ki67- and have CD44+/CD24- stem cell phenotype DTCs can occupy the hematopoietic stem cell niches Immunocytochemistry: Cytokeratin staining with mab A45-B/B3 2 x 10 6 MNC per patient
4 BM is a homing organ and putative reservoir for DTC derived from various primary sites Tumor type Detection rate (%) Breast Cancer Prostate cancer* Lung cancer (NSCLC) Gastric cancer Esophageal cancer Colorectal cancer Pancreatic cancer Head and neck cancer
5 Identification of DTC-associated genes Luminal A/B, HR+ BM- Luminal A/B, HR+ BM+ Classification of early stage breast tumors according to DTC status vs. Expression profiling on micro-dissected tumor tissue RAI2 Bioinformatic analysis and validation of identified genes Werner, Wikman, Pantel et al, Cancer Discovery, 2015
6 Editorial: Esposito & Kang, Cancer Discovery, 2015 RAI2 All-trans retinoic acid CTBP2 RAI2 as potential new metastasis-suppressor gene RAI2 loss S GATA3 FOXOA1 GRHL2 CTBP2 GATA3 FOXOA1 GRHL2 Vimentin ZEB1 SNAI1 SNAI2 CDH1 Hematogenous dissemination Werner, Wikman, Pantel et al, Cancer Discovery, 2015
7 Tumor cell dissemination and tumor cell plasticity Bednarz-Knoll, Alix-Panabières & Pantel Cancer & Met Rev 2012
8 Is hematogeneous dissemination of cancer cells an early event in tumor progression?
9 Detection of DTC in bone marrow of patients with ductal carcinoma in situ (DCIS) In 7/30 (23.3%) patients with pure DCIS and in 5/12 (41.7%) patients with DCIS plus microinvasion of the basement membrane DTC were detected (Sänger/Effenberger/Pantel et al., IJC 2011) BUT: Distant metastases are rare (3 %) -> Dormancy
10 Cancer Dormancy: Research questions Do all cancer patients have dormant tumor cells? Can host factors induce or break dormancy? Stress? Inflammation? Are there preferred reservoirs of dormant cells (e.g., bone marrow)? Does the immune system play a role in dormancy? What is the effect of current therapies on dormant cells or dormancy? What signaling pathways or events reactivate dormant cells? Do dormant cells have properties of cancer stem cells? How does genetic background affect dormancy? Kang & Pantel, Cancer Cell 2013
11 Immune escape mechanisms of CTCs in the peripheral blood Mohme, Riethdorf & Pantel, Nature Rev Clin Oncol 2016
12 Detection of CTC in the peripheral blood Advantages over DTC detection: Less invasive than BM sampling Pool of DTC from multiple distant sites
13 2010
14 Circulating tumor markers as liquid biopsy European Liquid Biopsy Academy: EU Marie Curie Network Simon Joosse Joosse & Pantel (2015) Cancer Cell
15 Aims of Liquid Biopsy Screening & early detection of cancer Estimation of the risk for metastatic relapse or metastatic progression (prognostic information) Stratification & real-time monitoring of therapies Identification of therapeutic targets and resistance mechanisms (biological therapies) Understanding the biology of metastatic development
16 CTC as Liquid Biopsy for metastatic cells Metastasis evolve many years after primary tumor resection and can harbor unique genomic alterations. Biopsy of metastases is an invasive and sometimes dangerous procedure. Intra-patient heterogeneity of metastases at different sites CTC/ctDNA might reveal representative information on metastatic cells located at different sites Alix-Panabières & Pantel, Clin Chem, 2013; Pantel & Alix- Panabieres, Cancer Res. 2013
17 Biological properties Protein expression Positive Selection (a) anti-e markers Ab (E.g., EpCAM) CTC anti-e/m markers Ab (E.g., Plastin 3) Ex vivo anti-m markers Ab (E.g., N-Cadherin) CTC (c) - CellSearch system - MagSweeper - EPHESIA CTC-chip - CTC-chip - Velcro-like device In vivo - CellCollector - Photoacoustic nanodetector Physical properties Label-free strategies (d) (e) (f) DEP DEP CTC-iChip (g) Out Anti-CD45 Negative Selection (b) Anti-CD45 CTCs anti-e markers Ab WBC Alix-Panabieres & Pantel, Nature Rev. Cancer 2014 CTC WBC RBC
18 New approach: In vivo capture of CTC Proof of principle data in breast, prostate, colon and lung cancer
19 Approaches for CTC detection Immunocytological technologies Molecular technologies Functional assays In vitro Cell Culture anti-e/m markers Ab (E.g., CK, Vimentin, E/N-Cadherin) - EPISPOT anti-marker Abs (E.g., CK19, HER2, EGFR, VEGF, PSA) CTC anti-tumor associated markers Ab (E.g., HER2, EGFR) anti-tissue-specific markers Ab (E.g., PSA, Mammaglobin, MAGE) CTC mrna RT-qPCR (single/multiple genes) Liquid bead array Viable CTC Cell culture - Invasion assay Fluo Ab2 Ab1 Secreted protein Immunospots Technologies Functional CTC - Immunocytochemistry - CellSearch system - Flow Cytometry - DEParray RNA-based Technologies Fluo matrix Xenotransplantation models (CDx) Alix-Panabieres & Pantel, Nature Rev. Cancer 2014 Viable CTC with stem-cell properties days Metastase s
20 Epithelial-Mesenchymal Plasticity of CTCs Intermediate E/M Phenotypes: Potential MICs! EpCAM, CK Vimentin Bednarz-Knoll, Alix-Panabières & Pantel Cancer & Met Rev 2012
21 CTCs in early stage cancer patients: Detection of MRD for risk assessment and improved staging
22 CellSearch System (FDA-cleared) MagNest TM 7.5ml Epithelial Cell Kit Enrichment of CTC with anti-epcam ferro fluids: Captures tumor cells with very low EpCAM expression
23 CellSearch System: Images of Tumor Cells Cytoplasm Nucleus Cell Membrane Composite CK-PE pos DAPI pos CD45-APC neg Tumor Cell + - = Leukocyte nucleus CD45 + Membrane Leukocyte Tumor Cell
24 Prognostic impact of EpCAM+/CK+ CTC in breast cancer patients (n > 2000) without overt metastases 2016 Rack, Janni, Pantel > et 3000 al, JNCI Patients 2014
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26 Mechanisms of intravascular tumor cell survival
27 TNM 2010: CTC in new cm0(i+) Classification
28 CTCs in brain cancer patients: Challenge the paradigm that brain tumors do not disseminate via the blood
29 Hematogeneous spread of primary brain tumors: Detection of CTCs in glioma patients (~20%) GFAP stain EGFR amplification Single Cell isolation Single Cell CGH Müller, Westphal, Pantel et al., Science TM, 2014
30 Monitoring of CTCs: Can early changes in CTC counts predict the efficacy of therapeutic interventions (e.g., chemotherapy, hormonal therapy)?
31 centres provided data for 1944 eligible patients from 20 studies Meta-analysis on raw data.
32 CTCs vs. conventional tumor markers (PFS, p values) in metastatic breast cancer patients receiving chemotherapy CTCBL ( baseline 3-5 weeks 6-8 weeks Model used as reference CA15-3BL CEABL CTC3-5 CA15-3 BL + CA CEABL + CEA 3-5 CTC6-8 CA15-3 BL + CA CEABL + CEA 6-8 N patients CP 6 E CP +CTCBL CP +CTCBL + CTC3-5 CP +CTCBL + CTC E E Few events Few events Bidard, Pierga, Michels, Pantel et al, Lancet Oncology 2014, European Pooled Analysis of CTCs in metastatic BC (n=1944)
33 Characterization of CTCs at the DNA, RNA and protein level: - Therapeutic targets - Resistance mechanisms
34 Liquid Biopsy for metastatic patients Metastasis evolve many years after primary tumor resection and can harbor unique genomic alterations. Biopsy of metastases is an invasive and sometimes dangerous procedure. Intra-patient heterogeneity of metastases at different sites CTC/ctDNA might reveal representative information on metastatic cells located at different sites Alix-Panabières & Pantel, Clin Chem, 2013; Pantel & Alix- Panabieres, Cancer Res. 2013
35 Heterogeneity of ER status in CTCs of breast cancer patients with ER-positive primary tumors Babayan, Joosse, Pantel et al., PLOS ONE 2013 ER CK DAPI CD45 Merge E R + E R - ER-negative CTCs may survive endocrine therapy
36 Genomic Characterization of single CTC CTC detection CTC isolation WGA + - Mutation analysis - CGH (conv./array) - NextGen Sequencing CTC Capillary CTC
37 Functional studies on CTCs
38 DTC cell lines as models for functional analyses DTC adapt to hypoxic conditions in bone marrow. Unfolded protein response Stem cell markers Bartkowiak et al., J Prot Res 2010 & Cancer Res Grabinski/Jücker et al., Cell Signal. 2011
39 Aquisition of CTC-derived cell lines or CDX models from cancer patients is challenging
40 Cell-free ctdna/mirna and exosomes as Blood-Based Biomarkers Schwarzenbach, Pantel et al., Nature Rev. Cancer 2011; Nature Rev. Clin. Oncol. 2014; Pantel et al., Nature Med. 2013; Speicher & Pantel, Nature Biotech. 2014; Joosse & Pantel, Cancer Cell, 2015; Alix-Panabieres & Pantel, Cancer Discovery, 2016 Cancer-ID is a project funded by the Innovative Medicines Initiative Joint Undertaking (IMI JU).
41 CANCER-ID EU Konsortium Scientific Managment: Klaus Pantel, UKE (Leon Terstappen) Coordination: Thomas Schlange, BAYER (Barbara Baggiani) 32 partners: Clinical EFPIA sites 6 EFPIA companies (lead Bayer, colead Menarini) 17 academic/clinical sites 6 SMEs 2 non-profit organizations Academic 1 non-sme/non-efpia institutions Prof. Klaus Pantel Blood-based Diagnostic in Lung and Breast Cancer (CTCs, ctdna & cfmirna) 37 EU Partners (Academic institutions, SMEs non-profit organisations & companies) Prof. Leon Terstappen Non-profit organizations Non-EFPIA/ non-sme Page 41 CANCER-ID evaluation hearing Brussels- Oct 7th 2014
42 Exosomes: Biogenesis, release, structure and uptake Current challenge: Detection of tumor-derived exosomes Hoshino, Pantel, Lyden et al. Nature 2015: Exosomes guide organ-specific metastasis Meng, Pantel, Schwarzenbach et al., Oncotarget 2016: Exosomes in early detection of ovarian cancer
43 2016 CTCs, ctdna and exosomes provide complementary information for liquid biopsy
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46 Micrometastasis Research Network at UCCH/UKE Institut für Klinische Chemie Institut für Anatomie II Klinik und Poliklinik für Gynäkologie Klinik und Poliklinik für Viszeralchirurgie I. Medizinische Klinik und Poliklinik Institut für Rechtsmedizin Institut für Tumorbiologie Klinik und Poliklinik für Neurochirurgie Labor für Strahlenbiologie und -onkologie Institut für Biochemie und Molekularbiologie II. Medizinische Klinik und Poliklinik Klinik und Poliklinik für Urologie/Martiniklinik Klinik und Poliklinik für Mund-, Kiefer- und Gesichtschirurgie
47 Center of Experimental Medicine Institute of Tumor Biology - Klaus Pantel ERC Advanced Investigator Grant DISSECT Grant Support: DFG Sabine Riethdorf, Sonja Mader BMBF ERC PoC Grant CTCapture Tobias Gorges, Andra Kuske, Claudia Hille EU / ERC Heidi Schwarzenbach, Volker Assmann Dt. Krebshilfe Harriet Wikman, Stefan Werner, Annkathrin Hanssen Sander-Stiftung Simon Joosse, Anna Babayan Roggenbuck-Stiftung Kai Bartkowiak, Natalia Bednarz-Koll
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