Osteoblasts remotely supply lung tumors with cancer-promoting SiglecFhigh neutrophils
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Osteoblasts remotely supply lung tumors with cancer-promoting SiglecFhigh neutrophils. Lung tumors disrupt bone homeostasis and increase osteoblast activity and bone formation. Osteoblasts amplify tumor-associated SiglecFhigh neutrophils that promote tumor growth through angiogenesis, immunosuppression and other mechanisms. Serum from tumor-bearing mice increases osteoblast activity through elevated sRAGE, which stimulates neutrophil maturation. SiglecFhigh neutrophils correlate with poor survival in lung cancer patients. Therefore, lung tumors communicate with bone through factors like sRAGE to modulate osteoblasts and promote neutrophil-driven tumor progression.
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Osteoblasts remotely supply lung tumors with cancer-promoting SiglecFhigh neutrophils
- 1. Center for Systems Biology, Massachusetts General Hospital Research Institute and Harvard Medical School, Boston, MA 02114, USA; Graduate Program in Immunology, Harvard Medical School, Boston, MA 02115, USA; Department of Systems Biology, Harvard Medical School, Boston, MA 02115, USA; Institute of Biotechnology, Vilnius University, Vilnius, LT 10257, Lithuania; Endocrine Unit, Massachusetts General Hospital, Harvard Medical School, Boston, MA 02114, USA; Department of Radiology, Massachusetts General Hospital, MA 02114, USA; Howard Hughes Medical Institute, Koch Institute for Integrative Cancer Research, Massachusetts Institute of Technology, Cambridge, MA 02139, USA; Center for Regenerative Medicine, Massachusetts General Hospital, Boston, MA 02114, USA; Swiss Institute for Experimental Cancer Research, School of Life Sciences, École Polytechnique Fédérale de Lausanne, 1015 Lausanne, Switzerland; Division of Immunology, Department of Microbiology and Immunobiology, Harvard Medical School, Boston, MA 02115, USA. Coach Professor: Dr. Chung-Yi Wu Course Coordinator: Dr. Charles P. Lai Sit-in Professor: Dr. Chi-Yu Fu Dated: 20181017 Presenter: Gul Muneer Science Dec 2017, 358(6367): eaal5081 DOI: 10.1126/science.aal5081 1 Osteoblasts Remotely Supply Lung Tumors With Cancer-promoting SiglecFhigh Neutrophils
- 2. Osteoblasts Remotely Supply Lung Tumors With Cancer-promoting SiglecFhigh Neutrophils Camilla Engblom, Christina Pfirschke, Rapolas Zilionis, Janaina Da Silva Martins, Stijn A. Bos, Gabriel Courties, Steffen Rickelt, Nicolas Severe, Ninib Baryawno, Julien Faget, Virginia Savova, David Zemmour, Jaclyn Kline, Marie Siwicki, Christopher Garris, Ferdinando Pucci, Hsin-Wei Liao, Yi-Jang Lin, Andita Newton, Omar K. Yaghi, Yoshiko Iwamoto, Benoit Tricot, Gregory R. Wojtkiewicz, Matthias Nahrendorf, Virna Cortez-Retamozo, Etienne Meylan, Richard O. Hynes, Marie Demay, Allon Klein, Miriam A. Bredella, David T. Scadden, Ralph Weissleder, Mikael J. Pittet 2
- 3. Bone SN Osteoblast Osteocyte Osteoclast Osteoblast Bone Remodeling Bone Formation Bone ResorptionBone Homeostasis Osteoblasts Osteoclasts Osteocalcin (Ocn) Bone Dynamics (Formation & Resorption) 3 Ocn is a marker for active bone formation. Bone is a dynamic tissue. Bone is constantly remodeled (formation & breakdown). G-CSF, TPO SDF-1, ANG-1 G-CSF: Granulocyte-colony stimulating factor TPO: Thrombopoietin ANG-1: Angiopoietin-1 SDF-1: Stromal Cell Derived Factor-1
- 4. 4 Bone Osteoblast Niche Progenitor cells Bone Marrow Vascular Niche (HSC Inactive State & Self renewal) Ang-1/Tie2, TPO/Mpl Bone and Hematopoietic Niche: A Tale of Stem Cell Bone-resident cells “also” regulate hematopoiesis & Immune cell fate. Niche: a physiological microenvironment in which Hematopoietic stem cells (HSC) reside Proliferation Differentiation G-CSF/R G-CSF/R H-Stem Cell Homing Migration SDF-1/CXCR4 Lymphocyte Granulocyte Erythrocyte
- 5. 5 Myeloid Cells in Tumor Stroma & Tumor Progression SiglecFlow Neutrophils Sialic acid-binding Immunoglobulin-type lectins Cell surface proteins Binds Sialic acid Present on Immune cells Involved in cell adhesion & cell signaling
- 6. ? ? ? ? ? ? ? Tumor-associated Hematopoietic Response? Tumor-associated Immune Response? Circulating Precursors? Remote effect of cancer? Tumor-infiltrating cells? Tumor-induced bone alterations? Remodeling of tumor shape? ? ? Aims and Motivations of the Study 6
- 7. Lung Tumors Modulate Bone Density Bisphosphonate (OsteoSense) On-going Bone formation Fluorescence Molecular Tomography After 4 hrs Before 24 hrs 7 KP or LLC Tumor bearing (or Tumor- free) Mice OsteoSense i.v. Lung-tumor disrupt bone stromal activity in the absence of local metastasis. ±Adenovirus-Cre 12-14 week KrasLSL-G12D/WT; p53flox/flox (KP) Mice
- 8. Lung Tumors Increases Bone Density Rotation Source Detector µ-Computed Tomography µ-CT of Bone microarchitecture Lung-tumor disrupt bone homeostatic activity & induce changes in bone. 8 3D reconstruction of µ-CT Scans of spongy bone volume BV/TV= Bone Vol./Total Vol. CT of 10th Thoracic Vertebra of 53-year old woman. HU= Hounsfield Units
- 9. Lung Tumors Increase Osteoblasts Number Cuboidal Shape Osteoblast Goldner’s Trichrome Staining of femur (thigh bone) Osteoid (gelatinous matrix) Characteristics of elevated osteoblast activity 9 Histological analysis identified more osteoblasts in KP tumor-bearing mice Green - Mineralized Bone Blue - Nuclei Pink - Osteoid
- 10. Von Kossa Staining of femur (Bone mineralization) Dynamic bone formation (histomorphometry) Bone Histomorphometriy: Kinetic Data on Bone Turnover Tumor bearing mice showed elevated mineralization and bone formation. ± Tumor-bearing mice Calcein (i.v.) 7days Demeclocycline (i.v.) 2days Imaging Analyzing System 10 Black - Calcium deposits Pink - Nuclei
- 11. STOP DTR iDTR Ocn⁺ Cells Specific Cre Ocn⁺ Cells Specific Cre;Dtr Dtr⁺ cells DTR Cre Dtr⁺ cells death DT Injection DTR DT 11 Ocn+ Osteoblasts Regulate Lung Cancer Growth Ocn+ cells foster lung tumor growth. Dtr⁺ Ocn⁺ cells
- 12. 12 Ocn+ Osteoblasts Supply Tumor-infiltrating Neutrophils Ocn+ cells are required for Amplification of Tumor-associated neutrophils
- 13. OcnCre;Dtr KP tumor-bearing Mice OcnCre;Dtr Parabiont Control Parabiont 13 Tumor-infiltrating Cells Display Tumor-promoting Functions Ocn+ cells contribute tumor-infiltrating neutrophils. Tumor-infiltrating neutrophils display tumor promoting functions.
- 14. 14 Ocn+ Cell-driven Neutrophils Ocn+ cells-driven neutrophils show discrete phenotypes & localize proximal to tumor cells Neutrophils are heterogenous - Molecular Changes - functional Changes
- 15. 15 Role of Osteoblasts in Contribution of SiglecFhigh Lung Neutrophils KP Tumor accumulation of SiglecFhigh neutrophils depends on Ocn+ cells Transfer CD45.1+ Lin-c-Kit+ hematopoietic cells in CD45.2+ host 6days Analysis: CD45.1+ Progeny
- 16. Differential Gene Expression SiglecFhigh neutrophils reveals cancer-promoting phenotypes: Angiogenesis, myeloid cell recruitment, tumor proliferation cytotoxicity, extracellular matrix remodeling and immunosuppression SiglecFhigh Neutrophils Show Tumor-promoting Phenotypes 16
- 17. SiglecFhigh neutrophils reveals cancer-promoting functions: ↑ ROS & ↑ F4/80-expressing cells (Macrophage) Tumor-bearing mice Splenic Monocytes and Myeloid precursors T-SiglecFhigh; T-SiglecFlow H-SiglecFlow; CSF-1 Flow Cytometry SiglecFhigh Neutrophils Show Tumor-promoting Functions 17 Ability of Neutrophils to support tumor promoting myeloid cells
- 18. Survival plots of lung adenocarcinoma patients SiglecFhigh Neutrophils are “Not Neutral” SiglecFhigh neutrophils are tumor-promoting cells: Polarizing towards cancer progression 18
- 19. OR Quantification of Osteoblastic Colonies Tumor-free (TF) KP tumor- bearing (TB) Serum Factor Contributes to Osteoblast-induced Neutrophils Response Serum 19 Serum components (from tumor-bearing mice) promote osteoblast cells. Bone marrow cells ALP: Alkaline Phosphatase
- 20. OR Tumor-free (TF) KP tumor- bearing (TB) Serum Compare Protein content (111 candidates) sRAGE upregulated in the serum of tumor bearing mice Protein content in blood of tumor- bearing mice by protein arrays 20 sRAGE was upregulated 2fold in the blood of tumor bearing mice. sRAGE: soluble Receptor for Advance Glycation End products Member of Immunoglobulin superfamily Binds Glycoproteins, Glycolipids & Glycans C C V RAGE binds to ligands to trigger pro- inflammatory cascade sRAGE: “Decoy Receptor” Binds RAGE ligands & inhibit signal through the receptor.
- 21. Quantification of Osteoblastic Colonies Tumor-free Serum ± sRAGE Bone marrow cells Role of RAGE in Osteoblastic Activity. 21 sRAGE elevated Osteoblasts activity.
- 22. Neutrophil maturation (CXCR2 up-regulation) Tumor-free Serum ± sRAGE Hematopoietic stem & progenitor cells (HSPCs) ± stromal cells sRAGE increases CXCR2 expression in developing neutrophils 22 sRAGE increased CXCR2 expression CXCR2 increased in the presence of Bone marrow Stromal Cells Tumor-associated factors can stimulate osteoblastic cells & regulate immune responses. gMFI: geometric mean fluorescence intensi Chemokine Receptor-2 (CXCR2) is required for neutrophil maturation and release into blood stream.
- 23. Amplification of tumor- associated neutrophils Tumor-supportive cells SiglecFhigh Neutrophil sRAGE SiglecFhigh Neutrophils Activated Ocn+ cells & ↑ activity Angiogenesis, ECM remodeling Immunosuppression, cytotoxicity, Tumor proliferation Conclusion: A Long-Distance Relay-tionship (LDRt) between Tumor and Bone Lung tumors “talk” to bone-resident cells to order for “not neutral” neutrophils to foster tumor growth23
- 24. Discussion & Future Perspective Limited components (111 factors) were analyzed to investigate the role of tumor in communication with bone cells. sRAGE-activated osteoblasts might also directly affect downstream myeloid progenitors. (why only neutrophils? There could be other components released by “tumor cells” to communicate with bone-residents cells. Elevated sRAGE in plasma is also associated with coronary artery disease, hypertension, the metabolic syndrome, arthritis and Alzheimer's disease. Neutrophils phenotypes could be analyzed in sRAGE associated diseases and cancer to understand the “connection” or rely-tionship. tEVs could be analyzed to delineate “communication mechanism” 24
- 25. Thank you very much For Your Patience! 25