Respiratory System

We are investigating how FGF, Wnt, and BMP signaling pathways interact to regulate growth of the lung and the complex process of branching morphogenesis. We are investigating mechanisms by which micro RNAs and other epigenetic factors regulateFgf9 expression during development and in the pathogenesis of Pleuropulmonary Blastoma, a familial pediatric lung cancer syndrome that is initiated by mutations inDICER1. We are investigating mechanisms by which FGFs are protective in lung epithelial repair and pathogenic in pulmonary fibrosis, and we are investigating mechanisms by which FGF signaling activates adult lung progenitor cells in models of adenocarcinoma and response to injury.

Lung Biology Publications:

  1. Woo KV, Ornitz DM, Singh GK. Diagnosis and Pathophysiological Mechanisms of Group 3 Hypoxia-Induced Pulmonary Hypertension. Current treatment options in cardiovascular medicine. 2019;21(3):16 PubMed: PMID30903302.
  2. Hegab AE, Ozaki M, Kameyama N, Gao J, Kagawa S, Yasuda H, Soejima K, Yin Y, Guzy RD, Nakamura Y, Ornitz DM, Betsuyaku T. Effect of FGF/FGFR pathway blocking on lung adenocarcinoma and its cancer-associated fibroblasts. J Pathol. 2019, 10.1002/path.5290 PubMed: PMID31090071.
  3. Hagan AS, Boylan M, Smith C, Perez-Santamarina E, Kowalska K, Hung IH, Lewis RM, Hajihosseini MK, Lewandoski M, Ornitz DM. Generation and validation of novel conditional flox and inducible Cre alleles targeting fibroblast growth factor 18 (Fgf18). Dev Dyn. 2019;in press PubMed: PMID31290205.
  4. Koo HY, El-Baz LMF, House SL, Cilvik SN, Dorry SJ, Shoukry NM, Salem ML, Hafez HS, Dulin NO, Ornitz DM, Guzy RD. Fibroblast growth factor 2 decreases bleomycin-induced pulmonary fibrosis and inhibits fibroblast collagen production and myofibroblast differentiation. J Pathol. 2018, 10.1002/path.5106 PubMed: PMID29873400.
  5. Hegab AE, Ozaki M, Kagawa S, Hamamoto J, Yasuda H, Naoki K, Soejima K, Yin Y, Kinoshita T, Yaguchi T, Kawakami Y, Ornitz DM, Betsuyaku T. Tumor associated macrophages support the growth of FGF9-induced lung adenocarcinoma by multiple mechanisms. Lung Cancer. 2018;119:25-35 PubMed: PMID29656749.
  6. Guzy RD, Li L, Smith C, Dorry SJ, Koo HY, Chen L, Ornitz DM. Pulmonary fibrosis requires cell-autonomous mesenchymal fibroblast growth factor (FGF) signaling. J Biol Chem. 2017;292(25):10364-78 PMCID: PMC5481550.
  7. Yin Y, Ren X, Smith C, Guo Q, Malabunga M, Guernah I, Zhang Y, Shen J, Sun H, Chehab N, Loizos N, Ludwig DL, Ornitz DM. Inhibition of fibroblast growth factor receptor 3-dependent lung adenocarcinoma with a human monoclonal antibody. Dis Model Mech. 2016;9(5):563-71 PMCID: PMC4892666.
  8. Hegab AE, Kameyama N, Kuroda A, Kagawa S, Yin Y, Ornitz D, Betsuyaku T. Using Micro-computed Tomography for the Assessment of Tumor Development and Follow-up of Response to Treatment in a Mouse Model of Lung Cancer. J Vis Exp. 2016, 10.3791/53904(111) PubMed: PMID27286135.
  9. Yin Y, Castro AM, Hoekstra M, Yan TJ, Kanakamedala AC, Dehner LP, Hill DA, Ornitz DM. Fibroblast Growth Factor 9 Regulation by MicroRNAs Controls Lung Development and Links DICER1 Loss to the Pathogenesis of Pleuropulmonary Blastoma. PLoS Genet. 2015;11(5):e1005242 PMCID: PMC4433140.
  10. Guzy RD, Stoilov I, Elton TJ, Mecham RP, Ornitz DM. Fibroblast growth factor 2 is required for epithelial recovery, but not for pulmonary fibrosis, in response to bleomycin. Am J Respir Cell Mol Biol. 2015;52(1):116-28 PMCID: PMC4370255.
  11. Arai D, Hegab AE, Soejima K, Kuroda A, Ishioka K, Yasuda H, Naoki K, Kagawa S, Hamamoto J, Yin Y, Ornitz DM, Betsuyaku T. Characterization of the cell of origin and propagation potential of the fibroblast growth factor 9-induced mouse model of lung adenocarcinoma. J Pathol. 2015;235(4):593-605 PMCID: PMC4329097.
  12. Oladipupo SS, Smith C, Santeford A, Park C, Sene A, Wiley LA, Osei-Owusu P, Hsu J, Zapata N, Liu F, Nakamura R, Lavine KJ, Blumer KJ, Choi K, Apte RS, Ornitz DM. Endothelial cell FGF signaling is required for injury response but not for vascular homeostasis. Proc Natl Acad Sci U S A. 2014;111(37):13379-84 PMCID: PMC4169958.
  13. Yin Y, Betsuyaku T, Garbow JR, Miao J, Govindan R, Ornitz DM. Rapid induction of lung adenocarcinoma by fibroblast growth factor 9 signaling through FGF receptor 3. Cancer Res. 2013;73(18):5730-41 PMCID: PMC3778117.
  14. Ornitz DM, Yin Y. Signaling networks regulating development of the lower respiratory tract. Cold Spring Harb Perspect Biol. 2012;4(5):1-19 PMCID: PMC3331697.
  15. Govindan R, Ding L, Griffith M, Subramanian J, Dees ND, Kanchi KL, Maher CA, Fulton R, Fulton L, Wallis J, Chen K, Walker J, McDonald S, Bose R, Ornitz D, Xiong D, You M, Dooling DJ, Watson M, Mardis ER, Wilson RK. Genomic landscape of non-small cell lung cancer in smokers and never-smokers. Cell. 2012;150(6):1121-34 PMCID: PMC3656590.
  16. Huh SH, Ornitz DM. Beta-catenin deficiency causes DiGeorge syndrome-like phenotypes through regulation of Tbx1. Development. 2010;137(7):1137-47 PMCID: PMC2835329.
  17. Yin Y, White AC, Huh SH, Hilton MJ, Kanazawa H, Long F, Ornitz DM. An FGF-WNT gene regulatory network controls lung mesenchyme development. Dev Biol. 2008;319(2):426-36 PMCID: PMC2757945.
  18. White AC, Lavine KJ, Ornitz DM. FGF9 and SHH regulate mesenchymal Vegfa expression and development of the pulmonary capillary network. Development. 2007;134(20):3743-52 PMCID: PMC2099314.
  19. White AC, Xu J, Yin Y, Smith C, Schmid G, Ornitz DM. FGF9 and SHH signaling coordinate lung growth and development through regulation of distinct mesenchymal domains. Development. 2006;133(8):1507-17 PubMed: PMID16540513.
  20. Colvin JS, White A, Pratt SJ, Ornitz DM. Lung hypoplasia and neonatal death in Fgf9-null mice identify this gene as an essential regulator of lung mesenchyme. Development. 2001;128:2095-106.
  21. Colvin JS, Feldman B, Nadeau JH, Goldfarb M, Ornitz DM. Genomic organization and embryonic expression of the mouse fibroblast growth factor 9 gene. Dev Dyn. 1999;216(1):72-88 PMCID: PMID: 10474167.