Herman Yeger

Herman Yeger, PhD,  is a Senior Scientist in the Research Institute, Program in Developmental & Stem Cell Biology, laboratory scientist in the Division of Pathology, and Professor, Dept of Laboratory Medicine & Pathobiology, University of Toronto. H. Yeger carries out independent research on pediatric and adult cancers, pediatric lung development, the pulmonary neuroendcorine cell system, and related diseases, including CF and neuroendocrine relevant pulmonary cancer. He is working collaboratively with clincians and scientist at SickKids to establish a focus in regenerative medicine and tissue engineering of pediatric tissues/organs for treatment of pediatric syndromes. In his efforts Dr Yeger fosters basic and translational research with relevance to the pathobiology of disease through collaborations and in the training of graduate students and fellows.

Dr Yeger is active in teaching activities in the Department Laboratory Medicine and Pathobiology, University of Toronto, at the graduate and undergraduate levels. He also holds a cross-appointment in the Institute of Medical Science and supervises trainees in this program. He serves on several committees concerned with academic appointments and promotions, and recognition of teaching excellence.             

Research Synopsis

The following research descriptions pertain to recent work in the laboratory with substantial potential for discovery of new modalities for the modeling and treatment of cancers.  

1. The pulmonary neuroendocrine cancers: Current understanding of the role of oxygen in the progression of cancers has indicated that solid tumors contain zones of hypoxia reflecting the degree of vascularization. Here extreme hypoxia (<2% O2) upregulates the O2 sensing HIF mediated pathway to engage a large transcriptional program, for example, critical for angiogenesis. However, all tissues respire. Much less is known about how tumor cells can respond to transitions from acute to sustained (chronic) levels of pO2 and pCO2 (carbon dioxide sensing) similar to those experienced by normal tissues. The pulmonary neuroendocrine tumors (NETs), carcinoids and small cell lung carcinoma (SCLC) are remarkable in recapitulating the plasma membrane localized O2 sensing complex found in their cell of origin, the pulmonary neuroendocrine cells (PNEC). These function as polymodal airway sensors, detecting changes in O2/CO2/H+ via O2/CO2 sensor complexes.  NETs resemble native PNEC in possessing a membrane delimited O2 sensor mechanism (NADPH oxidase/NOX2 sensitive K+ channel molecular complex) and the CO2/H+ (pH) sensor mechanism (via carbonic anhydrase (CA)).  Stimulus-secretion coupling links O2/CO2/H+ sensors to release of amine (serotonin, 5-HT) by NET cells, acting as an autocrine growth factor for NET. Our preliminary studies using SCLC and carcinoid cell line models show that O2/CO2/H+ sensors in NET cells are activated at mild to moderate levels of these stimuli causing secretion of bioactive 5-HT. We have evidence that the HIF pathway integrates with the sensor pathway. Manipulating O2 levels, and altering CO2 metabolism by downregulating CAs, pharmacologically and by shRNA, dramatically affects endocrine functions and tumor cell proliferation and survival, both in vitro and in informative xenograft models. 

Our studies will  exploit the O2/CO2 cell sensor mechanisms to understand how these drive tumor growth and survival. We posit that O2/CO2/H+sensors enhance the ability of NET to: i) adapt to hypoxia/ elevated CO2 (hypercapnia) /acidosis, and ii) preferentially select for hypoxia/acidosis-resistant tumor cells. Thus understanding the biology of NET will provide new insights into how cancer cells sense and respond to fluctuating O2/CO2 microenvironments found in all cancers.

2. Modeling and novel therapeutic approaches for pediatric cancer: Here we  focus on modeling in vivo the tumor biology of neuroblastoma (NB) with emphasis on metastatic progression and targeting by novel therapeutics. Despite previous work using the immunocompromised mouse to model NB progression, it would be of great advantage to both more closely approximate tumor masses and metastatic sites found in patients. This is made feasible by recapitulating NB tumor growth and metastaic patterns in the nude rat. The larger nude rat model affords non-invasive MR imaging with higher resolution and better interpretation. We have been working with co-applicant Dr H-L Cheng at SickKids to model human tumor growth and metastasis in the nude rat model including interrogation of vascularization patterns, temporally and spatially using selected contrast agents. In addition, aggressive tumor cells can be sensitively imaged by MRI. Thus we propose to demosntrate the advantages of non-invasive and continuous monitoring of tumor parameters by MRI that will help to enhance NB studies at SickKids. In addition, and importantly, we will xenograft patient direct tumor tissue representing pre- and post treatment relapse will be evaluated. These cases of comparable advanced stage NB harbor the full spectrum in cellular heterogeneity of metastatic subpopulations that reside within tumors and can be further identified and selected for the study. We will select current NB tumor stem cell markers and in vitro enhancement methods, established in our laboratory, to identify selected cancer stem cell(CSC) - like fractions. The CSC subpopulations are associated with the metastatic potential and intrinsic resistance to chemotherapies and this approach will provide us with a stringent model to validate new therapeutic approaches that can reduce or eliminate this subpopulation associated clinically with minimal residual disease (MRD) and relapse.

Finally, in all our xenograft work modeling different cancers in immunocompromised animals we are now expoiting the increased versatility and monitoring potential of MRI [collaboration with Dr H-L cheng at HSC]. This non-invasive imaging tool permits tracking of tumor progression events temporally and spatially without moleculary disturbing tumor cells and concomitantly examing the vascularization of the tumor masses, a critical prognostic component.

Recent Publications

Ganesh T, Mokhtari RB, Alhamami M, Yeger H, Cheng HL. “Manganese-enhanced MRI of minimally gadolinium-enhancing breast tumors,” Journal of Magnetic Resonance Imaging 2014 Mar 4 (Epub ahead of print).

Islam SS, Mokhtari RB, El Hout T, Azadi MA, Alauddin M, Yeger H, Farhat WA. TGFb1 induces EMT programming of porcine bladder urothelial cells into collagen producing fibroblasts-like cells in a Smad2/Smad3-dependent manner. J Cell Commun signal 2013 Dec12 [epub ]

Cao H, Machuca TN, Yeung JC, Du K, Duan C, Hashimoto K, Linacre V, Coates AL, Leung K, Wang J, Yeger H, Cutz E, Liu M, Keshavjee S, Hu H. Efficient delivery to pig airway and submucosal glands using helper-dependent adenoviral vectors. Mol Ther Nucleic Acids 2:e127, 2013.

Mokhtari RB, Kumar S, Islam IS, Yazdanpanah M, Adeli K, Cutz E, Yeger  H. Combination of carbonic anhydrase inhibitor, acetazolamide, and sulforaphane, reduces the viability and growth of bronchial carcinoid cell lines. BMC Cancer 13:378, 2013.

Kumar S, Mokhtari RB, Oliveira ID, Islam S, Toledo SR, Yeger H, Baruchel S.  Tumor dynamics in response to antiangiogenic therapy with oral metronomic topotecan and pazopanib in neuroblastoma xenografts. Transl Oncol 6:493-503, 2013.

Islam SS, Mokhtari RB, Kumar S, Maalouf J, Arab S, Yeger H, Farhat WA. Spatio-temporal distribution of Smads and role of Smads/TGF-β/BMP-4 in the regulation of mouse bladder organogenesis. PLoS One 8:e61340, 2013.

Das B, Kashino SS, Pulu I, Kalita D, Swami V, Yeger H, Felsher DW, Campos-Neto A. CD271+ bone marrow mesenschymal stem cells may provide a niche for dormant Mycobacterium tuberculosis. Sci Transl Med. 2013 Jan 30; 5(170):170ra13.

Pan J, Yeger H, Ratcliffe P, Bishop T, Cutz E. Hyperplasia of pulmonary neuroepithelial bodies (NEB) in lungs of prolyl hydroxylase -1(PHD-1) deficient mice. Adv Exp Biol Med 758:149-55, 2012.

Cutz E, Pan J, Yeger H, Domnik MJ, Fisher JT. Recent advances and contraversies on the role of pulmonary neuroepithelial bodies as airway sensors. Seminar Cell Dev Biol 21:1084-95,2012.

Kumar, S, Mokhtari RB, Yeger H, Baruchel S. Preclinical models for pediatric solid tumor drug discovery: current trends, challenges and the scopes for improvement. Expert Opin Drug Discov 7:1093-106 2012.

Buttigieg J, Pan J, Yeger H, Cutz E. NOX2 (gp91phox) is a predominant O2 sensor in a human airway chemoreceptor cell line: biochemical, molecular and electrophysiological evidence. Am J Physiol Lung Cell Mol Physiol 303:L598-607, 2012. 

Das B, Bayat-Mokhtari R, Tsui M, Lotfi S, Tsuchida R, Felsher DW, Yeger H. HIF-2a suppresses p53 to enhance the stemness and regenerative potential of human embryonic stem cells. Stem Cells 30:1685-95, 2012.

Antoon R, Yeger H, Loai Y, Islam S, Farhat WA. Impact of bladder-derived acellular matrix, growth factors, and extracellular matrix constitutents on the survival and multipotency of marrow-derived mesenchymal stem cells. J Biomed Mater Res A 100: 72-83, 2012.

Kumar S, Mokhtari RB, Sheikh R, wu B, Zhang L, Xu P, Man S, Dias OI, Yeger H, Kerbel RS, Baruchel S. Metronomic oral topotecan with pazopanib is an active antiangiogenic regimen in mouse models of aggressive pediatric solid tumor. Clin Cancer Res 17:5656-67,2011.

Oliver J, Kushwah R, Wu J, Pan J, Cutz E, Yeger H, Waddell TK, Hu J. Elf3 palys a role in regulating bronchiolar epithelial repair kinetics following Clara cell-specific injury. Lab Invest 91:1514-29, 2011.

Chen N, Hanly L, Rieder M, Yeger H, Koren G. The effect of N-acetylcystein on the antitumor activity of ifosfomide. Can J Physiol Pharmacol 89:335-43, 2011.

Ambekar C, Das B, Yeger H, Dror Y. SBDS-deficiency results in deregulation of reactive oxygen species leading to increased cell death and decreased cell growth. Pediatr Blood Cancer, in final revision, 2010.

McGovern S, Pan J, Oliver G, Cutz E,Yeger H. The role of hypoxia and neurogenic genes (Mash-1 and Prox-1) in the developmental programming and maturation of pulmonary neuroendocrine cells in fetal mouse lung. Lab Invest 90:180-95,2010.

Oliver J, Kushwah R, Wu J, Cutz E, Yeger H, Waddell TK, Hu J. Gender differences in pulmonary regenerative response to naphthalene-induced bronchiolar epithelial cell injury. Cell Prolif 42:672-87, 2009.

Cutz E, Pan J, Yeger H. The role of NOX2 and “novel oxidases” in airway chemoreceptor O(2) signaling. Adv Exp Med Biol 648:427-38, 2009.

Rigat B, Yeger H, Shehnaz D, Mahuran D. GM2 activator protein inhibits platelet activating factor signaling in rats. Biochem Biophys Res Commun 385:576-80, 2009.

Zhang L, Smith KM, Chong AL, Stempak D, Yeger H, Marrano P, Thorner PS, Irwin MS, Kaplan DR, Baruchel S. In vivo antitumor and antimetastatic activity of sunitinib in preclinical neuroblastoma mouse model. Neoplasia 11:426-35, 2009.

Riser BL, Najmabadi F, Perbal B, Peterson DR, Rambow JA, Riser ML, Sukowski E, Yeger H, Riser SC.  CCN3 (NOV) Is a Negative Regulator of CCN2 (CTGF) and a Novel Endogenous Inhibitor of the Fibrotic Pathway in an in Vitro Model of Renal Disease. Am J Pathol 174:1725-35, 2009.

Irvine AE, Perbal B,Yeger H. Report on the fifth international workshop on the CCN family of genes. J Cell Commun Signal 2:95-100,2009.

Cutz E, Fu XW, Yeger H, Nurse CA. Functional live imaging of the pulmonary neuroepithelial body microenvironment. Am J Respir Cell Mol Biol 40:119-20, 2009.