Bio

Honors & Awards


  • F32 Postdoctoral Fellowship, NCI (Deferred)
  • Postdoctoral Fellowship, TRDRP (2012-2015)
  • Dean' s Fellowship, Stanford University (2011-2012)
  • Predoctoral Fellowship, DOD Breast Cancer (2007-2010)

Professional Education


  • PhD, UC Berkeley, Molecular and Cell Biology (2010)
  • BS, UCLA, Molecular, Cell, and Developmental Biology (2005)

Stanford Advisors


Patents


  • Nadine Jahchan; Joel Dudley; Julien Sage; Atul Butte. "United StatesMETHODS FOR THE TREATMENT OF CANCER", THE BOARD OF TRUSTEES OF THE LELAND STANFORD JUNIOR UNIVERSITY

Research & Scholarship

Current Research and Scholarly Interests


Investigating the mechanisms of Small Cell Lung Cancer progression, maintenance, and treatment.
Development of a mouse model of Merkel Cell Carcinoma.

Lab Affiliations


Publications

Journal Articles


  • Genomic analysis of fibrolamellar hepatocellular carcinoma. Human molecular genetics Xu, L., Hazard, F. K., Zmoos, A., Jahchan, N., Chaib, H., Garfin, P. M., Rangaswami, A., Snyder, M. P., Sage, J. 2015; 24 (1): 50-63

    Abstract

    Pediatric tumors are relatively infrequent but are often associated with significant lethality and lifelong morbidity. A major goal of pediatric cancer research has been to identify key drivers of tumorigenesis to eventually develop targeted therapies to enhance cure rate and minimize acute and long-term toxic effects. Here we used genomics approaches to identify biomarkers and candidate drivers for fibrolamellar hepatocellular carcinoma (FL-HCC), a very rare subtype of pediatric liver cancer for which limited therapeutic options exist. In-depth genomics analyses of one tumor followed by immunohistochemistry validation on seven other tumors showed expression of neuroendocrine markers in FL-HCC. DNA and RNA sequencing data further showed that common cancer pathways are not visibly altered in FL-HCC but identified two novel structural variants, both resulting in fusion transcripts. The first, a 400kb deletion, results in a DNAJ1-PRKCA fusion transcript, which leads to increased PKA activity in the index tumor case and other FL-HCC cases compared to normal liver. This PKA fusion protein is oncogenic in HCC cells. The second gene fusion event, a translocation between the CLPTML1 and GLIS3 genes, generates a transcript whose product also promotes cancer phenotypes in HCC cell lines. These experiments further highlight the tumorigenic role of gene fusions in the etiology of pediatric solid tumors and identify both candidate biomarkers and possible therapeutic targets for this lethal pediatric disease.

    View details for DOI 10.1093/hmg/ddu418

    View details for PubMedID 25122662

  • A Drug Repositioning Approach Identifies Tricyclic Antidepressants as Inhibitors of Small Cell Lung Cancer and Other Neuroendocrine Tumors CANCER DISCOVERY Jahchan, N. S., Dudley, J. T., Mazur, P. K., Flores, N., Yang, D., Palmerton, A., Zmoos, A., Vaka, D., Tran, K. Q., Zhou, M., Krasinska, K., Riess, J. W., Neal, J. W., Khatri, P., Park, K. S., Butte, A. J., Sage, J. 2013; 3 (12): 1364-1377

    Abstract

    Small cell lung cancer (SCLC) is an aggressive neuroendocrine subtype of lung cancer with high mortality. We used a systematic drug repositioning bioinformatics approach querying a large compendium of gene expression profiles to identify candidate U.S. Food and Drug Administration (FDA)-approved drugs to treat SCLC. We found that tricyclic antidepressants and related molecules potently induce apoptosis in both chemonaïve and chemoresistant SCLC cells in culture, in mouse and human SCLC tumors transplanted into immunocompromised mice, and in endogenous tumors from a mouse model for human SCLC. The candidate drugs activate stress pathways and induce cell death in SCLC cells, at least in part by disrupting autocrine survival signals involving neurotransmitters and their G protein-coupled receptors. The candidate drugs inhibit the growth of other neuroendocrine tumors, including pancreatic neuroendocrine tumors and Merkel cell carcinoma. These experiments identify novel targeted strategies that can be rapidly evaluated in patients with neuroendocrine tumors through the repurposing of approved drugs.Our work shows the power of bioinformatics-based drug approaches to rapidly repurpose FDA-approved drugs and identifies a novel class of molecules to treat patients with SCLC, a cancer for which no effective novel systemic treatments have been identified in several decades. In addition, our experiments highlight the importance of novel autocrine mechanisms in promoting the growth of neuroendocrine tumor cells.

    View details for DOI 10.1158/2159-8290.CD-13-0183

    View details for Web of Science ID 000328257500023

    View details for PubMedID 24078773

  • Expression Profiles of SnoN in Normal and Cancerous Human Tissues Support Its Tumor Suppressor Role in Human Cancer PLOS ONE Jahchan, N. S., Ouyang, G., Luo, K. 2013; 8 (2)

    Abstract

    SnoN is a negative regulator of TGF-β signaling and also an activator of the tumor suppressor p53 in response to cellular stress. Its role in human cancer is complex and controversial with both pro-oncogenic and anti-oncogenic activities reported. To clarify its role in human cancer and provide clinical relevance to its signaling activities, we examined SnoN expression in normal and cancerous human esophageal, ovarian, pancreatic and breast tissues. In normal tissues, SnoN is expressed in both the epithelium and the surrounding stroma at a moderate level and is predominantly cytoplasmic. SnoN levels in all tumor epithelia examined are lower than or similar to that in the matched normal samples, consistent with its anti-tumorigenic activity in epithelial cells. In contrast, SnoN expression in the stroma is highly upregulated in the infiltrating inflammatory cells in high-grade esophageal and ovarian tumor samples, suggesting that SnoN may potentially promote malignant progression through modulating the tumor microenvironment in these tumor types. The overall levels of SnoN expression in these cancer tissues do not correlate with the p53 status. However, in human cancer cell lines with amplification of the snoN gene, a strong correlation between increased SnoN copy number and inactivation of p53 was detected, suggesting that the tumor suppressor SnoN-p53 pathway must be inactivated, either through downregulation of SnoN or inactivation of p53, in order to allow cancer cell to proliferate and survive. These data strongly suggest that SnoN can function as a tumor suppressor at early stages of tumorigenesis in human cancer tissues.

    View details for DOI 10.1371/journal.pone.0055794

    View details for Web of Science ID 000315970300052

    View details for PubMedID 23418461

  • SnoN regulates mammary gland alveologenesis and onset of lactation by promoting prolactin/Stat5 signaling DEVELOPMENT Jahchan, N. S., Wang, D., Bissell, M. J., Luo, K. 2012; 139 (17): 3147-3156

    Abstract

    Mammary epithelial cells undergo structural and functional differentiation at late pregnancy and parturition to produce and secrete milk. Both TGF-β and prolactin pathways are crucial regulators of this process. However, how the activities of these two antagonistic pathways are orchestrated to initiate lactation has not been well defined. Here, we show that SnoN, a negative regulator of TGF-β signaling, coordinates TGF-β and prolactin signaling to control alveologenesis and lactogenesis. SnoN expression is induced at late pregnancy by the coordinated actions of TGF-β and prolactin. The elevated SnoN promotes Stat5 signaling by enhancing its stability, thereby sharply increasing the activity of prolactin signaling at the onset of lactation. SnoN-/- mice display severe defects in alveologenesis and lactogenesis, and mammary epithelial cells from these mice fail to undergo proper morphogenesis. These defects can be rescued by an active Stat5. Thus, our study has identified a new player in the regulation of milk production and revealed a novel function of SnoN in mammary alveologenesis and lactogenesis in vivo through promotion of Stat5 signaling.

    View details for DOI 10.1242/dev.079616

    View details for Web of Science ID 000307925200010

    View details for PubMedID 22833129

  • SnoN in mammalian development, function and diseases CURRENT OPINION IN PHARMACOLOGY Jahchan, N. S., Luo, K. 2010; 10 (6): 670-675

    Abstract

    SnoN (Ski-novel protein) was discovered as a nuclear proto-oncogene on the basis of its ability to induce transformation of chicken and quail embryonic fibroblasts. As a crucial negative regulator of transforming growth factor-β (TGF-β) signaling and also an activator of p53, it plays an important role in regulating cell proliferation, senescence, apoptosis, and differentiation. Recent studies of its expression patterns and functions in mouse models and mammalian cells have revealed important functions of SnoN in normal epithelial development and tumorigenesis. Evidence suggests that SnoN has both pro-oncogenic and anti-oncogenic functions by modulating multiple signaling pathways. These studies suggest that SnoN may have broad functions in the development and homeostasis of embryonic and postnatal tissues.

    View details for DOI 10.1016/j.coph.2010.08.006

    View details for Web of Science ID 000284749400010

    View details for PubMedID 20822955

  • Transforming Growth Factor-beta Regulator SnoN Modulates Mammary Gland Branching Morphogenesis, Postlactational Involution, and Mammary Tumorigenesis CANCER RESEARCH Jahchan, N. S., You, Y., Muller, W. J., Luo, K. 2010; 70 (10): 4204-4213

    Abstract

    SnoN is an important negative regulator of transforming growth factor-beta (TGF-beta) signaling that was originally identified as a transforming oncogene in chicken embryonic fibroblasts. Both pro-oncogenic and antioncogenic activities of SnoN have been reported, but its function in normal epithelial cells has not been defined. In the mouse mammary gland, SnoN is expressed at relatively low levels, but it is transiently upregulated at late gestation before being downregulated during lactation and early involution. To assess the effects of elevated levels of SnoN, we generated transgenic mice expressing a SnoN fragment under the control of the mouse mammary tumor virus promoter. In this model system, SnoN elevation increased side-branching and lobular-alveolar proliferation in virgin glands, while accelerating involution in postlactation glands. Increased proliferation stimulated by SnoN was insufficient to induce mammary tumorigenesis. In contrast, elevated levels of SnoN cooperated with polyoma middle T antigen to accelerate the formation of aggressive multifocal adenocarcinomas and to increase the formation of pulmonary metastases. Our studies define functions of SnoN in mammary epithelial cell proliferation and involution, and provide the first in vivo evidence of a pro-oncogenic role for SnoN in mammalian tumorigenesis.

    View details for DOI 10.1158/0008-5472.CAN-10-0135

    View details for Web of Science ID 000278486300038

    View details for PubMedID 20460516

  • A la-related protein modulates 7SK snRNP integrity to suppress P-TEFb-dependent transcriptional elongation and tumorigenesis MOLECULAR CELL He, N., Jahchan, N. S., Hong, E., Li, Q., Bayfield, M. A., Maraia, R. J., Luo, K., Zhou, Q. 2008; 29 (5): 588-599

    Abstract

    The general transcription factor P-TEFb stimulates RNA polymerase II elongation and cotranscriptional processing of pre-mRNA. Contributing to a functional equilibrium important for growth control, a reservoir of P-TEFb is maintained in an inactive snRNP where 7SK snRNA is a central scaffold. Here, we identify PIP7S as a La-related protein stably associated with and required for 7SK snRNP integrity. PIP7S binds and stabilizes nearly all the nuclear 7SK via 3' -UUU-OH, leading to the sequestration and inactivation of P-TEFb. This function requires its La domain and intact C terminus. The latter is frequently deleted in human tumors due to microsatellite instability-associated mutations. Consistent with the tumor suppressor role of a Drosophila homolog of PIP7S, loss of PIP7S function shifts the P-TEFb equilibrium toward the active state, disrupts epithelial differentiation, and causes P-TEFb-dependent malignant transformation. Through PIP7S modulation of P-TEFb, our data thus link a general elongation factor to growth control and tumorigenesis.

    View details for DOI 10.1016/j.molcel.2008.01.003

    View details for Web of Science ID 000254100200009

    View details for PubMedID 18249148

  • Phosphorylation and activation of PINOID by the phospholipid signaling kinase 3-phosphoinositidedependent protein kinase 1 (PDK1) in Arabidopsis PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA Zegzouti, H., Anthony, R. G., Jahchan, N., Bogre, L., Christensen, S. K. 2006; 103 (16): 6404-6409

    Abstract

    Activity of the serine-threonine protein kinase PINOID (PID) has been implicated in the asymmetrical localization of the membrane-associated PINFORMED (PIN) family of auxin transport facilitators. However, the means by which PID regulates PIN protein distribution is unknown. We have used recombinant PID protein to dissect the regulation of PID activity in vitro. We demonstrate that intramolecular PID autophosphorylation is required for the ability of PID to phosphorylate an exogenous substrate. PID-like mammalian AGC kinases act in a phosphorylation cascade initiated by the phospholipid-associated kinase, 3-phosphoinositide-dependent protein kinase 1 (PDK1), which binds to the C-terminal hydrophobic PDK1-interacting fragment (PIF) domain found in PDK1 substrates. We find that Arabidopsis PDK1 interacts with PID, and that transphosphorylation by PDK1 increases PID autophosphorylation. We show that a PID activation loop serine is required for PDK1-dependent PID phosphorylation. This activation is rapid and requires the PIF domain. Cell extracts from flowers and seedling shoots dramatically increase PID phosphorylation in a tissue-specific manner. A PID protein variant in which the PIF domain was mutated failed to be activated by the seedling shoot extracts. PID immunoprecipitated from Arabidopsis cells in which PDK1 expression was inhibited by RNAi showed a dramatic reduction in transphosphorylation of myelin basic protein substrate. These results indicate that AtPDK1 is a potent enhancer of PID activity and provide evidence that phospholipid signaling may play a role in the signaling processes controlling polar auxin transport.

    View details for DOI 10.1073/pnas.0510283103

    View details for Web of Science ID 000236999000062

    View details for PubMedID 16601102

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