Honors & Awards

  • The Breast Cancer Research Program (BCRP) Three Years Predoctoral Traineeship Award., Department of Defense (DOD) (2008~2011)
  • Dean's Postdoctoral Fellowships, Stanford School of Medicine (2012~2013)
  • Senior Research Training Fellowship award, American Lung Association (2013~2015)

Professional Education

  • Ph.D., Cornell University (2011)
  • M.S, National Yang Ming University, Microbiology and Immunology (2003)
  • B.S, National Yang Ming University, Life Sciences (2001)

Stanford Advisors

Research & Scholarship

Current Research and Scholarly Interests

Metastasis is a major clinical challenge driven by poorly understood cell state alterations. The goal of my project is to use unbiased genomic methods and in vivo models to better understand the molecular and cellular changes that underlie tumor progression and each step of the metastatic cascade. We use genetically-engineered mouse models of metastatic cancer in which the resulting tumors recapitulate the genetic alterations and histological progression of the human disease.

In these models, tumors develop within their appropriate microenvironment and undergo changes in their gene expression programs that endow them with the ability to invade blood and lymphatic vessels, survive in circulation, enter various distant organs, and ultimately grow into new tumor lesions. Given the dearth of human tissue samples from metastatic disease, especially from primary tumors and metastases from the same patient prior to therapy, these models represent a unique opportunity to understand the molecular biography of the most prevalent tumor types.

By generating activating and inactivating germline and inducible alleles, and modulating gene expression using lentiviral vectors, these models allow us to characterize the function of candidate genes and pathways during tumor progression and metastasis in vivo. By incorporating increasingly quantitative methods and powerful in vivo methods, our work is focused on uncovering general rules that govern tumor progression and metastatic spread and discovering novel therapeutic targets across the continuum of cancer progression including the lethal metastatic stage.


All Publications

  • Pancreatic cancer modeling using retrograde viral vector delivery and in vivo CRISPR/Cas9-mediated somatic genome editing GENES & DEVELOPMENT Chiou, S., Winters, I. P., Wang, J., Naranjo, S., Dudgeon, C., Tamburini, F. B., Brady, J. J., Yang, D., Gruener, B. M., Chuang, C., Caswell, D. R., Zeng, H., Chu, P., Kim, G. E., Carpizo, D. R., Kim, S. K., Winslow, M. M. 2015; 29 (14): 1576-1585


    Pancreatic ductal adenocarcinoma (PDAC) is a genomically diverse, prevalent, and almost invariably fatal malignancy. Although conventional genetically engineered mouse models of human PDAC have been instrumental in understanding pancreatic cancer development, these models are much too labor-intensive, expensive, and slow to perform the extensive molecular analyses needed to adequately understand this disease. Here we demonstrate that retrograde pancreatic ductal injection of either adenoviral-Cre or lentiviral-Cre vectors allows titratable initiation of pancreatic neoplasias that progress into invasive and metastatic PDAC. To enable in vivo CRISPR/Cas9-mediated gene inactivation in the pancreas, we generated a Cre-regulated Cas9 allele and lentiviral vectors that express Cre and a single-guide RNA. CRISPR-mediated targeting of Lkb1 in combination with oncogenic Kras expression led to selection for inactivating genomic alterations, absence of Lkb1 protein, and rapid tumor growth that phenocopied Cre-mediated genetic deletion of Lkb1. This method will transform our ability to rapidly interrogate gene function during the development of this recalcitrant cancer.

    View details for DOI 10.1101/gad.264861.115

    View details for Web of Science ID 000358596300010

    View details for PubMedID 26178787

  • Upregulation of the microRNA cluster at the Dlkl-Dio3 locus in lung adenocarcinoma ONCOGENE Valdmanis, P. N., Roy-Chaudhuri, B., Kim, H. K., Sayles, L. C., Zheng, Y., Chuang, C., Caswell, D. R., Chu, K., Zhang, Y., Winslow, M. M., Sweet-Cordero, E. A., Kay, M. A. 2015; 34 (1): 94-103


    Mice in which lung epithelial cells can be induced to express an oncogenic Kras(G12D) develop lung adenocarcinomas in a manner analogous to humans. A myriad of genetic changes accompany lung adenocarcinomas, many of which are poorly understood. To get a comprehensive understanding of both the transcriptional and post-transcriptional changes that accompany lung adenocarcinomas, we took an omics approach in profiling both the coding genes and the non-coding small RNAs in an induced mouse model of lung adenocarcinoma. RNAseq transcriptome analysis of Kras(G12D) tumors from F1 hybrid mice revealed features specific to tumor samples. This includes the repression of a network of GTPase-related genes (Prkg1, Gnao1 and Rgs9) in tumor samples and an enrichment of Apobec1-mediated cytosine to uridine RNA editing. Furthermore, analysis of known single-nucleotide polymorphisms revealed not only a change in expression of Cd22 but also that its expression became allele specific in tumors. The most salient finding, however, came from small RNA sequencing of the tumor samples, which revealed that a cluster of ∼53 microRNAs and mRNAs at the Dlk1-Dio3 locus on mouse chromosome 12qF1 was markedly and consistently increased in tumors. Activation of this locus occurred specifically in sorted tumor-originating cancer cells. Interestingly, the 12qF1 RNAs were repressed in cultured Kras(G12D) tumor cells but reactivated when transplanted in vivo. These microRNAs have been implicated in stem cell pleuripotency and proteins targeted by these microRNAs are involved in key pathways in cancer as well as embryogenesis. Taken together, our results strongly imply that these microRNAs represent key targets in unraveling the mechanism of lung oncogenesis.Oncogene advance online publication, 9 December 2013; doi:10.1038/onc.2013.523.

    View details for DOI 10.1038/onc.2013.523

    View details for Web of Science ID 000349740100009

    View details for PubMedID 24317514

  • Obligate Progression Precedes Lung Adenocarcinoma Dissemination CANCER DISCOVERY Caswell, D. R., Chuang, C., Yang, D., Chiou, S., Cheemalavagu, S., Kim-Kiselak, C., Connolly, A., Winslow, M. M. 2014; 4 (7): 781-789


    Despite its clinical importance, very little is known about the natural history and molecular underpinnings of lung cancer dissemination and metastasis. Here we employed a genetically-engineered mouse model of metastatic lung adenocarcinoma in which cancer cells are fluorescently marked to determine whether dissemination is an inherent ability or a major acquired phenotype during lung adenocarcinoma metastasis. We find very little evidence for dissemination from oncogenic Kras-driven hyperplasias or most adenocarcinomas. p53 loss is insufficient to drive dissemination but rather enables rare cancer cells in a small fraction of primary adenocarcinomas to gain alterations that drive dissemination. Molecular characterization of disseminated tumors cells indicates that down-regulation of the transcription factor Nkx2-1 precedes dissemination. Finally, we show that metastatic primary tumors possess a highly proliferative sub-population of cells with characteristics matching those of disseminating cells. We propose that dissemination is a major hurdle during the natural course of lung adenocarcinoma metastasis.

    View details for DOI 10.1158/2159-8290.CD-13-0862

    View details for Web of Science ID 000338708900024

  • A Conditional System to Specifically Link Disruption of Protein-Coding Function with Reporter Expression in Mice CELL REPORTS Chiou, S., Kim-Kiselak, C., Risca, V. I., Heimann, M. K., Chuang, C., Burds, A. A., Greenleaf, W. J., Jacks, T. E., Feldser, D. M., Winslow, M. M. 2014; 7 (6): 2078-2086
  • Post-transcriptional homeostasis and regulation of MCM2-7 in mammalian cells NUCLEIC ACIDS RESEARCH Chuang, C., Yang, D., Bai, G., Freeland, A., Pruitt, S. C., Schimenti, J. C. 2012; 40 (11): 4914-4924


    The MiniChromosome Maintenance 2-7 (MCM2-7) complex provides essential replicative helicase function. Insufficient MCMs impair the cell cycle and cause genomic instability (GIN), leading to cancer and developmental defects in mice. Remarkably, depletion or mutation of one Mcm can decrease all Mcm levels. Here, we use mice and cells bearing a GIN-causing hypomophic allele of Mcm4 (Chaos3), in conjunction with disruption alleles of other Mcms, to reveal two new mechanisms that regulate MCM protein levels and pre-RC formation. First, the Mcm4(Chaos3) allele, which disrupts MCM4:MCM6 interaction, triggers a Dicer1 and Drosha-dependent ? 40% reduction in Mcm2-7 mRNAs. The decreases in Mcm mRNAs coincide with up-regulation of the miR-34 family of microRNAs, which is known to be Trp53-regulated and target Mcms. Second, MCM3 acts as a negative regulator of the MCM2-7 helicase in vivo by complexing with MCM5 in a manner dependent upon a nuclear-export signal-like domain, blocking the recruitment of MCMs onto chromatin. Therefore, the stoichiometry of MCM components and their localization is controlled post-transcriptionally at both the mRNA and protein levels. Alterations to these pathways cause significant defects in cell growth reflected by disease phenotypes in mice.

    View details for DOI 10.1093/nar/gks176

    View details for Web of Science ID 000305032500026

    View details for PubMedID 22362746

  • MCM4 mutation causes adrenal failure, short stature, and natural killer cell deficiency in humans JOURNAL OF CLINICAL INVESTIGATION Hughes, C. R., Guasti, L., Meimaridou, E., Chuang, C., Schimenti, J. C., King, P. J., Costigan, C., Clark, A. J., Metherell, L. A. 2012; 122 (3): 814-820


    An interesting variant of familial glucocorticoid deficiency (FGD), an autosomal recessive form of adrenal failure, exists in a genetically isolated Irish population. In addition to hypocortisolemia, affected children show signs of growth failure, increased chromosomal breakage, and NK cell deficiency. Targeted exome sequencing in 8 patients identified a variant (c.71-1insG) in minichromosome maintenance-deficient 4 (MCM4) that was predicted to result in a severely truncated protein (p.Pro24ArgfsX4). Western blotting of patient samples revealed that the major 96-kDa isoform present in unaffected human controls was absent, while the presence of the minor 85-kDa isoform was preserved. Interestingly, histological studies with Mcm4-depleted mice showed grossly abnormal adrenal morphology that was characterized by non-steroidogenic GATA4- and Gli1-positive cells within the steroidogenic cortex, which reduced the number of steroidogenic cells in the zona fasciculata of the adrenal cortex. Since MCM4 is one part of a MCM2-7 complex recently confirmed as the replicative helicase essential for normal DNA replication and genome stability in all eukaryotes, it is possible that our patients may have an increased risk of neoplastic change. In summary, we have identified what we believe to be the first human mutation in MCM4 and have shown that it is associated with adrenal insufficiency, short stature, and NK cell deficiency.

    View details for DOI 10.1172/JCI60224

    View details for Web of Science ID 000301021500009

    View details for PubMedID 22354170

  • Incremental Genetic Perturbations to MCM2-7 Expression and Subcellular Distribution Reveal Exquisite Sensitivity of Mice to DNA Replication Stress PLOS GENETICS Chuang, C., Wallace, M. D., Abratte, C., Southard, T., Schimenti, J. C. 2010; 6 (9)


    Mutations causing replication stress can lead to genomic instability (GIN). In vitro studies have shown that drastic depletion of the MCM2-7 DNA replication licensing factors, which form the replicative helicase, can cause GIN and cell proliferation defects that are exacerbated under conditions of replication stress. To explore the effects of incrementally attenuated replication licensing in whole animals, we generated and analyzed the phenotypes of mice that were hemizygous for Mcm2, 3, 4, 6, and 7 null alleles, combinations thereof, and also in conjunction with the hypomorphic Mcm4(Chaos3) cancer susceptibility allele. Mcm4(Chaos3/Chaos3) embryonic fibroblasts have ?40% reduction in all MCM proteins, coincident with reduced Mcm2-7 mRNA. Further genetic reductions of Mcm2, 6, or 7 in this background caused various phenotypes including synthetic lethality, growth retardation, decreased cellular proliferation, GIN, and early onset cancer. Remarkably, heterozygosity for Mcm3 rescued many of these defects. Consistent with a role in MCM nuclear export possessed by the yeast Mcm3 ortholog, the phenotypic rescues correlated with increased chromatin-bound MCMs, and also higher levels of nuclear MCM2 during S phase. The genetic, molecular and phenotypic data demonstrate that relatively minor quantitative alterations of MCM expression, homeostasis or subcellular distribution can have diverse and serious consequences upon development and confer cancer susceptibility. The results support the notion that the normally high levels of MCMs in cells are needed not only for activating the basal set of replication origins, but also "backup" origins that are recruited in times of replication stress to ensure complete replication of the genome.

    View details for DOI 10.1371/journal.pgen.1001110

    View details for Web of Science ID 000282369200048

    View details for PubMedID 20838603

  • Comparison of Tir from enterohemorrahgic and enteropathogenic Escherichia coli strains: two homologues with distinct intracellular properties JOURNAL OF BIOMEDICAL SCIENCE Chuang, C. H., Chiu, H. J., Hsu, S. C., Ho, J. Y., Syu, W. J. 2006; 13 (1): 73-87


    Tir of enteropathogenic Escherichia coli (EPEC) or enterohemorrahgic E. coil (EHEC) is translocated by a type III secretion system to the host cell membranes where it serves as a receptor for the binding of a second bacterial membrane protein. In response to the binding, EPEC Tir is phosphorylated at Tyr474, and this phosphorylation is necessary for the signaling of pedestal formation. Tir of EHEC has no equivalent phosphorylation site but it is similarly needed for cytoskeleton rearrangement. How these two Tir molecules achieve their function by apparently different mechanisms is not completely clear. To examine their intrinsic differences, the two Tirs were expressed in HeLa cells and compared. Actin in complexes could be pelleted down from the lysate of cells expressing EHEC Tir but not EPEC Tir. By immunostaining, neither Tir molecule was found in phosphorylated state. In the cytoplasm, EHEC Tir was frequently found in fibrous structures whereas EPEC Tir was observed completely in a diffusive form. The determinant critical for the EHEC Tir fibrous formation was mapped to the C-terminal region of the molecule that deviates from the EPEC counterpart. This region may play a role in taking an alternative route different from Tyr474 phosphorylation to transduce signals.

    View details for DOI 10.1007/s11373-005-9034-x

    View details for Web of Science ID 000234924100007

    View details for PubMedID 16228285

  • Construction of a tagging system for subcellular localization of proteins encoded by open reading frames JOURNAL OF BIOMEDICAL SCIENCE Chuang, C. H., Hsu, S. C., Hsu, C. L., Hsu, T. C., Syu, W. J. 2001; 8 (2): 170-175


    We have previously characterized a monoclonal antibody (SC1D7) that is directed to maltose-binding protein (MBP) of Escherichia coli and other closely related enteric bacteria. SC1D7 does not cross-react with proteins in eucaryotes and appears to be a highly specific tool in immunochemical analyses. To better map the epitope, we took advantage of an available plasmid, pMAL-c2, that encodes the E. coli MBP-coding sequence and constructed plasmids to express MBP fragments. A construct containing the N-terminal portion of MBP does not react with SC1D7, whereas a second construct expressing glutathione S-transferase fused with the C-terminal half of MBP does react with SC1D7. To precisely define the epitope, random peptides displayed on M13 were used to react with SC1D7. Sequences of reactive peptides were aligned, and a consensus sequence of XDXRIPX was deduced. This sequence matches MBP with an amino acid stretch of KDPRIAA. To consolidate the mapping result, a sequence encoding this epitope was inserted into an expression vector and the resulting recombinant protein did react with SC1D7. Thereafter, this epitope was incorporated into a eucaryotic expression plasmid containing a previously defined hepatitis delta virus epitope for protein tagging. This two-epitope-tagging vector is useful in various molecular analyses. We demonstrate its usage for localization of a bacterial virulence factor in host cells. This vector should be applicable for high-throughput characterization of new open reading frames found in genome sequencing.

    View details for Web of Science ID 000167637400003

    View details for PubMedID 11287747