As an independent scientist, I started my laboratory at KAIST, from Nov. 2015. My expertise is cancer genomics, which aims to understand somatic mutations and their functional consequences in human cancers. Now, I am interested in understanding the mutational processes operative in human somatic cells at variant time points across the life history of human cells, from fertilized-egg to advanced and very late stage of cancer cells (1).
Graduate School of Medical Science and Engineering at KAIST (https://www.julab.kaist.ac.kr/) has a unique and specialized PhD training program for distinguished medical doctors and biologists in South Korea to perform cutting-edge biomedical research. We are in very good position to perform both the basic medical research for understanding the basic disease mechanisms and translational medical research for bringing genome technologies to promote enhancements in cancer diagnosis and therapies.
1. Understanding the genetic etiology of uncommon and undiagnosed cancers
For the last a couple of years, international cancer genome consortia (i.e. ICGC and TCGA) have extensively revealed genomic mutations in many human cancers. However, many rare cancer types are still left unexplored by genome technologies (2). In South Korea, approximately 20% of all cancer cases are classified as “uncommon or undiagnosed”. These patients are disadvantaged because their diseases are frequently neglected from the development of therapeutic agents and clinical trials. Usually, the patients are treated by empirical treatments, such as cytotoxic agents, without any specific supporting evidence for their cancer. Therefore, it is necessary to shift our focus of cancer genome research from common into these rare tumor types.
As soon as I started my laboratory in KAIST, I constructed a translational research pipeline with clinicians in Korea. (We are always open to collaboration research! Please contact us if you are interested in.) Here, we intend to collect all the uncommon and undiagnosed cancer cases, which are to be used for derivation of cancer cell-lines and for analyses of cancer genomes and transcriptomes. Our efforts will definitely enable us to understand the pathophysiology of these cancers at a molecular level. Furthermore, at least in some fortunate cases, clinically actionable targets will be identified. From 2016, we started to sequence some undiagnosed cases in clinic. From two tumor case, we identified an oncogenic fusion between NUT and BRD3 genes (PMID:28203693). This allowed us to diagnose the case as NUT midline carcinoma and to suggest the best treatment option (BRD-inhibitor) for the patient. In addition, we revealed that complex genome rearrangement mechanisms, i.e. chromoplexy, are underlying for the fusion genes. These cases directly shows that our translational research would be very productive for the next few years.
2. Understanding tumor heterogeneity using organoid deep sequencing and single-cell RNA imaging
Cancer evolves by continuous acquisition of somatic mutations and natural selection resulting in the emergence of intra-tumor heterogeneity (3). Heterogeneity among intra-tumor clones enhances the fitness of the tumor and allows it to grow under the challenges of new or altered environments. The Darwinian concept of clone evolution explains how growing genetic complexity among the tumor cell population induces tumor metastasis and resistance to medical intervention. Until recently, however, the theoretical model of Darwinian tumor evolution has not been fully scrutinized due to technical limitations. For example, single cell technologies are immature with sub-optimal accuracy. Multi-regional bulk sequencing with bioinformatic reconstruction lacks clonal resolution. By integration of cutting edge technologies, i.e. organoids, genome sequencing, and high resolution imaging, we intend to understand the spatial landscape of intra-tumor heterogeneity at single-cell resolution.
3. Understanding cell dynamics in human early embryogenesis by cellular lineage tracing using somatic mutations
The human individual consists of ~30 trillion somatic cells. The beginning of our lives is a single cell, or fertilized-egg. Human early embryogenesis, from one cell to blastocyst stage, is a very complex and tightly controlled process and is fundamental to understand the formation of human bodies. However, the early embryonic stage of humans is mostly unexplored, partly due to ethical issues and/or technical limitations. In other words, we do not understand the pattern of cell divisions, the relative contribution of each blastomere to adult tissues, and whether overall the embryo-formation process is deterministic or stochastic.
Using adult blood sequencing data, we sought somatic mutations that occurred during human early embryogenesis (PMID:28329761). This study provided us an insight that ~3 somatic substitution mutations accumulate in every cell division from the very early embryogenesis. These mutations are then maintained in all of the descendants of the cell. Therefore, the cell lineage can be differentiated from the others. I intend to use this to reconstruct the exact family tree of somatic cells by extensive sequencing of clonal lines established from an individual. This will provide an insight into how cell fates were determined in early human embryogenesis. The proof-of-concept of this study was introduced in mice in small scale (4), but not yet applied to humans systematically.
As described above, using genome sequencing technologies and through international collaboration, we will expand our research field and will perform innovative and challenging studies which I believe are all essential to understand basic biological mechanisms underlying neoplastic diseases and human early embryogenesis.
2012년 이후 대표논문
Lee JK, Lee J, Kim S, Kim S, Youk J, Park S, An Y, Keam B, Kim DW, Heo DS, Kim YT, Kim JS, Kim SH, Lee JS, Lee SH, Park K, Ku JL, Jeon YK, Chung DH, Park PJ, Kim J, Kim TM, Ju YS (2017)
Clonal history and genetic predictors of transformation into small-cell carcinomas from lung adenocarcinomas. J Clin Oncol.
Ju YS, Martincorena I, Gerstung M, Petljak M, Alexandrov LB, Rahbari R, Wedge DC, Davies HR, Ramakrishna M, Fullam A, Martin S, Alder C, Patel N, Gamble S, O'Meara S, Giri DD, Sauer T, Pinder SE, Purdie CA, Borg A, Stunnenberg H, van de Vijver M, Tan BK, Caldas C, Tutt A, Ueno NT, van 't Veer LJ, Martens JW, Sotiriou C, Knappskog S, Span PN, Lakhani SR, Eyfjord JE, Borresen-Dale AL, Richardson A, Thompson AM, Viari A, Hurles ME, Nik-Zainal S, Campbell PJ, Stratton MR (2017)
Somatic mutations reveal asymmetric cellular dynamics in the early human embryo. Nature, 543(7647):714-718
Lee JK, Louzada S, An Y, Kim SY, Kim S, Youk J, Park S, Koo SH, Keam B, Jeon YK, Ku JL, Yang F, Kim TM, Ju YS (2017)
Complex chromosomal rearrangements by single catastrophic pathogenesis in NUT midline carcinoma. Ann Oncol., 28(4):890-897
Alexandrov LB, Ju YS, Haase K, Van Loo P, Martincorena I, Nik-Zainal S, Totoki Y, Fujimoto A, Nakagawa H, Shibata T, Campbell PJ, Vineis P, Phillips DH, Stratton MR (2016)
Mutational signatures associated with tobacco smoking in human cancer. Science, 354(6312):618-622
Shlien A, Raine K, Fuligni F, Arnold R, Nik-Zainal S, Dronov S, Mamanova L, Rosic A, Ju YS, Cooke SL, Ramakrishna M, Papaemmanuil E, Davies HR, Tarpey PS, Van Loo P, Wedge DC, Jones DR, Martin S, Marshall J, Anderson E, Hardy C; ICGC Breast Cancer Working Group, Oslo Breast Cancer Research Consortium, Barbashina V, Aparicio SA, Sauer T, Garred O, Vincent-Salomon A, Mariani O, Boyault S, Fatima A, Langerod A, Borg A, Thomas G, Richardson AL, Borresen-Dale AL, Polyak K, Stratton MR, Campbell PJ (2016)
Direct transcriptional consequences of somatic mutation in breast cancer. Cell Rep., 16(7):2032-46
Kemper K, Krijgsman O, Kong X, Cornelissen-Steijger P, Shahrabi A, Weeber F, van der Velden DL, Bleijerveld OB, Kuilman T, Kluin RJ, Sun C, Voest EE, Ju YS, Schumacher TN, Altelaar AF, McDermott U, Adams DJ, Blank CU, Haanen JB, Peeper DS (2016)
BRAF(V600E) kinase domain duplication identified in therapy-refractory melanoma patient-derived xenografts. Cell Rep., 16(1):263-77
Nik-Zainal S, Davies H, Staaf J, Ramakrishna M, Glodzik D, Zou X, Martincorena I, Alexandrov LB, Martin S, Wedge DC, Van Loo P, Ju YS, Smid M, Brinkman AB, Morganella S, Aure MR, Lingjaaede OC, Langerod A, Ringneer M, Ahn SM, Boyault S, Brock JE, Broeks A, Butler A, Desmedt C, Dirix L, Dronov S, Fatima A, Foekens JA, Gerstung M, Hooijer GK, Jang SJ, Jones DR, Kim HY, King TA, Krishnamurthy S, Lee HJ, Lee JY, Li Y, McLaren S, Menzies A, Mustonen V, O'Meara S, Pauporte I, Pivot X, Purdie CA, Raine K, Ramakrishnan K, Rodriguez-Gonzalez FG, Romieu G, Sieuwerts AM, Simpson PT, Shepherd R, Stebbings L, Stefansson OA, Teague J, Tommasi S, Treilleux I, Van den Eynden GG, Vermeulen P, Vincent-Salomon A, Yates L, Caldas C, van't Veer L, Tutt A, Knappskog S, Tan BK4, Jonkers J, Borg A, Ueno NT, Sotiriou C, Viari A, Futreal PA, Campbell PJ, Span PN, Van Laere S, Lakhani SR, Eyfjord JE, Thompson AM, Birney E, Stunnenberg HG, van de Vijver MJ, Martens JW, Borresen-Dale AL, Richardson AL, Kong G, Thomas G, Stratton MR (2016)
Landscape of somatic mutations in 560 breast cancer whole-genome sequences. Nature, 534(7605):47-54
Ju YS (2016)
Intracellular mitochondrial DNA transfers to the nucleus in human cancer cells. Curr Opin Genet Dev., 38:23-30
Kim J, Kim S, Ko S, In YH, Moon HG, Ahn SK, Kim MK, Lee M, Hwang JH, Ju YS, Kim JI, Noh DY, Kim S, Park JH, Rhee H, Kim S, Han W (2015)
Recurrent fusion transcripts detected by whole-transcriptome sequencing of 120 primary breast cancer samples. Genes Chromosomes Cancer, 54(11):681-91
Yates LR, Gerstung M, Knappskog S, Desmedt C, Gundem G, Van Loo P, Aas T, Alexandrov LB, Larsimont D, Davies H, Li Y, Ju YS, Ramakrishna M, Haugland HK, Lilleng PK, Nik-Zainal S, McLaren S, Butler A, Martin S, Glodzik D, Menzies A, Raine K, Hinton J, Jones D, Mudie LJ, Jiang B, Vincent D, Greene-Colozzi A, Adnet PY, Fatima A, Maetens M, Ignatiadis M, Stratton MR, Sotiriou C, Richardson AL, Lonning PE, Wedge DC, Campbell PJ (2015)
Subclonal diversification of primary breast cancer revealed by multiregion sequencing. Nat Med., 21(7):751-9
Ju YS, Tubio JM, Mifsud W, Fu B, Davies HR, Ramakrishna M, Li Y, Yates L, Gundem G, Tarpey PS, Behjati S, Papaemmanuil E, Martin S, Fullam A, Gerstung M; ICGC Prostate Cancer Working Group; ICGC Bone Cancer Working Group; ICGC Breast Cancer Working Group, Nangalia J, Green AR, Caldas C, Borg A, Tutt A, Lee MT, van't Veer LJ, Tan BK, Aparicio S, Span PN, Martens JW, Knappskog S, Vincent-Salomon A, Borresen-Dale AL, Eyfjord JE, Myklebost O, Flanagan AM, Foster C, Neal DE, Cooper C, Eeles R, Bova SG, Lakhani SR, Desmedt C, Thomas G, Richardson AL, Purdie CA, Thompson AM, McDermott U, Yang F, Nik-Zainal S, Campbell PJ, Stratton MR (2015)
Frequent somatic transfer of mitochondrial DNA into the nuclear genome of human cancer cells. Genome Res., 25(6):814-24
Ju YS, Alexandrov LB, Gerstung M, Martincorena I, Nik-Zainal S, Ramakrishna M, Davies HR, Papaemmanuil E, Gundem G, Shlien A, Bolli N, Behjati S, Tarpey PS, Nangalia J, Massie CE, Butler AP, Teague JW, Vassiliou GS, Green AR, Du MQ, Unnikrishnan A, Pimanda JE, Teh BT, Munshi N, Greaves M, Vyas P, El-Naggar AK, Santarius T, Collins VP, Grundy R, Taylor JA, Hayes DN, Malkin D; ICGC Breast Cancer Group; ICGC Chronic Myeloid Disorders Group; ICGC Prostate Cancer Group, Foster CS, Warren AY, Whitaker HC, Brewer D, Eeles R, Cooper C, Neal D, Visakorpi T, Isaacs WB, Bova GS, Flanagan AM, Futreal PA, Lynch AG, Chinnery PF, McDermott U, Stratton MR, Campbell PJ. (2014)
Origins and functional consequences of somatic mitochondrial DNA mutations in human cancer. eLife, 3:e02935
Tubio JM, Li Y, Ju YS, Martincorena I, Cooke SL, Tojo M, Gundem G, Pipinikas CP, Zamora J, Raine K, Menzies A, Roman-Garcia P, Fullam A, Gerstung M, Shlien A, Tarpey PS, Papaemmanuil E, Knappskog S, Van Loo P, Ramakrishna M, Davies HR, Marshall J, Wedge DC, Teague JW, Butler AP, Nik-Zainal S, Alexandrov L, Behjati S, Yates LR, Bolli N, Mudie L, Hardy C, Martin S, McLaren S, O'Meara S, Anderson E, Maddison M, Gamble S; ICGC Breast Cancer Group; ICGC Bone Cancer Group; ICGC Prostate Cancer Group, Foster C, Warren AY, Whitaker H, Brewer D, Eeles R, Cooper C, Neal D, Lynch AG, Visakorpi T, Isaacs WB, van't Veer L, Caldas C, Desmedt C, Sotiriou C, Aparicio S, Foekens JA, Eyfjord JE, Lakhani SR, Thomas G, Myklebost O, Span PN, Borresen-Dale AL, Richardson AL, Van de Vijver M, Vincent-Salomon A, Van den Eynden GG, Flanagan AM, Futreal PA, Janes SM, Bova GS, Stratton MR, McDermott U, Campbell PJ (2014)
Extensive transduction of nonrepetitive DNA mediated by L1 retrotransposition in cancer genomes. Science, 345(6196):1251343
Go H, Jung YJ, Kang HW, Park IK, Kang CH, Lee JW, Ju YS, Seo JS, Chung DH, Kim YT. (2013)
Diagnostic method for the detection of KIF5B-RET transformation in lung adenocarcinoma. Lung Cancer, 82(1):44-50
Kim HJ, Yoo YJ, Ju YS, Lee S, Cho SI, Sung J, Kim JI, Seo JS. (2013)
Combined linkage and association analyses identify a novel locus for obesity near PROX1 in Asians. Obesity (Silver Spring), 21(11):2405-12
Hong D, Lee J, Bleazard T, Jung H, Ju YS, Yu SB, Kim S, Park SS, Kim JI, Seo JS. (2013)
TIARA genome database: update 2013. Database (Oxford), 2013:bat003
Bleazard T, Ju YS, Sung J, Seo JS. (2013)
Fine-scale mapping of meiotic recombination in Asians. BMC Genet., 14:19
Park H, Kim HJ, Lee S, Yoo YJ, Ju YS, Lee JE, Cho SI, Sung J, Kim JI, Seo JS. (2013)
A family-based association study after genome-wide linkage analysis identified two genetic loci for renal function in a Mongolian population. Kidney Int., 83(2):285-92
Park H, Lee S, Kim HJ, Ju YS, Shin JY, Hong D, von Grotthuss M, Lee DS, Park C, Kim JH, Kim B, Yoo YJ, Cho SI, Sung J, Lee C, Kim JI, Seo JS. (2012)
Comprehensive genomic analyses associate UGT8 variants with musical ability in a Mongolian population. J Med Genet., 49(12):747-52
Seo JS, Ju YS, Lee WC, Shin JY, Lee JK, Bleazard T, Lee J, Jung YJ, Kim JO, Shin JY, Yu SB, Kim J, Lee ER, Kang CH, Park IK, Rhee H, Lee SH, Kim JI, Kang JH, Kim YT. (2012)
The transcriptional landscape and mutational profile of lung adenocarcinoma. Genome Res., 22(11):2109-19
Hong D, Rhie A, Park SS, Lee J, Ju YS, Kim S, Yu SB, Bleazard T, Park HS, Rhee H, Chong H, Yang KS, Lee YS, Kim IH, Lee JS, Kim JI, Seo JS. (2012)
FX: an RNA-Seq analysis tool on the cloud. Bioinformatics, 28(5):721-3
Paik SH, Kim HJ, Son HY, Lee S, Im SW, Ju YS, Yeon JH, Jo SJ, Eun HC, Seo JS, Kwon OS, Kim JI. (2012)
Gene mapping study for constitutive skin color in an isolated Mongolian population. Exp Mol Med., 44(3):241-9
Ju YS, Lee WC, Shin JY, Lee S, Bleazard T, Won JK, Kim YT, Kim JI, Kang JH, Seo JS. (2012)
A transforming KIF5B and RET gene fusion in lung adenocarcinoma revealed from whole-genome and transcriptome sequencing. Genome Res., 22(3):436-45
Graduate students : 박성열,육정환,안요한,강규혁,이기종,임준오
Administrative assistants : 김효정