CRACD Suppresses Neuroendocrinal Plasticity of Lung Adenocarcinoma
Bongjun Kim*, Shengzhe Zhang*, Yuanjian Huang, Kyung-Pil Ko, Gengyi Zou, Jie Zhang, Sohee Jun, Kee-Beom Kim, Youn-Sang Jung, Kwon-Sik Park, Jae-Il Park
Tumor cell plasticity contributes to intratumoral heterogeneity and therapy resistance. Through cell plasticity, lung adenocarcinoma (LUAD) cells transform into neuroendocrinal (NE) cell-like tumor cells. However, the mechanisms of NE cell plasticity remain unclear. CRACD, a capping protein inhibitor, is frequently inactivated in cancers. CRACD knock-out (KO) de-represses NE-related gene expression in the pulmonary epithelium and LUAD cells. In LUAD mouse models, Cracd KO increases intratumoral heterogeneity with NE gene expression. Single-cell transcriptomic analysis showed that Cracd KO-induced NE plasticity is associated with cell de-differentiation and activated stemness-related pathways. The single-cell transcriptomes of LUAD patient tumors recapitulate that the distinct LUAD NE cell cluster expressing NE genes is co-enriched with SOX2, OCT4, and NANOG pathway activation, and impaired actin remodeling. This study reveals an unexpected role of CRACD in restricting NE cell plasticity that induces cell de-differentiation, which provides new insights into cell plasticity of LUAD.
Tumor Niche Network-Defined Subtypes Predict Immunotherapy Response of Esophageal Squamous Cell Cancer
Kyung-Pil Ko, Shengzhe Zhang, Yuanjian Huang, Bongjun Kim, Gengyi Zou, Sohee Jun, Jie Zhang, Cecilia Martin, Karen J. Dunbar, Gizem Efe, Anil K. Rustgi, Haiyang Zhang, Hiroshi Nakagawa, Jae-Il Park
Despite the promising outcome of immune checkpoint blockade (ICB), ICB resistance is a new challenge. Thus, selecting patients for specific ICB applications is crucial for maximizing therapeutic efficacy. Herein we curated 69 human esophageal squamous cell cancer (ESCC) patients’ tumor microenvironment (TME) single-cell transcriptomic datasets for ESCC subtyping. Notably, integrative analyses of the cellular network transcriptional signatures of T cells, myeloid cells, and fibroblasts define distinct ESCC subtypes characterized by T cell exhaustion, Interferon alpha and beta signaling, TIGIT enrichment, and specific marker genes. Furthermore, this approach classifies ESCC patients into ICB responders and non-responders, validated by liquid biopsy single-cell transcriptomics. This study stratifies ESCC patients by TME transcriptional network, which provides a novel insight into tumor niche remodeling and helps predict ICB responses of ESCC patients.
Loss of CRACD Tumor Suppressor Promotes Small Cell Lung Cancer Tumorigenesis via EZH2-Mediated Immune Evasion
Shengzhe Zhang*, Kee-Beom Kim*, Yuanjian Huang*, Dong-Wook Kim, Bongjun Kim, Kyung-Pil Ko, Gengyi Zou, Jie Zhang, Sohee Jun, Nicole A. Kirk, Ye Eun Hwang, Young Ho Ban, Joseph M. Chan, Charles M. Rudin, Kwon-Sik Park, Jae-Il Park
Small cell lung carcinoma (SCLC) is a type of neuroendocrine lung cancer with limited therapeutic options, including immunotherapy that has limited efficacy in a subset of SCLC patients. The mechanisms underlying immune evasion and immunotherapy resistance in SCLC remain unclear. In this study, we investigate the role of CRACD tumor suppressor in SCLC. We found that CRACD is frequently inactivated in SCLC, and Cracd knockout (KO) significantly accelerates SCLC development driven by loss of Rb1, Trp53, and Rbl2. Notably, the Cracd-deficient SCLC tumors display CD8+ T cell depletion and suppression of antigen presentation pathway. Mechanistically, CRACD loss silences the MHC-I pathway through EZH2. Inhibition of EZH2 restores the MHC-I pathway and inhibits CRACD loss-associated SCLC tumorigenesis. Additionally, single-cell transcriptomic analysis identifies SCLC patient tumors with concomitant inactivation of CRACD, impairment of tumor antigen presentation, and downregulation of EZH2 target genes. Our findings define CRACD loss as a new molecular signature associated with immune evasion of SCLC cells.
PCLAF-DREAM Drives Alveolar Cell Plasticity for Lung Regeneration
Bongjun Kim, Yuanjian Huang, Kyung-Pil Ko, Shengzhe Zhang, Gengyi Zou, Jie Zhang, Moonjong Kim, Danielle Little, Lisandra Vila Ellis, Margherita Paschini, Sohee Jun, Kwon-Sik Park, Jichao Chen, Carla Kim, Jae-Il Park
Spatiotemporal control of stem and progenitor cells is essential for lung regeneration, the failure of which leads to lung disease. However, the mechanism of alveolar cell plasticity during regeneration remains elusive. We previously found that PCLAF remodels the DREAM complex for cell cycle re-entry. PCLAF expression is specifically enriched in proliferating lung progenitor cells, along with the DREAM target genes by lung damage. Genetic ablation of Pclaf inhibited alveolar type I (AT1) cell regeneration from alveolar type II (AT2) cells, inducing lung fibrosis. Mechanistically, the PCLAF-DREAM complex directly transactivates CLIC4, promoting TGF-beta signaling that regulates the balance between AT1 and AT2 cells. Furthermore, a drug candidate that mimics the PCLAF-DREAM transcriptional signatures for lung regeneration was identified and validated in organoids and mice. Our study unveils an unexpected role of the PCLAF-DREAM axis in controlling alveolar cell plasticity for lung regeneration and proposes a viable option for lung fibrosis prevention.
Diffuse-type gastric adenocarcinoma (DGAC) is a deadly cancer often diagnosed late and resistant to treatment. While hereditary DGAC is linked to CDH1 gene mutations, causing E-Cadherin loss, its role in sporadic DGAC is unclear. We discovered CDH1 inactivation in a subset of DGAC patient tumors. Analyzing single-cell transcriptomes in malignant ascites, we identified two DGAC subtypes: DGAC1 (CDH1 loss) and DGAC2 (lacking immune response). DGAC1 displayed distinct molecular signatures, activated DGAC-related pathways, and an abundance of exhausted T cells in ascites. Genetically engineered murine gastric organoids showed that Cdh1 knock-out (KO), KrasG12D, Trp53 KO (EKP) accelerates tumorigenesis with immune evasion compared to KrasG12D, Trp53 KO (KP). We also identified EZH2 as a key mediator promoting CDH1 loss-associated DGAC tumorigenesis. These findings highlight DGAC's molecular diversity and potential for personalized treatment in CDH1-inactivated patients.
Key Genetic Determinants Driving Esophageal Squamous Cell Carcinoma Initiation and Immune Evasion
Kyung-Pil Ko, Yuanjian Huang, Shengzhe Zhang, Gengyi Zou, Bongjun Kim, Jie Zhang, Sohee Jun, Cecilia Martin, Karen J. Dunbar, Gizem Efe, Anil K. Rustgi, Hiroshi Nakagawa, Jae-Il Park
Gastroenterology 2023 Sep;165(3):613-628.e20.(https://doi.org/10.1053/j.gastro.2023.05.030)
Background and aims: Despite recent progress in identifying aberrant genetic and epigenetic alterations in esophageal squamous cell carcinoma (ESCC), the mechanism of ESCC initiation remains unknown. Methods: Using CRISPR/Cas 9-based genetic ablation, we targeted 9 genes (TP53, CDKN2A, NOTCH1, NOTCH3, KMT2D, KMT2C, FAT1, FAT4, and AJUBA) in murine esophageal organoids (EOs). Transcriptomic phenotypes of organoids and chemokine released by organoids were analyzed by single-cell RNA sequencing (scRNA-seq). Tumorigenicity of organoids and tumor-infiltrated immune cells were monitored by allograft transplantation. Human ESCC scRNA-seq datasets were analyzed to classify patients and find subsets relevant to organoid models and immune evasion. Results: We established 32 genetically engineered EOs and identified key genetic determinants that drive ESCC initiation. A single-cell transcriptomic analysis uncovered that Trp53, Cdkn2a, and Notch1 (PCN) triple knockout (KO) induces neoplastic features of ESCC by generating cell lineage heterogeneity and high cell plasticity. PCN KO also generates immunosuppressive niche enriched with exhausted T cells and M2 macrophages via the CCL2-CCR2 axis. Mechanistically, CDKN2A inactivation transactivates CCL2 via NF-B. Moreover, comparative single-cell transcriptomic analyses stratified ESCC patients and identified a specific subtype recapitulating the PCN-type ESCC signatures, including the high expression of CCL2 and CD274/PD-L1. Conclusions: Our study unveils that loss of TP53, CDKN2A, and NOTCH1 induces esophageal neoplasia and immune evasion for ESCC initiation and proposes the CCL2 blockade as a viable approach to target PCN-type ESCC.
Lysosomal TMEM9-LAMTOR4-controlled mTOR signaling integrity is required for mammary tumorigenesis
Shengzhe Zhang, Sung Ho Lee, Litong Nie, Yuanjian Huang, Gengyi Zou, Youn-sang Jung, Sohee Jun, Jie Zhang, Esther M. Lien, Junjie Chen, Jae-Il Park
Cancer Communications 2023 Jan;43(1):159-163. PMID: 36336962, PMCID: PMC9859727
Nuclear Actin Dynamics in Gene Expression, DNA Repair, and Cancer
Yuanjian Huang,* Shengzhe Zhang,* Jae-Il Park
In: Kloc, M., Kubiak, J.Z. (eds) Nuclear, Chromosomal, and Genomic Architecture in Biology and Medicine. Results and Problems in Cell Differentiation, vol 70. Springer, Cham.
Actin is a highly conserved protein in mammals. The actin dynamics is regulated by actin-binding proteins and actin-related proteins. Nuclear actin and these regulatory proteins participate in multiple nuclear processes, including chromosome architecture organization, chromatin remodeling, transcription machinery regulation, and DNA repair. It is well known that the dysfunctions of these processes contribute to the development of cancer. Moreover, emerging evidence has shown that the deregulated actin dynamics is also related to cancer. This chapter discusses how the deregulation of nuclear actin dynamics contributes to tumorigenesis via such various nuclear events.
WNT5A-RHOA signaling is a driver of tumorigenesis and represents a therapeutically actionable vulnerability in small cell lung cancer
Kee-Beom Kim, Dong-Wook Kim, Youngchul Kim, Jun Tang, Nicole Kirk, Yongyu Gan, Bongjun Kim, Bingliang Fang, Jae-Il Park, Yi Zheng, Kwon-Sik Park
Cancer Research 14 Sep 2022, CAN-22-1170. doi: 10.1158/0008-5472.CAN-22-1170
PMID: 36102736 PMCID: PMC9669186
WNT Signaling in Liver Regeneration, Disease, and Cancer
Gengyi Zou and Jae-Il Park
Clin Mol Hepatol 2022 Jul 4;. doi: 10.3350/cmh.2022.0058. PMID: 35785913
Establishing Transgenic Murine Esophageal Organoids
Kyung-Pil Ko, Jie Zhang, Jae-Il Park
STAR Protocols Volume 3, Issue 2, 17 June 2022, 101317, https://doi.org/10.1016/j.xpro.2022.101317
PMID: 35496812, PMCID: PMC9048136
KIX domain determines a selective tumor-promoting role for EP300 and its vulnerability in small-cell lung cancer
Kee-Beom Kim, Ashish Kabra, Dong-Wook Kim, Yongming Xue, Yuanjian Huang, Pei-Chi Hou, Yunpeng Zhou, Leilani J. Miranda, Jae-Il Park, Xiaobing Shi, Timothy P. Bender, John H. Bush welder, Kwon-Sik Park
Science Advances 2022 Feb 18;8(7):eabl4618. doi: 10.1126/sciadv.abl4618. Epub 2022 Feb 16, PMID: 35171684
Biyun Zheng,* Kyung-Pil Ko,* Xuefen Fang, Xiaozhong Wang, Jie Zhang, Sohee Jun, Bong-Jun Kim, Wenyi Luo, Moon Jong Kim, Youn-Sang Jung, Christopher L. Cervantes, Jae-Il Park
Supplemental Information (PDF)
Yap/Taz-Activated Tert-Expressing Acinar Cells Are Required for Pancreatic Regeneration
Han Na Suh, Moon Jong Kim, Sung Ho Lee, Sohee Jun, Jie Zhang, Randy L Johnson, and Jae-Il Park
Moon Jong Kim, Christopher Cervantes, Youn-Sang Jung, Xiaoshan Zhang, Jie Zhang, Sung Ho Lee, Sohee Jun, Larisa Litovchick, Wenqi Wang, Junjie Chen, Bingliang Fang, and Jae-Il Park
TMEM9-v-ATPase Activates Wnt/β-Catenin Signaling via APC Lysosomal Degradation for Liver Regeneration and Tumorigenesis
Youn-Sang Jung, Sabrina Stratton, Sung Ho Lee, Moon Jong Kim, Sohee Jun, Jie Zhang, Biyun Zheng, Michelle C. Barton, Jae-Il Park
Xi Shen, Rui Wang, Moon Jong Kim, Qianghua Hu, Chih-Chao Hsu, Jun Yao, Naeh Klages-Mundt, Yanyan Tian, Erica Lynn, Thomas F. Brewer, Yilei Zhang, Banu Arun, Boyi Gan, Michael Andreeff, Shunichi Takeda, Junjie Chen, Jae-il Park, Xiaobing Shi, Christopher J. Chang, Sung Yun Jung, Jun Qin, Lei Li
Molecular Cell 2020 Dec 17;80(6):1013-1024.e6. doi: 10.1016/j.molcel.2020.11.040. PubMed PMID: 33338401.
Targeting Wnt Signaling for Gastrointestinal Cancer Therapy: Present and Evolving Views
Moon Jong Kim,* YuanJian Huang,* Jae-Il Park
Cancers (Basel) 2020 Dec 4;12(12). doi: 10.3390/cancers12123638. PubMed PMID: 33291655.
Blockers of Wnt3a, Wnt10a or β-catenin prevent chemotherapy-induced neuropathic pain in vivo
Hee Kee Kim, Jingi Bae, Sung Ho Lee, Seon-Hee Hwang, Min-Sik Kim, Moon Jong Kim, Sohee Jun, Chris L. Cervantes, Youn-Sang Jung, Seunghoon Back, Hangyeore Lee, Seung-Eun Lee, Patrick M Dougherty, Sang-Won Lee, Jae-Il Park, Salahadin Abdi
Wnt Signaling in Cancer: Therapeutic Targeting of Wnt Signaling beyond β-Catenin and Destruction Complex
Youn-Sang Jung, Jae-Il Park
Experimental Molecular Medicine 2020 Feb 10;. doi: 10.1038/s12276-020-0380-6. PMID: 32037398, PMCID: PMC7062731
LncGata6-Controlled Stemness in Regeneration and Cancer
Youn-Sang Jung,* Moon Jong Kim,* Jae-Il Park
TMEM9 Promotes Intestinal Tumorigenesis via v-ATPase-Activated Wnt/β-Catenin Signaling
Youn-Sang Jung,* Sohee Jun,* Moon Jong Kim, Sung Ho Lee, Han Na Suh, Esther M. Lien, Hae-Yun Jung, Sunhye Lee, Jie Zhang, Jung-In Yang, Hong Ji, Ji Yuan Wu, Wenqi Wang, Rachel K. Miller, Junjie Chen, Pierre D. McCrea, Scott Kopetz, Jae-Il Park
PAF-Myc-Controlled Cell Stemness Is Required for Intestinal Regeneration and Tumorigenesis
Moon Jong Kim, Xia Bo, Han Na Suh, Sung Ho Lee, Sohee Jun, Esther M. Lien, Jie Zhang, Kaifu Chen, Jae-Il Park
Quiescence Exit of Tert+ Stem Cells by Wnt/β-Catenin Is Indispensable for Intestinal Regeneration
Han Na Suh, Moon Jong Kim, Youn-Sang Jung, Esther M. Lien, Sohee Jun, Jae-Il Park
Identification of KIAA1199 as a Biomarker for Pancreatic Intraepithelial Neoplasia
Suh HN,* Jun S,* Oh AY, Srivastava M, Lee S, Taniguchi CM, Zhang S, Lee WS, Chen J, Park BJ, Park JI
Scientific Reports 6:38273, 12/2016. e-Pub 12/2016. PMCID: PMC5138641
LIG4 mediates Wnt signalling-induced radioresistance
Jun S,* Jung YS,* Suh HN, Wang W, Kim MJ, Oh YS, Lien EM, Shen X, Matsumoto Y, McCrea PD, Li L, Chen J, Park JI
Nature Communications 7:10994, 2016. e-Pub 3/2016. PMCID: PMC4820809
PAF-Wnt Signaling-Induced Cell Plasticity Is Required for Maintenance of Breast Cancer Cell Stemness
Wang X,* Jung YS,* Jun S, Lee S, Wang W, Schneider A, Sun Oh Y, Lin SH, Park BJ, Chen J, Keyomarsi K, Park JI
Nature Communications doi:10.1038/ncomms10633:10633, 2016. e-Pub 2/2016. PMCID: PMC4743006
Wnt2 complements Wnt/β-catenin signaling in colorectal cancer
Jung YS, Jun S, Lee SH, Sharma A, Park JI
Oncotarget 6(35)(35):37257-68, 11/2015. e-Pub 10/2015. PMCID: PMC4741928.
PAF and EZH2 Induce Wnt/β-Catenin Signaling Hyperactivation
Jung HY, Jun S, Lee M, Kim HC, Wang X, Ji H, McCrea PD, Park JI
Molecular Cell 52(2):193-205, 10/2013. e-Pub 9/2013. PMCID: PMC4040269
PAF-Mediated MAPK Signaling Hyperactivation via LAMTOR3 Induces Pancreatic Tumorigenesis
Jun S, Lee SH, Kim HC, Ng C, Schneider AM, Ji H, Ying H, Wang H, DePinho RA, Park JI
Cell Reports e-Pub 10/2013. PMCID: PMC4157353
FOXKs Promote Wnt/β-Catenin Signaling by Translocating DVL into the Nucleus
Wang W, Li X, Lee M, Jun S, Aziz KE, Feng L, Tran MK, Li N, McCrea PD, Park JI, Chen J.
Developmental Cell 32(6):707-18, 3/2015. PMCID: PMC4374128
P120-catenin regulates REST/CoREST, and modulates mouse embryonic stem cell differentiation
Lee M, Ji H, Furuta Y, Park JI, McCrea PD.
Journal of Cell Science 127(Pt 18):4037-51, 9/2014. e-Pub 7/2014. PMCID: PMC4163646
HIV-1 Vpr Inhibits Telomerase Activity Via EDD-DDB1-VPRB3 E3 Ligase Complex
Wang X, Singh S, Jung HY, Yang G, Jun S, Sastry KJ, Park JI.
Journal of Biological Chemistry 288(22):15474-80, 5/2013. e-Pub 4/2013. PMCID: PMC3668709
Dyrk2-Associated EDD-DDB1-VprBP E3 Ligase Inhibits Telomerase by TERT Degradation
Jung HY, Wang X, Jun S, Park JI.
Journal of Biological Chemistry 288(10):7252-62, 3/2013. e-Pub 1/2013. PMCID: PMC3591633
Down's-syndrome-related kinase Dyrk1A modulates the p120-catenin-Kaiso trajectory of the Wnt signaling pathway
Hong JY, Park JI, Lee M, Muñoz WA, Miller RK, Ji H, Gu D, Ezan J, Sokol SY, McCrea PD.
Journal of Cell Science 125(Pt 3):561-9, 2/2012. PMCID: PMC3367828
PTPN14 is required for the density-dependent control of YAP1
Wang W, Huang J, Wang X, Yuan J, Li X, Feng L, Park JI, Chen J.
Genes and Development 26(17):1959-71, 9/2012. PMCID: PMC3435498
Shared molecular mechanisms regulate multiple catenin proteins: canonical Wnt signals and components modulate p120-catenin isoform-1 and additional p120 subfamily members
Hong JY, Park JI, Cho K, Gu D, Ji H, Artandi SE, McCrea PD.
Journal of Cell Science 123(Pt 24):4351-4365, 12/2010. e-Pub 11/2010. PMCID: PMC2995616
Telomerase modulates Wnt signalling by association with target gene chromatin
Park JI, Venteicher AS, Hong JY, Choi J, Jun S, Shkreli M, Chang W, Meng Z, Cheung P, Ji H, McLaughlin M, Veenstra TD, Nusse R, McCrea PD, Artandi SE.
Nature 460 (7251):66-72, 7/2009. PMCID: PMC4349391
Nature Reviews Genetics Highlights
Requirement of Wnt/beta-catenin signaling in pronephric kidney development
Lyons JP, Miller RK, Zhou X, Weidinger G, Deroo T, Denayer T, Park JI, Ji H, Hong JY, Li A, Moon RT, Jones EA, Vleminckx K, Vize PD, McCrea PD.
Mechanisms of Development e-Pub 12/2008. PMCID: PMC2684468. 126(3-4):142-59, 3/2009.
Developmental functions of the P120-catenin sub-family
McCrea PD, Park JI.
Biochimica et Biophysica Acta 2007; 1773(1):17-33. PMID: 16942809
Frodo links Dishevelled to the p120-catenin/Kaiso pathway: distinct catenin subfamilies promote Wnt signals
Park JI, Ji H, Jun S, Gu D, Hikasa H, Li L, Sokol SY, McCrea PD.
Developmental Cell 11(5):683-95, 11/2006. PMID: 17084360.
Kaiso/p120-catenin and TCF/beta-catenin complexes coordinately regulate canonical Wnt gene targets
Park JI, Kim SW, Lyons JP, Ji H, Nguyen TT, Cho K, Barton MC, Deroo T, Vleminckx K, Moon RT, McCrea PD.
Developmental Cell 8(6):843-54, 6/2005. PMID: 15935774.
Non-canonical Wnt signals are modulated by the Kaiso transcriptional repressor and p120-catenin
Kim SW, Park JI, Spring CM, Sater AK, Ji H, Otchere AA, Daniel JM, McCrea PD.
Nature Cell Biology 6(12):1212-20, 12/2004. e-Pub 11/2004. PMID: 15543138.
Vertebrate development requires ARVCF and p120 catenins and their interplay with RhoA and Rac
Fang X, Ji H, Kim SW, Park JI, Vaught TG, Anastasiadis PZ, Ciesiolka M, McCrea PD.
Journal of Cell Biology 165(1):87-98, 4/2004. e-Pub 4/2004. PMCID: PMC2172091.
Transforming growth factor-beta1 activates interleukin-6 expression in prostate cancer cells through the synergistic collaboration of the Smad2, p38-NF-kappaB, JNK, and Ras signaling pathways
Park JI, Lee MG, Cho K, Park BJ, Chae KS, Byun DS, Ryu BK, Park YK, Chi SG.
Oncogene 22(28):4314-32, 7/2003. PMID: 12853969.
Frequent monoallelic deletion of PTEN and its reciprocal association with PIK3CA amplification in gastric carcinoma
Byun DS, Cho K, Ryu BK, Lee MG, Park JI, Chae KS, Kim HJ, Chi SG.
International Journal of Cancer 104(3):318-27, 4/2003. PMID: 12569555.
Mitogenic conversion of transforming growth factor-beta1 effect by oncogenic Ha-Ras-induced activation of the mitogen-activated protein kinase signaling pathway in human prostate cancer
Park BJ, Park JI, Byun DS, Park JH, Chi SG.
Cancer Research 60(11):3031-8, 6/2000. PMID: 10850453.
Loss of imprinting and elevated expression of wild-type p73 in human gastric adenocarcinoma
Kang MJ, Park BJ, Byun DS, Park JI, Kim HJ, Park JH, Chi SG.
Clinical Cancer Research 6(5):1767-71, 5/2000. PMID: 10815895.
*Equally contributed authors.