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  • American Association for Cancer Research (AACR)  (4)
  • 1
    Online Resource
    Online Resource
    Abstract 836: CRACD/CRAD , a tumor suppressor for gastric cancer development
    American Association for Cancer Research (AACR) ; 2022
    In:  Cancer Research Vol. 82, No. 12_Supplement ( 2022-06-15), p. 836-836
    Details
    In: Cancer Research, American Association for Cancer Research (AACR), Vol. 82, No. 12_Supplement ( 2022-06-15), p. 836-836
    Abstract: Gastric cancer (GC) is the third most common cancer and the second most common cause of cancer death in Asia. The highest incidence rates are observed in Eastern Asia. To date, the comprehensive mechanism of GC initiation remains elusive. Here, we discovered CRACD (Capping Protein Inhibiting Regulator of Actin Dynamics/CRAD/KIAA1211) as a tumor suppressor, frequently inactivated in GC. To determine the pathologic roles of CRACD, we employed Cracd knock-out (KO) mice and gastric organoids (GOs). Intriguingly, Cracd KO mice and GOs displayed hyperplastic gastric epithelium. Mechanistically, CRACD is essential for stabilizing the cadherin-catenin-actin (CCA) complex. The loss of CRACD leads to the release and nuclear translocation of β-catenin for Wnt target gene transactivation. Indeed, the genetic ablation of Cracd hyperactivated Wnt/β-catenin signaling with the disruption of the CCA complex. The genes encoding the Receptor Tyrosine Kinase (RTK)-RAS signaling pathway and the TP53 are genetically altered in 60% and 50% of gastric adenocarcinomas, respectively. To define the genetic interaction of Cracd loss with the RTK-RAS and TP53 signaling, we established genetically engineered GOs models carrying Trp53 deletion and KrasG12D activation in combination with Cracd KO (CKP) or Cracd wild type (KP). Compared to KP, CKP GOs exhibited neoplasia, higher mucin deposition, and increased carcinoma embryonic antigen (CEA) expression, pathologically related to the poor prognosis in GC patients. Meanwhile, loss of Cracd significantly accelerated the growth of CKP GOs with increased stemness. Furthermore, the CKP cell line derived from GOs exhibited relatively poor prognosis features of GC than KP cells in the xenograft models, represented by boosted tumor size and weight, poor differentiation, hyperplasia, increased CEA, and mucin secretion. Together, we identified CRACD as a tumor suppressor, of which inactivation contributes to GC initiation and progression, which may be translated into the development of a biomarker-guided regimen for CRACD mutations-associated GC patients. Citation Format: Gengyi Zou, Yuanjian Huang, Kyung Pil Ko, Shengzhe Zhang, Bong Jun Kim, Jie Zhang, Sohee Jun, Youn-Sang Jung, Biyun Zheng, Jae-Il Park. CRACD/CRAD, a tumor suppressor for gastric cancer development [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2022; 2022 Apr 8-13. Philadelphia (PA): AACR; Cancer Res 2022;82(12_Suppl):Abstract nr 836.
    Type of Medium: Online Resource
    ISSN: 1538-7445
    URL: Article
    DOI: 10.1158/1538-7445.AM2022-836
    Language: English
    Publisher: American Association for Cancer Research (AACR)
    Publication Date: 2022
    detail.hit.zdb_id: 2036785-5
    detail.hit.zdb_id: 1432-1
    detail.hit.zdb_id: 410466-3
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  • 2
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    Online Resource
    Abstract 1714: CRACD/KIAA1211 loss drives cell plasticity and immune evasion of small cell lung cancer
    American Association for Cancer Research (AACR) ; 2023
    In:  Cancer Research Vol. 83, No. 7_Supplement ( 2023-04-04), p. 1714-1714
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    In: Cancer Research, American Association for Cancer Research (AACR), Vol. 83, No. 7_Supplement ( 2023-04-04), p. 1714-1714
    Abstract: Small cell lung carcinoma (SCLC) is a lethal neuroendocrine type of lung cancer with limited therapeutic options. Despite recent advances in cancer immunotherapy, its efficacy is limited to a small subset of SCLC patient tumors. The molecular origin of the refractoriness to immunotherapy remains elusive. CRACD (Capping protein inhibiting regulator of actin dynamics; KIAA1211/CRAD) gene is frequently mutated and transcriptionally downregulated in SCLC. Cracd knockout (KO) causes the transformation of preneoplastic neuroendocrine cells and significantly accelerates SCLC development in a mouse model initiated by the loss of Rb1, Trp53, and Rbl2 in the lung epithelium. Cracd KO induces tumor cell plasticity generating deregulated cell lineage trajectories of SCLC tumors. Strikingly, Cracd KO SCLC tumors display the complete loss of CD8+ T cells due to epigenetic suppression of the MHC-I pathway. Furthermore, single-cell transcriptomic analyses of SCLC patient samples classified SCLC by concurrent features: CRACD inactivation and tumor antigen presentation impairment. This study suggests CRACD as a tumor suppressor of SCLC that regulates proliferation and immune recognition of cells, providing novel insight into the mechanism of SCLC evading immune surveillance. Citation Format: Shengzhe Zhang, Kee-Bum 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. CRACD/KIAA1211 loss drives cell plasticity and immune evasion of small cell lung cancer [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 1 (Regular and Invited Abstracts); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(7_Suppl):Abstract nr 1714.
    Type of Medium: Online Resource
    ISSN: 1538-7445
    URL: Article
    DOI: 10.1158/1538-7445.AM2023-1714
    Language: English
    Publisher: American Association for Cancer Research (AACR)
    Publication Date: 2023
    detail.hit.zdb_id: 2036785-5
    detail.hit.zdb_id: 1432-1
    detail.hit.zdb_id: 410466-3
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  • 3
    Online Resource
    Online Resource
    Direct Targeting of MEK1/2 and RSK2 by Silybin Induces Cell-Cycle Arrest and Inhibits Melanoma Cell Growth
    American Association for Cancer Research (AACR) ; 2013
    In:  Cancer Prevention Research Vol. 6, No. 5 ( 2013-05-01), p. 455-465
    Details
    In: Cancer Prevention Research, American Association for Cancer Research (AACR), Vol. 6, No. 5 ( 2013-05-01), p. 455-465
    Abstract: Abnormal functioning of multiple gene products underlies the neoplastic transformation of cells. Thus, chemopreventive and/or chemotherapeutic agents with multigene targets hold promise in the development of effective anticancer drugs. Silybin, a component of milk thistle, is a natural anticancer agent. In the present study, we investigated the effect of silybin on melanoma cell growth and elucidated its molecular targets. Our study revealed that silybin attenuated the growth of melanoma xenograft tumors in nude mice. Silybin inhibited the kinase activity of mitogen-activated protein kinase (MEK)-1/2 and ribosomal S6 kinase (RSK)-2 in melanoma cells. The direct binding of silybin with MEK1/2 and RSK2 was explored using a computational docking model. Treatment of melanoma cells with silybin attenuated the phosphorylation of extracellular signal-regulated kinase (ERK)-1/2 and RSK2, which are regulated by the upstream kinases MEK1/2. The blockade of MEK1/2-ERK1/2-RSK2 signaling by silybin resulted in a reduced activation of NF-κB, activator protein-1, and STAT3, which are transcriptional regulators of a variety of proliferative genes in melanomas. Silybin, by blocking the activation of these transcription factors, induced cell-cycle arrest at the G1 phase and inhibited melanoma cell growth in vitro and in vivo. Taken together, silybin suppresses melanoma growth by directly targeting MEK- and RSK-mediated signaling pathways. Cancer Prev Res; 6(5); 455–65. ©2013 AACR.
    Type of Medium: Online Resource
    ISSN: 1940-6207 , 1940-6215
    URL: Article
    DOI: 10.1158/1940-6207.CAPR-12-0425
    Language: English
    Publisher: American Association for Cancer Research (AACR)
    Publication Date: 2013
    detail.hit.zdb_id: 2422346-3
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  • 4
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    Online Resource
    Abstract 943: Modeling and dissecting of esophageal squamous cell carcinoma initiation
    American Association for Cancer Research (AACR) ; 2022
    In:  Cancer Research Vol. 82, No. 12_Supplement ( 2022-06-15), p. 943-943
    Details
    In: Cancer Research, American Association for Cancer Research (AACR), Vol. 82, No. 12_Supplement ( 2022-06-15), p. 943-943
    Abstract: Esophageal cancer is the 7th common cancer with the 6th highest cancer mortality rate worldwide. The 5-year survival rate of esophageal cancer is 10 ~ 25%. Esophageal cancer is mainly divided into esophageal squamous cell carcinoma (ESCC) and esophageal adenocarcinoma. ESCC accounts for 80% of all esophageal cancer cases and shows a poor prognosis due to a lack of symptoms at early stages. Given that early diagnosis of ESCC may lead to better outcomes, understanding the biology of ESCC initiation is imperative. To recapitulate the early events of ESCC, we employed the murine esophageal organoid (EO) system recently developed. Based on in silico analyses, we selected nine candidate genes (TP53, CDKN2A, NOTCH1, NOTCH3, KMT2D, KMT2C, FAT1, FAT4, and AJUBA) frequently mutated in ESCC patients. The EOs were then genetically manipulated with the combinatorial ablation of nine genes by CRISPR/Cas9 system. The EOs carrying PN (Trp53 and Notch1 KO), PC (Trp53 and Cdkn2a KO), and PCN (Trp53, Cdkn2a, and Notch1 KO) showed hyperplastic and neoplastic properties with impaired squamous cell differentiation and organoid integrity, compared to the wild-type (WT) EOs. Single-cell RNA-seq (scRNA-seq) analyses of WT, PC, PN, and PCN organoids showed the highest enrichment of ESCC cancer stem cell markers in PCN organoids. Unlike the cell lineage in WT EOs, neoplastic EOs (PC, PN, and PCN) exhibited distinct cell lineage along with multiple root cell clusters. While WT EOs failed to become neoplastic, PN, PC, and PCN EOs displayed the transforming activity in vitro and in vivo xenograft transplantation assays. Intriguingly, in allograft mouse models, while PN organoids-derived cells barely developed tumors, PC and PCN organoids-derived cells developed tumors with marked downregulation of genes related to antigen processing and presentation. These results suggest that combinatorial loss of P53, CDKN2A, and NOTCH1 play a pivotal role in ESCC neoplasia, stemness, and immune checkpoint, unveiling the biology of ESCC initiation. Citation Format: Kyung Pil Ko, Gengyi Zou, Yuanjian Huang, Bongjun Kim, Jie Zhang, Sohee Jun, Jae-Il Park. Modeling and dissecting of esophageal squamous cell carcinoma initiation [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2022; 2022 Apr 8-13. Philadelphia (PA): AACR; Cancer Res 2022;82(12_Suppl):Abstract nr 943.
    Type of Medium: Online Resource
    ISSN: 1538-7445
    URL: Article
    DOI: 10.1158/1538-7445.AM2022-943
    Language: English
    Publisher: American Association for Cancer Research (AACR)
    Publication Date: 2022
    detail.hit.zdb_id: 2036785-5
    detail.hit.zdb_id: 1432-1
    detail.hit.zdb_id: 410466-3
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