Your browser doesn't support javascript.
loading
Epithelial SOX9 drives progression and metastases of gastric adenocarcinoma by promoting immunosuppressive tumour microenvironment.
Fan, Yibo; Li, Yuan; Yao, Xiaodan; Jin, Jiangkang; Scott, Ailing; Liu, Bovey; Wang, Shan; Huo, Longfei; Wang, Ying; Wang, Ruiping; Pool Pizzi, Melissa; Ma, Lang; Shao, Shan; Sewastjanow-Silva, Matheus; Waters, Rebecca; Chatterjee, Deyali; Liu, Bin; Shanbhag, Namita; Peng, Guang; Calin, George Adrian; Mazur, Pawel Karol; Hanash, Samir M; Ishizawa, Jo; Hirata, Yuki; Nagano, Osamu; Wang, Zhenning; Wang, Linghua; Xian, Wa; McKeon, Frank; Ajani, Jaffer A; Song, Shumei.
Afiliação
  • Fan Y; Department of Gastrointestinal Medical Oncology, The University of Texas MD Anderson Cancer Center, Houston, TX, USA.
  • Li Y; Department of Surgical Oncology and General Surgery, First Hospital of China Medical University, Shenyang, PR China.
  • Yao X; Department of Gastrointestinal Medical Oncology, The University of Texas MD Anderson Cancer Center, Houston, TX, USA.
  • Jin J; Department of Gastrointestinal Medical Oncology, The University of Texas MD Anderson Cancer Center, Houston, TX, USA.
  • Scott A; Department of Gastrointestinal Medical Oncology, The University of Texas MD Anderson Cancer Center, Houston, TX, USA.
  • Liu B; Department of Biology and Biochemistry, University of Houston, Houston, TX, USA.
  • Wang S; Department of Biology and Biochemistry, University of Houston, Houston, TX, USA.
  • Huo L; Department of Gastrointestinal Medical Oncology, The University of Texas MD Anderson Cancer Center, Houston, TX, USA.
  • Wang Y; Department of Gastrointestinal Medical Oncology, The University of Texas MD Anderson Cancer Center, Houston, TX, USA.
  • Wang R; Departments of Genomic Medicine, The University of Texas MD Anderson Cancer Center, Houston, TX, USA.
  • Pool Pizzi M; Department of Gastrointestinal Medical Oncology, The University of Texas MD Anderson Cancer Center, Houston, TX, USA.
  • Ma L; Department of Gastrointestinal Medical Oncology, The University of Texas MD Anderson Cancer Center, Houston, TX, USA.
  • Shao S; Department of Gastrointestinal Medical Oncology, The University of Texas MD Anderson Cancer Center, Houston, TX, USA.
  • Sewastjanow-Silva M; Department of Gastrointestinal Medical Oncology, The University of Texas MD Anderson Cancer Center, Houston, TX, USA.
  • Waters R; Department of Pathology, The University of Texas MD Anderson Cancer Center, Houston, TX, USA.
  • Chatterjee D; Department of Pathology, The University of Texas MD Anderson Cancer Center, Houston, TX, USA.
  • Liu B; Department of Epigenet & Mol Carcinogenesis, The University of Texas MD Anderson Cancer Center, Houston, TX, USA.
  • Shanbhag N; Department of Gastrointestinal Medical Oncology, The University of Texas MD Anderson Cancer Center, Houston, TX, USA.
  • Peng G; Department of Clinical Cancer Prevention, The University of Texas MD Anderson Cancer Center, Houston, TX, USA.
  • Calin GA; Department of Translational Molecular Pathology, The University of Texas MD Anderson Cancer Center, Houston, TX, USA.
  • Mazur PK; Department of Experimental Radiation Oncology, The University of Texas MD Anderson Cancer Center, Houston, TX, USA.
  • Hanash SM; Department of Clinical Cancer Prevention, The University of Texas MD Anderson Cancer Center, Houston, TX, USA.
  • Ishizawa J; Department of Leukemia, The University of Texas MD Anderson Cancer Center, Houston, TX, USA.
  • Hirata Y; Department of Surgical Oncology, The University of Texas MD Anderson Cancer Center, Houston, TX, USA.
  • Nagano O; Division of Gene Regulation, Institute for Advanced Medical Research, Keio University School of Medicine Graduate School of Medicine, Tokyo, Japan.
  • Wang Z; Department of Surgical Oncology and General Surgery, First Hospital of China Medical University, Shenyang, PR China.
  • Wang L; Departments of Genomic Medicine, The University of Texas MD Anderson Cancer Center, Houston, TX, USA.
  • Xian W; Department of Biology and Biochemistry, University of Houston, Houston, TX, USA.
  • McKeon F; Department of Biology and Biochemistry, University of Houston, Houston, TX, USA.
  • Ajani JA; Department of Gastrointestinal Medical Oncology, The University of Texas MD Anderson Cancer Center, Houston, TX, USA ssong@mdanderson.org jajani@mdanderson.org jajani@mdanderson.org.
  • Song S; Department of Gastrointestinal Medical Oncology, The University of Texas MD Anderson Cancer Center, Houston, TX, USA ssong@mdanderson.org jajani@mdanderson.org jajani@mdanderson.org.
Gut ; 72(4): 624-637, 2023 04.
Article em En | MEDLINE | ID: mdl-36002248
ABSTRACT

OBJECTIVE:

Many cancers engage embryonic genes for rapid growth and evading the immune system. SOX9 has been upregulated in many tumours, yet the role of SOX9 in mediating immunosuppressive tumour microenvironment is unclear. Here, we aim to dissect the role of SOX9-mediated cancer stemness attributes and immunosuppressive microenvironment in advanced gastric adenocarcinoma (GAC) for novel therapeutic discoveries.

METHODS:

Bulk RNAseq/scRNA-seq, patient-derived cells/models and extensive functional studies were used to identify the expression and functions of SOX9 and its target genes in vitro and in vivo. Immune responses were studied in PBMCs or CD45+ immune cells cocultured with tumour cells with SOX9high or knockout and the KP-Luc2 syngeneic models were used for efficacy of combinations.

RESULTS:

SOX9 is one of the most upregulated SOX genes in GAC and highly expressed in primary and metastatic tissues and associated with poor prognosis. Depletion of SOX9 in patient-derived GAC cells significantly decreased cancer stemness attributes, tumour formation and metastases and consistently increased CD8+ T cell responses when cocultured with PBMCs/CD45+ cells from GAC patients. RNA sequencing identified the leukaemia inhibitory factor (LIF) as the top secreted molecule regulated by SOX9 in tumour cells and was enriched in malignant ascites and mediated SOX9-induced M2 macrophage repolarisation and inhibited T cell function.

CONCLUSION:

Epithelial SOX9 is critical in suppressing CD8+ T cell responses and modified macrophage function in GAC through the paracrine LIF factor. Cotargeting LIF/LIFR and CSF1R has great potential in targeting SOX9-mediated cancer stemness, T cell immunosuppression and metastases suggesting the novel combination therapy against advanced GAC.
Assuntos
Palavras-chave
Texto completo
Adicionar na Minha BVS
Imprimir
XML
PubMed Links
Buscar no Google

Texto completo: 1 Bases de dados: MEDLINE Assunto principal: Neoplasias Gástricas / Adenocarcinoma Tipo de estudo: Prognostic_studies Limite: Humans Idioma: En Revista: Gut Ano de publicação: 2023 Tipo de documento: Article País de afiliação: Estados Unidos
Texto completo
Adicionar na Minha BVS
Imprimir
XML
PubMed Links
Buscar no Google

Texto completo: 1 Bases de dados: MEDLINE Assunto principal: Neoplasias Gástricas / Adenocarcinoma Tipo de estudo: Prognostic_studies Limite: Humans Idioma: En Revista: Gut Ano de publicação: 2023 Tipo de documento: Article País de afiliação: Estados Unidos