TMED9-gated CNIH4 and TGFa signaling promotes pro-metastatic states in human primary colon cancer cells
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PROVIDER: PRJNA515737 | ENA |
REPOSITORIES: ENA
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Project description:How cells in primary tumors initially become pro-metastatic is not understood. A previous genome-wide RNAi screen uncovered colon cancer metastatic suppressor and WNT promoting functions of TMED3, a member of the p24 ER-to-Golgi protein secretion family. Repression of WNT signaling upon knock-down (kd) of TMED3 might thus be sufficient to drive metastases. However, searching for transcriptional influences on other family members here we find that TMED3 kd leads to enhanced TMED9, that TMED9 acts downstream of TMED3 and that TMED9 kd compromises metastasis. Importantly, TMED9 pro-metastatic function is linked to but distinct from the repression of TMED3-WNT-TCF signaling. Functional rescue of the migratory deficiency of TMED9 kd cells identifies TGFa as a mediator of TMED9 pro-metastatic activity. Moreover, TMED9 kd compromises the membrane localization, and thus function, of TGFa. Analyses in three colon cancer cell types highlight a TMED9-dependent gene set that includes CNIH4, a member of the CORNICHON family of TGFa exporters. Our data indicate that TGFA and CNIH4, which display predictive value for disease-free survival, promote colon cancer cell metastatic behavior and suggest that TMED9 pro-metastatic function involves the modulation of the secretion of TGFa ligand. Finally, TMED9/TMED3 antagonism impacts WNT-TCF and GLI signaling, where TMED9 primacy over TMED3 leads to the establishment of a positive feedback loop together with CNIH4, TGFa and GLI1 that enhances metastases. We suggest that primary colon cancer cells can transition between two states characterized by secretion-transcription regulatory loops gated by TMED3 and TMED9 that modulate their metastatic proclivities.
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Project description:Colorectal Cancer ranks as the second-leading cause of cancer-related death worldwide. Recent progress in colon cancer research has vastly expanded our understanding of colon cancer on the cellular and molecular levels and have improved the survival of CRC patients considerably. However, most of these genomic and gene expression profiling were usually characterized by bulk tumor tissue. In order to further understanding colon cancer, knowledge at the single cell level is urgently needed and expected to have clinical utility in cancer treatment. Single-cell transcriptome profiling of tumor tissues allows the characterization of heterogeneous tumor cells with neighbor microenvironment cell components and investigation of underlying mechanism of tumorigenesis and metastasis. Here, we adopt single cell RNA-Seq to colon cancer and analyze 3,585 cells from 6 patients with matching adjacent normal tissues, primary tumors and metastatic tumors. Most of tumor cells exhibit copy number variations and diverse CNV patterns existed. Novel markers have been identified to distinguish tumour from normal cells and even work for cancer cells that did not have CNVs. Compared with adjacent normal tissue, the number of stem cell and Paneth cell increased and the surrounding cancer-association cells like immune cells in microenvironment increased in tumour region. Moreover, the interaction of tumour cell and microenvironment cells have been elaborated. Our results demonstrate that colon cancer transcriptome has a wide range of intratumoral heterogeneity, which is shaped by tumor cells and cancer associated cells in the surrounding microenvironment.
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