Virtual Library
Start Your Search
P.S. Choi
Author of
-
+
MA 06 - Lung Cancer Biology I (ID 660)
- Event: WCLC 2017
- Type: Mini Oral
- Track: Biology/Pathology
- Presentations: 1
- Moderators:N. Motoi, Keith M Kerr
- Coordinates: 10/16/2017, 15:45 - 17:30, Room 501
-
+
MA 06.14 - Oncogenic SOS1 Mutations in Lung Adenocarcinoma (ID 9166)
17:10 - 17:15 | Author(s): P.S. Choi
- Abstract
- Presentation
Background:
Lung adenocarcinomas are characterized by genetic alterations along receptor tyrosine kinase pathways. Around 50% of lung adenocarcinomas contain alterations in KRAS and EGFR alone. Nonetheless, genetic drivers in a large proportion of other cases remain to be determined. Recent exome sequencing analysis of lung adenocarcinomas in our lab has identified SOS1, a guanine nucleotide exchange factor, as being significantly mutated in lung cancers lacking canonical oncogenic mutations. However, the functional significance of the mutations is unclear.
Method:
In vitro cellular assays as well as in vivo transplatation experiments were performed to determine the phenotype of SOS1 mutants. Biochemical approaches were used to determine the mechanism by which SOS1 mutants confer an oncogenic phenotype. RNA sequencing of SOS1 mutant cells was performed to transcriptionally profile the cells, and inhibitors of the RTK/Ras/MAPK pathway were tested for their efficacy against SOS1 mutants.
Result:
We demonstrate that ectopic expression of mutated SOS1 induces anchorage-independent cell growth in vitro and tumor formation in vivo. Biochemical experiments suggest mutant SOS1 drives over-activation of the Ras pathway, and through RNA sequencing, we identify an upregulation of MYC targets in cells expressing mutant SOS1. Furthermore, we demonstrate that cancer cells with mutant SOS1 are dependent on SOS1 for survival and are also sensitive to inhibitors of the MAPK pathway.
Conclusion:
Our work provides experimental evidence for the role of SOS1 as a novel oncogene and suggests possible therapeutic mechanisms to target SOS1-mutated cancers.
Only Members that have purchased this event or have registered via an access code will be able to view this content. To view this presentation, please login, select "Add to Cart" and proceed to checkout. If you would like to become a member of IASLC, please click here.
-
+
P3.02 - Biology/Pathology (ID 620)
- Event: WCLC 2017
- Type: Poster Session with Presenters Present
- Track: Biology/Pathology
- Presentations: 1
- Moderators:
- Coordinates: 10/18/2017, 09:30 - 16:00, Exhibit Hall (Hall B + C)
-
+
P3.02-086 - MGA Suppresses the MYC Pathway in Lung Adeocarcinoma (ID 8022)
09:30 - 09:30 | Author(s): P.S. Choi
- Abstract
Background:
Recent exome-sequencing efforts have revealed that the MGA gene, which encodes a heterodimeric partner of the MYC-interacting protein MAX, is significantly mutated (~8%) in lung adenocarcinomas. Most MGA mutations are loss-of-function, suggesting that MGA may act as a tumor suppressor. MGA mutations are mutually exclusive to MYC gene amplification, suggesting the involvement of MGA in the MYC pathway. Here, we aimed to characterize both the cellular and molecular role of MGA in lung adenocarcinoma, with a focus on studying its role in modulating the MYC pathway.
Method:
Chromatin immunoprecipitation-sequencing (ChIP-seq) and RNA-sequencing (RNA-seq) analysis were used to identify MYC and MGA DNA binding sites and binding motifs. Inmunoprecipitation assays and mass spectrometry were used to elucidate MGA gene repression mechanism. Cell competition assay was performed to measure cell proliferation with and without MGA overexpression. Finally, electrophoretic mobility shift assays (EMSA) were used to functionally evaluate MGA DNA binding ability to E-boxes when missense mutations in the basic-Helix-Loop-Helix (bHLH) domain of MGA occur.
Result:
We found that ectopic expression of wild-type MGA represses the cellular growth of lung adenocarcinoma cell lines. Chromatin immunoprecipitation-sequencing (ChIP-seq) and RNA-sequencing (RNA-seq) analyses revealed that MGA recognizes the same DNA binding motif as MYC, shares a large proportion of genomic DNA binding sites with MYC, and represses expression of MYC target genes. Immunoprecipitation assays in combination with mass spectrometry analysis reported that MGA interacts with several gene repressing proteins and complexes, such as the Polycomb repressive complex 1 (PRC1), histone deacetylases HDAC1/2, and the E2F6 transcriptional repressor, suggesting a potential mechanism by which MGA represses its target genes. In addition, we analyzed the mutation profile of MGA on a pan-cancer scale, revealing recurrent missense mutations in the basic-Helix-Loop-Helix (bHLH) domain of MGA in other cancer types such as colorectal and endometrial carcinomas. Electrophoretic mobility shift assays (EMSA) showed that these missense mutations impair the DNA binding ability of MGA, suggesting that these missense mutations, in addition to truncation mutations, disrupt the function of MGA in cancer cells.
Conclusion:
In summary, our results suggest that MGA plays a tumor suppressor role by binding to and repressing MYC target genes, thus expanding our current knowledge of genomic mechanisms for MYC pathway activation in cancer.
