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Published on: April 28, 2023
SEMA3C Supports Pancreatic Cancer Progression by Regulating the Autophagy Process and Tumor Immune Microenvironment
Dalin Zhang1, Aaron Lindstrom1, Edward J Kim2
1Department of Biochemistry and Molecular Medicine, UC Davis Comprehensive Cancer Center, University of California, Davis, Sacramento, CA, United States.
Abstract:
To date, driver genes for pancreatic cancer treatment are difficult to pursue therapeutically. Targeting mutated KRAS, the most renowned driver gene in pancreatic cancer, is an active area of study. We discovered a gene named SEMA3C was highly expressed in pancreatic cancer cell lines and patients with a G12D mutation in KRAS. High expression of SEMA3C in patients was significantly associated with the decreased survival of pancreatic cancer patients based on the TCGA database. In pancreatic cancer cells, SEMA3C knockdown or inhibition exhibited growth/colony inhibition and cell cycle arrest. In addition, SEMA3C inhibition sensitized KRAS or MEK1/2 inhibition in pancreatic cancer cells. Overexpression of SEMA3C resulted in the induction of autophagy, whereas depletion of SEMA3C compromised induction of autophagy. SEMA3C modified the PD-L1 expression in tumor and immune cells and is correlated with the M2-like macrophage marker ARG1/CD163 expression, which could reshape the tumor microenvironment. Inhibition of SEMA3C decreased tumor formation in the xenograft model in vivo. Taken together, our data suggest that SEMA3C plays a substantial role in promoting cancer cell survival by regulating the autophagy process and impacting the tumor environment immune response. SEMA3C can be used as a novel target or marker with therapeutic or diagnostic potential in pancreatic cancer especially in tumors harboring the specific KRAS G12D mutation.
Insights
SEMA3C is highly expressed in pancreatic ductal adenocarcinoma (PDAC) with KRAS G12D mutations, promoting cancer cell survival and impacting the tumor microenvironment. Targeting SEMA3C offers therapeutic potential for PDAC patients.
Area of Science:
- Oncology
- Molecular Biology
- Cancer Genetics
Background:
- Driver genes in pancreatic cancer, particularly KRAS mutations, present therapeutic challenges.
- SEMA3C is identified as a gene of interest in pancreatic ductal adenocarcinoma (PDAC).
Purpose of the Study:
- To investigate the role of SEMA3C in PDAC, especially in tumors with KRAS G12D mutations.
- To evaluate SEMA3C as a potential therapeutic target or diagnostic marker for PDAC.
Main Methods:
- Analysis of SEMA3C expression in PDAC cell lines and patient data (TCGA database).
- In vitro studies involving SEMA3C knockdown/inhibition and overexpression in PDAC cells.
- In vivo xenograft models to assess the effect of SEMA3C inhibition on tumor growth.
- Assessment of autophagy, PD-L1, and immune cell markers (ARG1/CD163) in response to SEMA3C modulation.
Main Results:
- High SEMA3C expression correlates with decreased survival in PDAC patients with KRAS G12D mutations.
- SEMA3C inhibition suppressed PDAC cell proliferation, induced cell cycle arrest, and sensitized cells to KRAS/MEK inhibition.
- SEMA3C regulates autophagy and influences the tumor microenvironment by modulating PD-L1 and M2-like macrophage markers.
- Inhibition of SEMA3C reduced tumor formation in vivo.
Conclusions:
- SEMA3C promotes PDAC cell survival via autophagy regulation and impacts the tumor immune microenvironment.
- SEMA3C represents a promising therapeutic target and diagnostic marker for PDAC, particularly in KRAS G12D-mutated tumors.
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