Related Experiment Video
Updated: Apr 19, 2026
Utilizing 18F-FDG PET/CT Imaging and Quantitative Histology to Measure Dynamic Changes in the Glucose Metabolism in Mouse Models of Lung Cancer
Published on: July 21, 2018
Aberrant RSPO3-LGR4 signaling in Keap1-deficient lung adenocarcinomas promotes tumor aggressiveness
X Gong1,2, J Yi1,2, K S Carmon1,2
1Brown Foundation Institute of Molecular Medicine, University of Texas Health Science Center at Houston, Houston, TX, USA.
Abstract:
The four R-spondins (RSPO1-4) and their three related receptors LGR4, 5 and 6 (LGR4-6) have emerged as a major ligand-receptor system with critical roles in development and stem cell survival through modulation of Wnt signaling. Recurrent, gain-of-expression gene fusions of RSPO2 (to EIF3E) and RSPO3 (to PTPRK) occur in a subset of human colorectal cancer. However, the exact roles and mechanisms of the RSPO-LGR system in oncogenesis remain largely unknown. We found that RSPO3 is aberrantly expressed at high levels in approximately half of Keap1-mutated lung adenocarcinomas (ADs). This high RSPO3 expression is driven by a combination of demethylation of its own promoter region and deficiency in Keap1 instead of gene fusion as in colon cancer. Patients with RSPO3-high tumors (~9%, 36/412) displayed much poorer survival than the rest of the cohort (median survival of 28 vs 163 months, log-rank test P<0.0001). Knockdown (KD) of RSPO3, LGR4 or their signaling mediator IQGAP1 in lung cancer cell lines with Keap1 deficiency and high RSPO3-LGR4 expression led to reduction in cell proliferation and migration in vitro, and KD of LGR4 or IQGAP1 resulted in decrease in tumor growth and metastasis in vivo. These findings suggest that aberrant RSPO3-LGR4 signaling potentially acts as a driving mechanism in the aggressiveness of Keap1-deficient lung ADs.
Insights
Aberrant R-spondin 3 (RSPO3) signaling drives aggressive Keap1-mutated lung adenocarcinoma. High RSPO3 levels in these tumors correlate with poor patient survival and increased cell proliferation, migration, growth, and metastasis.
Area of Science:
- Oncology
- Molecular Biology
- Cancer Genetics
Background:
- The R-spondin-LGR system modulates Wnt signaling, crucial for development and stem cell survival.
- Gene fusions involving RSPO2 and RSPO3 are implicated in colorectal cancer.
- The role of the RSPO-LGR system in oncogenesis is not fully understood.
Purpose of the Study:
- To investigate the role of the RSPO-LGR system in Keap1-mutated lung adenocarcinomas.
- To determine the mechanism driving high RSPO3 expression in these tumors.
- To evaluate the therapeutic potential of targeting the RSPO3-LGR4 pathway.
Main Methods:
- Analysis of RSPO3 expression in lung adenocarcinoma patient cohorts.
- Investigation of RSPO3 promoter methylation and Keap1 deficiency.
- In vitro knockdown studies of RSPO3, LGR4, and IQGAP1 in lung cancer cell lines.
- In vivo studies assessing tumor growth and metastasis after LGR4 or IQGAP1 knockdown.
Main Results:
- High RSPO3 expression, driven by promoter demethylation and Keap1 deficiency, occurs in ~9% of lung adenocarcinomas.
- RSPO3-high tumors are associated with significantly poorer patient survival.
- Knockdown of RSPO3, LGR4, or IQGAP1 reduced cancer cell proliferation and migration in vitro.
- LGR4 or IQGAP1 knockdown decreased tumor growth and metastasis in vivo.
Conclusions:
- Aberrant RSPO3-LGR4 signaling is a potential driver of aggressiveness in Keap1-deficient lung adenocarcinomas.
- Targeting the RSPO3-LGR4 pathway may offer a therapeutic strategy for this patient subgroup.
Related Concept Videos
02:38The Ras Gene
Ras is a...
02:23Abnormal Proliferation
01:22PI3K/mTOR/AKT Signaling Pathway