Friday, April 25, 2025
4/25/2025
Targeting the ROR2/p-GSK3bS9 pathway to suppress metastasis in SMARCA4-deficient lung adenocarcinoma - Metastatic lung cancer kills >160,000 people in the US annually, and 10%-50% of patients with surgically resected lung cancer will develop distant metastasis. There remains an unmet need to understand the tumor genomics that drive metastases. SMARCA4 is the most frequently mutated member of the SWI/SNF complex in lung adenocarcinoma (LUAD), and its alterations are associated with development of metastatic disease. Whereas SMARCA4 canonically acts as a chromatin remodeler, mechanistic investigations from our lab reveal a noncanonical ROR2/p-GSK3βS9 pathway involved in loss-of-SMARCA4–mediated transcriptional regulation and metastasis in LUAD. Specifically, knockdown of SMARCA4 in LUAD cells increases invasion and metastases. Increased SMARCA2 upregulates ROR2 and inhibition of ROR2 abrogates invasion and metastasis of SMARCA4-deficient LUAD. Moreover, ROR2 increases the abundance of transcription factor C/EBPa by inactivation of nuclear GSK3b. Using a GSK3β inhibitor, we rescued invasion of SMARCA4KD/ROR2KD cells. Our overarching goals are 1) to elucidate the mechanisms through which SMARCA4-deficient LUAD regulates transcription and promotes metastases and 2) to determine the role of ROR2/p-GSK3βS9 pathway in metastasis of SMARCA4-deficient LUAD. Two specific aims will test our hypotheses. Aim 1: Investigate the mechanisms through which deficiency of SMARCA4 promotes metastasis of LUAD. We will perform RNA-seq, ChIP-seq, ATAC-seq, and selected reaction monitoring–mass spectrometry using LUAD SMARCA4dTAG cells to measure gene transcription and chromatin accessibility and to quantify transcription factors in real time. An in vivo CRISPR/sgRNA screen will be performed to identify functional downstream transcription factors of ROR2/p-GSK3βS9 pathway. Next, we will use mass spectrometry and immunoFISH to decode the mechanism(s) through which SMARCA2 upregulates ROR2 in SMARCA4-deficient LUAD and to explore alternative target(s) to suppress metastases. Aim 2: Evaluate the therapeutic efficacy of targeting ROR2 to suppress metastasis in SMARCA4-deficient LUAD. We will assess the clinical relevance of ROR2/p-GSK3βS9 pathway in SMARCA4-altered LUAD by leveraging our clinically annotated biorepository of >2000 human LUAD specimens. We will then use our LUAD patient-derived organoid model to examine the requirement for p-GSK3βS9 for metastases of SMARCA4-altered LUAD and to test whether pharmacologic inhibition of ROR2 using an antibody-drug conjugate currently in clinical trials decreases metastases in SMARCA4-deficient LUAD. Finally, using a published KrasLSL-G12D/Trp53fl/fl/Smarca4fl/fl genetically engineered mouse model, we will investigate the cell-specific dependency of ROR2/p-GSK3βS9 pathway. Impact: Our work will provide mechanistic and translational evidence that will highlight deficiency of SMARCA4 as an important metastatic driver in LUAD through ROR2/p-GSK3βS9 pathway and will provide an important preclinical justification for future clinical trials targeting ROR2 in SMARCA4-deficient LUAD to decrease metastasis.
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