Slit2/Robo1 signaling inhibits small‐cell lung cancer by targeting β‐catenin signaling in tumor cells and macrophages

Abstract

Small‐cell lung cancer (SCLC) is an aggressive neuroendocrine subtype of lung cancer with poor patient prognosis. However, the mechanisms that regulate SCLC progression and metastasis remain undefined. Here, we show that the expression of the slit guidance ligand 2 ( SLIT2 ) tumor suppressor gene is reduced in SCLC tumors relative to adjacent normal tissue. In addition, the expression of the SLIT2 receptor, roundabout guidance receptor 1 ( ROBO1 ), is upregulated. We find a positive association between SLIT2 expression and the Yes1 associated transcriptional regulator ( YAP1 )‐expressing SCLC subtype (SCLC‐Y), which shows a better prognosis. Using genetically engineered SCLC cells, adenovirus gene therapy, and preclinical xenograft models, we show that SLIT2 overexpression or the deletion of ROBO1 restricts tumor growth in vitro and in vivo . Mechanistic studies revealed significant inhibition of myeloid‐derived suppressor cells (MDSCs) and M2‐like tumor‐associated macrophages (TAMs) in the SCLC tumors. In addition, SLIT2 enhances M1‐like and phagocytic macrophages. Molecular analysis showed that ROBO1 knockout or SLIT2 overexpression suppresses the transforming growth factor beta 1 (TGF‐β1)/β‐catenin signaling pathway in both tumor cells and macrophages. Overall, we find that SLIT2 and ROBO1 have contrasting effects on SCLC tumors. SLIT2 suppresses, whereas ROBO1 promotes, SCLC growth by regulating the Tgf‐β1/glycogen synthase kinase‐3 beta (GSK3)/β‐catenin signaling pathway in tumor cells and TAMs. These studies indicate that SLIT2 could be used as a novel therapeutic agent against aggressive SCLC.

High-accuracy prediction of colorectal cancer chemotherapy efficacy using machine learning applied to gene expression data

“…Additionally, in colon cancer, SLIT2/ROBO1 has been shown to encourage tumor growth. On the other hand, SLIT2 has been shown to suppress β-catenin levels which are positively correlated with chemotherapy resistance ( Ahirwar et al, 2021 ; Ahirwar et al, 2023 ). The responders show a reduced SLIT2 expression which should reduce the contributions of SLIT2 signaling.…”

The genomic landscape of the immune system in lung cancer: present insights and continuing investigations

“…Additionally, inhibition of Wnt/β-catenin signaling with the molecular inhibitor of Wnt secretion, LGK-974, increased M1 markers and decreased M2 markers in NSCLC cells (A549 and H1299) ( Tang et al, 2021 ). Moreover, the TGF-β1/β-catenin pathway in tumor cells and TAMs was observed to be involved in SCLC pathogenesis ( Ahirwar et al, 2023 ). In gene silencing/upregulating studies, different genes have been discovered downstream of the β-catenin pathway.…”

“…Furthermore, it was discovered that slit guidance ligand 2 (SLIT2) and its receptor, roundabout guidance receptor 1 (ROBO1), are downstream of the TGF-β1/β-catenin pathway. SLIT2 has been identified as a tumor suppressor gene in SCLC, with its expression significantly reduced in this type of tumor, while ROBO1 expression is significantly higher in SCLC cells compared to adjacent normal cells ( Peifer et al, 2012 ; Ahirwar et al, 2023 ). Overexpression of SLIT2 and deletion of ROBO1 in SCLC cells have shown the anti-tumor and pro-tumor effects of SLIT2 and ROBO1, respectively, through macrophage polarization ( Ahirwar et al, 2023 ).…”

PIEZO2 promotes cell proliferation and metastasis in colon carcinoma through the SLIT2/ROBO1/VEGFC pathway

“…Studies on the expression and function of SLIT/ROBO signaling in various cancers have been conducted. [13][14][15] Recently, the molecular mechanism of SLIT2/ ROBO1 signaling in the regulation of colon cancer tumorigenesis has also been deeply studied. The SLIT2 was highly expressed in colon cancer and its expression increased in pathological stages.…”