ASPM Activates Hedgehog and Wnt Signaling to Promote Small Cell Lung Cancer Stemness and Progression

Abstract

Small cell lung cancer (SCLC) is among the most aggressive and lethal human malignancies. Most patients with SCLC who initially respond to chemotherapy develop disease relapse. Therefore, there is a pressing need to identify novel driver mechanisms of SCLC progression to unlock treatment strategies to improve patient prognosis. SCLC cells comprise subsets of cells possessing progenitor or stem cell properties, while the underlying regulatory pathways remain elusive. Here, we identified the isoform 1 of the neurogenesis-associated protein ASPM (ASPM-I1) as a prominently upregulated stemness-associated gene during the self-renewal of SCLC cells. The expression of ASPM-I1 was found to be upregulated in SCLC cells and tissues, correlated with poor patient prognosis, and indispensable for SCLC stemness and tumorigenesis. A reporter array screening identified multiple developmental signaling pathways, including Hedgehog (Hh) and Wnt pathways, whose activity in SCLC cells depended upon ASPM-I1 expression. Mechanistically, ASPM-I1 stabilized the Hh transcriptional factor GLI1 at the protein level through a unique exon-18-encoded region by competing with the E3 ligases β-TrCP and CUL3. In parallel, ASPM-I1 sustains the transcription of the Hh pathway transmembrane regulator SMO through the WntDVL3β-catenin signaling axis. Functional studies verified that the ASPM-I1-regulated Hh and Wnt activities significantly contributed to SCLC aggressiveness in vivo. Consistently, the expression of ASPM-I1 positively correlated with GLI1 and stemness markers in SCLC tissues. This study illuminates an ASPM-I1-mediated regulatory module that drives tumor stemness and progression in SCLC, providing an exploitable diagnostic and therapeutic target.

ASPM stabilizes the NOTCH intracellular domain 1 and promotes oncogenesis by blocking FBXW7 binding in hepatocellular carcinoma cells

“…ASPM positively regulates the protein stability of its binding partners, such as cyclin E, DVL, GLI1, and BRCA1, in neuro‐progenitor cells and cancer cells [18,19,21,29,34,35]. Since the expression of NICD is under strict regulation by specific E3‐ubiquitin ligases [36,37], we posited that ASPM‐i1 might regulate the protein stability of NICD1 in HCC cells.…”

“…The development-associated Notch signaling pathway is activated in a considerable subset of human HCC and contributes to tumor development and progression [10][11][12]. The reported roles of ASPM in neurogenesis and development-associated pathways, such as the Wnt and Hedgehog signaling pathways [29], prompted speculation about its role in the Notch pathway in HCC cells. Consistently, gene set enrichment analyses (GSEA) of the TCGA-LIHC data set revealed that the Notch pathway gene sets are significantly enriched in patients with HCC with high ASPM expression (Fig.…”

Knockdown of TOP2A suppresses IL‐17 signaling pathway and alleviates the progression of ulcerative colitis

“…26 ASPM has also been shown to promote cancer progression. 27,28 TOP2A and CDNK3 have been screened to be involved in colorectal cancer progression. 29 Currently, TOP2 has been widely used in targeted therapy of cancers.…”

“…Chen et al identify 14 key genes related to the pathogenesis of colon cancer, including CEP55, TOP2A, RRM2, NCAPG2, providing new directions for elucidating the molecular mechanisms of colon cancer 26 . ASPM has also been shown to promote cancer progression 27,28 . TOP2A and CDNK3 have been screened to be involved in colorectal cancer progression 29 …”

Natural compounds: Wnt pathway inhibitors with therapeutic potential in lung cancer

“…In summary, aberrant Wnt/β-catenin activation maintains LC stem cell-like characteristics and promotes LC progression. The Wnt/β-catenin signaling pathway has been implicated in the regulation of CSCs, although the underlying regulatory pathways of CSCs remain elusive ( Cheng et al, 2023 ).…”