1. ALK upregulates POSTN and WNT signaling to drive neuroblastoma
- Author
-
Huang, Miller, Fang, Wanqi, Farrel, Alvin, Li, Linwei, Chronopoulos, Antonios, Nasholm, Nicole, Cheng, Bo, Zheng, Tina, Yoda, Hiroyuki, Barata, Megumi J, Porras, Tania, Miller, Matthew L, Zhen, Qiqi, Ghiglieri, Lisa, McHenry, Lauren, Wang, Linyu, Asgharzadeh, Shahab, Park, JinSeok, Gustafson, W Clay, Matthay, Katherine K, Maris, John M, and Weiss, William A
- Subjects
Biological Sciences ,Genetics ,Cancer ,Pediatric ,Rare Diseases ,Neuroblastoma ,Stem Cell Research ,Neurosciences ,Pediatric Cancer ,5.1 Pharmaceuticals ,Humans ,Anaplastic Lymphoma Kinase ,Cell Adhesion Molecules ,Cell Line ,Tumor ,N-Myc Proto-Oncogene Protein ,Receptor Protein-Tyrosine Kinases ,Wnt Signaling Pathway ,ALK ,CP: Cancer ,MYCN ,POSTN ,WNT ,human pluripotent stem cells ,neuroblastoma ,Biochemistry and Cell Biology ,Medical Physiology ,Biological sciences - Abstract
Neuroblastoma is the most common extracranial solid tumor of childhood. While MYCN and mutant anaplastic lymphoma kinase (ALKF1174L) cooperate in tumorigenesis, how ALK contributes to tumor formation remains unclear. Here, we used a human stem cell-based model of neuroblastoma. Mis-expression of ALKF1174L and MYCN resulted in shorter latency compared to MYCN alone. MYCN tumors resembled adrenergic, while ALK/MYCN tumors resembled mesenchymal, neuroblastoma. Transcriptomic analysis revealed enrichment in focal adhesion signaling, particularly the extracellular matrix genes POSTN and FN1 in ALK/MYCN tumors. Patients with ALK-mutant tumors similarly demonstrated elevated levels of POSTN and FN1. Knockdown of POSTN, but not FN1, delayed adhesion and suppressed proliferation of ALK/MYCN tumors. Furthermore, loss of POSTN reduced ALK-dependent activation of WNT signaling. Reciprocally, inhibition of the WNT pathway reduced expression of POSTN and growth of ALK/MYCN tumor cells. Thus, ALK drives neuroblastoma in part through a feedforward loop between POSTN and WNT signaling.
- Published
- 2024