Cell Reports (Mar 2024)
ALK upregulates POSTN and WNT signaling to drive neuroblastoma
- Miller Huang,
- Wanqi Fang,
- Alvin Farrel,
- Linwei Li,
- Antonios Chronopoulos,
- Nicole Nasholm,
- Bo Cheng,
- Tina Zheng,
- Hiroyuki Yoda,
- Megumi J. Barata,
- Tania Porras,
- Matthew L. Miller,
- Qiqi Zhen,
- Lisa Ghiglieri,
- Lauren McHenry,
- Linyu Wang,
- Shahab Asgharzadeh,
- JinSeok Park,
- W. Clay Gustafson,
- Katherine K. Matthay,
- John M. Maris,
- William A. Weiss
Affiliations
- Miller Huang
- Children’s Hospital Los Angeles, Cancer and Blood Disease Institutes, and The Saban Research Institute, Los Angeles, CA, USA; Keck School of Medicine, University of Southern California, Los Angeles, CA, USA; Corresponding author
- Wanqi Fang
- Children’s Hospital Los Angeles, Cancer and Blood Disease Institutes, and The Saban Research Institute, Los Angeles, CA, USA; Keck School of Medicine, University of Southern California, Los Angeles, CA, USA
- Alvin Farrel
- Division of Oncology and Center for Childhood Cancer Research, Children’s Hospital of Philadelphia, Philadelphia, PA, USA; Department of Biomedical and Health Informatics, Children’s Hospital of Philadelphia, Philadelphia, PA, USA
- Linwei Li
- Children’s Hospital Los Angeles, Cancer and Blood Disease Institutes, and The Saban Research Institute, Los Angeles, CA, USA
- Antonios Chronopoulos
- Children’s Hospital Los Angeles, Cancer and Blood Disease Institutes, and The Saban Research Institute, Los Angeles, CA, USA
- Nicole Nasholm
- Department of Neurology, University of California, San Francisco, San Francisco, CA, USA; Helen Diller Family Comprehensive Cancer Center, University of California, San Francisco, San Francisco, CA, USA
- Bo Cheng
- Children’s Hospital Los Angeles, Cancer and Blood Disease Institutes, and The Saban Research Institute, Los Angeles, CA, USA
- Tina Zheng
- Helen Diller Family Comprehensive Cancer Center, University of California, San Francisco, San Francisco, CA, USA
- Hiroyuki Yoda
- Department of Neurology, University of California, San Francisco, San Francisco, CA, USA; Helen Diller Family Comprehensive Cancer Center, University of California, San Francisco, San Francisco, CA, USA
- Megumi J. Barata
- Department of Neurology, University of California, San Francisco, San Francisco, CA, USA; Helen Diller Family Comprehensive Cancer Center, University of California, San Francisco, San Francisco, CA, USA
- Tania Porras
- Children’s Hospital Los Angeles, Cancer and Blood Disease Institutes, and The Saban Research Institute, Los Angeles, CA, USA
- Matthew L. Miller
- Department of Neurology, University of California, San Francisco, San Francisco, CA, USA; Helen Diller Family Comprehensive Cancer Center, University of California, San Francisco, San Francisco, CA, USA
- Qiqi Zhen
- Department of Neurology, University of California, San Francisco, San Francisco, CA, USA; Helen Diller Family Comprehensive Cancer Center, University of California, San Francisco, San Francisco, CA, USA
- Lisa Ghiglieri
- Department of Neurology, University of California, San Francisco, San Francisco, CA, USA; Helen Diller Family Comprehensive Cancer Center, University of California, San Francisco, San Francisco, CA, USA
- Lauren McHenry
- Helen Diller Family Comprehensive Cancer Center, University of California, San Francisco, San Francisco, CA, USA
- Linyu Wang
- Department of Neurology, University of California, San Francisco, San Francisco, CA, USA; Helen Diller Family Comprehensive Cancer Center, University of California, San Francisco, San Francisco, CA, USA
- Shahab Asgharzadeh
- Children’s Hospital Los Angeles, Cancer and Blood Disease Institutes, and The Saban Research Institute, Los Angeles, CA, USA; Keck School of Medicine, University of Southern California, Los Angeles, CA, USA
- JinSeok Park
- Children’s Hospital Los Angeles, Cancer and Blood Disease Institutes, and The Saban Research Institute, Los Angeles, CA, USA; Keck School of Medicine, University of Southern California, Los Angeles, CA, USA
- W. Clay Gustafson
- Helen Diller Family Comprehensive Cancer Center, University of California, San Francisco, San Francisco, CA, USA; Departments of Pediatrics and Neurological Surgery, University of California, San Francisco, San Francisco, CA, USA
- Katherine K. Matthay
- Departments of Pediatrics and Neurological Surgery, University of California, San Francisco, San Francisco, CA, USA
- John M. Maris
- Division of Oncology and Center for Childhood Cancer Research, Children’s Hospital of Philadelphia, Philadelphia, PA, USA; Department of Pediatrics, Perelman School of Medicine at the University of Pennsylvania, Philadelphia, PA, USA
- William A. Weiss
- Department of Neurology, University of California, San Francisco, San Francisco, CA, USA; Helen Diller Family Comprehensive Cancer Center, University of California, San Francisco, San Francisco, CA, USA; Departments of Pediatrics and Neurological Surgery, University of California, San Francisco, San Francisco, CA, USA; Corresponding author
- Journal volume & issue
-
Vol. 43,
no. 3
p. 113927
Abstract
Summary: 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.
