ALK upregulates POSTN and WNT signaling to drive neuroblastoma

被引：4

作者：

Huang, Miller ^{[1
,2
,3
]}

Fang, Wanqi ^{[1
,2
,3
]}

Farrel, Alvin ^{[4
,5
,6
]}

Li, Linwei ^{[1
,2
]}

Chronopoulos, Antonios ^{[1
,2
]}

Nasholm, Nicole ^{[7
,8
]}

Cheng, Bo ^{[1
,2
]}

Zheng, Tina ^{[8
]}

Yoda, Hiroyuki ^{[7
,8
]}

Barata, Megumi J. ^{[8
]}

Porras, Tania ^{[1
,2
]}

Miller, Matthew L. ^{[7
,8
]}

Zhen, Qiqi ^{[7
,8
]}

Ghiglieri, Lisa ^{[7
,8
]}

Mchenry, Lauren ^{[8
]}

Wang, Linyu ^{[7
,8
]}

Asgharzadeh, Shahab ^{[1
,2
,3
]}

Park, Jinseok ^{[2
,3
]}

Gustafson, W. Clay ^{[9
,10
]}

Matthay, Katherine K. ^{[9
,10
]}

Maris, John M. ^{[4
,5
,11
]}

Weiss, William A. ^{[7
,8
,9
,10
]}

机构：

[1] Childrens Hosp Los Angeles, Canc & Blood Dis Inst, Los Angeles, CA 90024 USA

[2] Childrens Hosp Los Angeles, Saban Res Inst, Los Angeles, CA 90024 USA

[3] Univ Southern Calif, Keck Sch Med, Los Angeles, CA 90007 USA

[4] Childrens Hosp Philadelphia, Div Oncol, Philadelphia, PA USA

[5] Childrens Hosp Philadelphia, Ctr Childhood Canc Res, Philadelphia, PA USA

[6] Childrens Hosp Philadelphia, Dept Biomed & Hlth Informat, Philadelphia, PA USA

[7] Univ Calif San Francisco, Dept Neurol, San Francisco, CA 94143 USA

[8] Univ Calif San Francisco, Helen Diller Family Comprehens Canc Ctr, San Francisco, CA 94143 USA

[9] Univ Calif San Francisco, Dept Pediat, San Francisco, CA 94143 USA

[10] Univ Calif San Francisco, Dept Neurol Surg, San Francisco, CA 94143 USA

[11] Univ Penn, Perelman Sch Med, Dept Pediat, Philadelphia, PA USA

来源：

CELL REPORTS | 2024年 / 43卷 / 03期

关键词：

ACTIVATING MUTATIONS; N-MYC; CELLS; DIFFERENTIATION; DISEASE; KINASE; CRISPR; TUMORS;

D O I：

10.1016/j.celrep.2024.113927

中图分类号：

Q2 [细胞生物学];

学科分类号：

071009 ; 090102 ;

摘要：

Neuroblastoma is the most common extracranial solid tumor of childhood. While MYCN and mutant anaplastic lymphoma kinase (ALK(F1174L)) 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 ALK(F1174L) 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.

引用

页数：17

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