Neuroblastoma (NB) is a childhood cancer arising from neural crest cells. Despite aggressive therapy, NB with distant metastasis is associated with an overall survival rate of 30-50%. Thus, NB metastasis poses a significant obstacle in achieving remission. NB adhesion receptors in the integrin family, impact cell adhesion, migration, proliferation and survival. Integrin [alpha]4, a fibronectin and vascular cell adhesion molecule-1 (VCAM-1) receptor, is essential for neural crest cell motility during development. In adults, integrin [alpha]4 is primarily expressed on leukocytes and is critical for transendothelial migration. Accordingly, cancer cells that express this receptor may acquire an enhanced ability to extravasate into surrounding tissues, increasing their metastatic potential. The work described in this dissertation examines whether integrin [alpha]4 plays a role in neuroblastoma malignancy. I found that reconstitution of [alpha]4 expression in human and murine neuroblastoma cell lines selectively enhances in vitro interaction with fibronectin and VCAM-1 and increases migration. In vivo, [alpha]4 expression enhanced experimental metastasis in a syngeneic tumor model, reconstituting a pattern of organ involvement similar to that seen in patients. Accordingly, antagonism of integrin [alpha]4 blocked metastasis, suggesting adhesive function of the integrin is required. However, adhesive function was not sufficient, as mutants of integrin [alpha]4 that conserved the matrix-adhesive and promigratory function in vitro were compromised in their metastatic capacity in vivo. Clinically, integrin [alpha]4 is selectively associated with poor prognosis in non-MYCN amplified neuroblastoma. These results reveal an unexpected role for integrin [alpha]4 in neuroblastoma dissemination and identify [alpha]4 as a prognostic indicator and potential therapeutic target

High-risk neuroblastoma is associated with an overall survival rate of 30-50%. Neuroblastoma-expressed cell adhesion receptors of the integrin family impact cell adhesion, migration, proliferation and survival. Integrin α4 is essential for neural crest cell motility during development, is highly expressed on leukocytes, and is critical for transendothelial migration. Thus, cancer cells that express this receptor may exhibit increased metastatic potential. We show that α4 expression in human and murine neuroblastoma cell lines selectively enhances in vitro interaction with the alternatively spliced connecting segment 1 of fibronectin, as well as vascular cell adhesion molecule-1 and increases migration. Integrin α4 expression enhanced experimental metastasis in a syngeneic tumor model, reconstituting a pattern of organ involvement similar to that seen in patients. Accordingly, antagonism of integrin α4 blocked metastasis, suggesting adhesive function of the integrin is required. However, adhesive function was not sufficient, as mutants of integrin α4 that conserved the matrix-adhesive and promigratory function in vitro were compromised in their metastatic capacity in vivo. Clinically, integrin α4 is more frequently expressed in non-MYNC amplified tumors, and is selectively associated with poor prognosis in this subset of disease. These results reveal an unexpected role for integrin α4 in neuroblastoma dissemination and identify α4 as a potential prognostic indicator and therapeutic target.

Identification of specific oncogenic gene changes has enabled the modern generation of targeted cancer therapeutics. In high-grade serous ovarian cancer (OV), the bulk of genetic changes is not somatic point mutations, but rather somatic copy-number alterations (SCNAs). The impact of SCNAs on tumour biology remains poorly understood. Here we build haploinsufficiency network analyses to identify which SCNA patterns are most disruptive in OV. Of all KEGG pathways (N=187), autophagy is the most significantly disrupted by coincident gene deletions. Compared with 20 other cancer types, OV is most severely disrupted in autophagy and in compensatory proteostasis pathways. Network analysis prioritizes MAP1LC3B (LC3) and BECN1 as most impactful. Knockdown of LC3 and BECN1 expression confers sensitivity to cells undergoing autophagic stress independent of platinum resistance status. The results support the use of pathway network tools to evaluate how the copy-number landscape of a tumour may guide therapy.