Identification of acquired Notch3 dependency in metastatic Head and Neck Cancer

Abstract

During cancer development, tumor cells acquire changes that enable them to invade surrounding tissues and seed metastasis at distant sites. These changes contribute to the aggressiveness of metastatic cancer and interfere with success of therapy. Our comprehensive analysis of “matched” pairs of HNSCC lines derived from primary tumors and corresponding metastatic sites identified several components of Notch3 signaling that are differentially expressed and/or altered in metastatic lines and confer a dependency on this pathway. These components were also shown to be differentially expressed between early and late stages of tumors in a TMA constructed from over 200 HNSCC patients. Finally, we show that suppression of Notch3 improves survival in mice in both subcutaneous and orthotopic models of metastatic HNSCC. Novel treatments targeting components of this pathway may prove effective in targeting metastatic HNSCC cells alone or in combination with conventional therapies.

Identification of Muc1-C as a Target for Suppressing Progression of Head and Neck Squamous Cell Carcinomas

“… 8, 9, 30–32, 70 ). By extension and in addition to ∆Np63 and SOX2, we found that MUC1-C regulates expression of NOTCH3, which is necessary for HNSCC cell self-renewal and progression ( 35 ).…”

“…Functional and genomic analyses have identified an important role for the NOTCH3 stemness factor in HNSCC progression ( 35 ). Silencing MUC1-C in CAL27 and HSC3 cells decreased expression of (i) NOTCH3, (ii) jagged canonical ligand 1 (JAG1), (iii) the delta-like ligand 3 (DLL3), and (iv) downstream NOTCH target HEY1 (refs.…”

“…Silencing MUC1-C in CAL27 and HSC3 cells decreased expression of (i) NOTCH3, (ii) jagged canonical ligand 1 (JAG1), (iii) the delta-like ligand 3 (DLL3), and (iv) downstream NOTCH target HEY1 (refs. 35, 60 ; Fig. 6A ; Supplementary Fig.…”

Optimization of a Three-Dimensional Culturing Method for Assessing the Impact of Cisplatin on Notch Signaling in Head and Neck Squamous Cell Carcinoma (HNSCC)

“…This may further include functional compensation between the four NOTCH receptors, especially in advanced, aggressive tumor cells, although this potential is currently very poorly understood and under-researched. Only recently, evidence for a potential compensation between NOTCH1 and NOTCH3, with an increased dependence of metastatic HNSCC on NOTCH3 overexpression, has been reported [15]. Functional compensation may overcome the loss of NOTCH1 in the early stages of cancer initiation and recovery of Notch signaling activity, thus acquiring a potentially oncogenic role that may promote tumor progression, relapse, invasion, tumor cell plasticity, and drug resistance-similar to the situation observed in TNBC.…”

“…For example, it has recently been reported that overexpression of NOTCH1 in HNSCC may be associated with poor patient survival and therapy outcome [13], expanding on earlier reports that increased NOTCH1 expression may be associated with cisplatin resistance in HNSCC [14]. Another recent report further suggests the involvement of NOTCH3 (over-) expression in metastatic HNSCC [15]. On the other hand, Notch ligands are rarely mutated, deleted, or amplified, but JAG1 and JAG2 are overexpressed in more than 30% of HNSCC [16].…”