JAK Kinase Inhibition Abrogates STAT3 Activation and Head and Neck Squamous Cell Carcinoma Tumor Growth

Sen, Malabika; Pollock, Netanya; Black, John J.; DeGrave, Kara A.; Wheeler, Sarah; Freilino, Maria L.; Joyce, Sonali; Lui, Vivian Wai Yan; Zeng, Yan; Chiosea, Simion I.; Grandis, Jennifer R.

doi:10.1016/j.neo.2015.01.003

Cited by 64 publications

(48 citation statements)

References 34 publications

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“…Hypomethylated, overexpressed genes included LCK in C5 and SYK (Figure 4D; Tables S2K and S2L). These are SRC family kinases implicated in signal activation of STAT transcription factors in SCC and in activated immune cells expressing immunoregulatory checkpoint molecules (Lund et al, 1999; Ma et al, 2015; Sen et al, 2015). …”

Section: Resultsmentioning

confidence: 99%

Genomic, Pathway Network, and Immunologic Features Distinguishing Squamous Carcinomas

Campbell¹,

Yau²,

Bowlby³

et al. 2018

Cell Reports

275

303

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SUMMARY This integrated, multiplatform PanCancer Atlas study co-mapped and identified distinguishing molecular features of squamous cell carcinomas (SCCs) from five sites associated with smoking and/or human papillomavirus (HPV). SCCs harbor 3q, 5p, and other recurrent chromosomal copy-number alterations (CNAs), DNA mutations, and/or aberrant methylation of genes and microRNAs, which are correlated with the expression of multi-gene programs linked to squamous cell stemness, epithelial-to-mesenchymal differentiation, growth, genomic integrity, oxidative damage, death, and inflammation. Low-CNA SCCs tended to be HPV(+) and display hypermethylation with repression of TET1 demethylase and FANCF, previously linked to predisposition to SCC, or harbor mutations affecting CASP8, RAS-MAPK pathways, chromatin modifiers, and immunoregulatory molecules. We uncovered hypomethylation of the alternative promoter that drives expression of the ΔNp63 oncogene and embedded miR944. Co-expression of immune checkpoint, T-regulatory, and Myeloid suppressor cells signatures may explain reduced efficacy of immune therapy. These findings support possibilities for molecular classification and therapeutic approaches.

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Section: Resultsmentioning

confidence: 99%

Genomic, Pathway Network, and Immunologic Features Distinguishing Squamous Carcinomas

Campbell¹,

Yau²,

Bowlby³

et al. 2018

Cell Reports

275

303

View full text Add to dashboard Cite

show abstract

“…On the other hand, PTEN or PIK3CA mutations are rather infrequent in HNC, 7% and 8% respectively (44). Hence, in the setting of HNC the intrinsic oncogenic signaling mostly depends on overexpressed wild type EGFR stimulation and presents as a unique feature of this type of cancer, in which the JAK/STAT3 oncogenic pathway is best characterized (45). Importantly, in our series, STAT3 showed no significant correlation with PD-L1 expression in HPV + tumors and only a weak correlation in HPV − tumors, most likely because of higher EGFR expression in these tumors versus HPV + ones.…”

Section: Discussionmentioning

confidence: 99%

Identification of the Cell-Intrinsic and -Extrinsic Pathways Downstream of EGFR and IFNγ That Induce PD-L1 Expression in Head and Neck Cancer

et al. 2016

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Many cancer types, including head and neck cancers (HNC), express programmed death ligand 1 (PD-L1). Interaction between PD-L1 and its receptor, programmed death 1 (PD-1), inhibits the function of activated T cells and results in an immunosuppressive microenvironment, but the stimuli that induce PD-L1 expression are not well characterized. Interferon gamma (IFNγ) and the epidermal growth factor receptor (EGFR) utilize Janus kinase 2 (JAK2) as a common signaling node to transmit tumor cell-mediated extrinsic or intrinsic signals, respectively. In this study, we investigated the mechanism by which these factors upregulate PD-L1 expression in HNC cells in the context of JAK/STAT pathway activation, Th1 inflammation, and HPV status. We found that wild type, overexpressed EGFR significantly correlated with JAK2 and PD-L1 expression in a large cohort of HNC specimens. Furthermore, PD-L1 expression was induced in an EGFR- and JAK2/STAT1-dependent manner, and specific JAK2 inhibition prevented PD-L1 upregulation in tumor cells and enhanced their immunogenicity. Collectively, our findings suggest a novel role for JAK2/STAT1 in EGFR-mediated immune evasion, and therapies targeting this signaling axis may be beneficial to block PD-L1 upregulation found in a large subset of HNC tumors.

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“…The heterogeneous nature of cancer and the known changes that arise when tumors are immortalized in cell culture contribute to the limitations of cell line-derived xenograft model systems (24–26). We developed patient-derived xenografts from primary HNSCC specimens in an effort to better understand the capacity and limitations of these models as well as to test discrete hypotheses regarding response to molecular targeted therapies (3, 27, 28). Some studies have demonstrated no difference in engraftment with tumor biology or clinical characteristics (8), while other studies have demonstrated some increase in engraftment with poorly differentiated primary HNSCC or the presence of nodal disease (29).…”

Section: Discussionmentioning

confidence: 99%

Proteomic Characterization of Head and Neck Cancer Patient–Derived Xenografts

Wheeler

Park

et al. 2016

Molecular Cancer Research

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Despite advances in treatment approaches for head and neck squamous cell carcinoma (HNSCC), survival rates have remained stagnant due to the paucity of preclinical models that accurately reflect the human tumor. Patient-derived xenografts (PDXs) are an emerging model system where patient tumors are implanted directly into mice. Increased understanding of the application and limitations of PDXs will facilitate their rational use. Studies to date have not reported protein profiles of PDXs. Therefore, we developed a large cohort of HNSCC PDXs and found that tumor take rate was not influenced by the clinical, pathologic or processing features. Protein expression profiles, from a subset of the PDXs, were characterized by reverse phase protein array (RPPA) and the data was compared to The Cancer Genome Atlas (TCGA) HNSCC data. Cluster analysis revealed that HNSCC PDXs were more similar to primary HNSCC than to any other tumor type. Interestingly, while a significant fraction of proteins were expressed similarly in both primary HNSCC and PDXs, a subset of proteins/phosphoproteins were expressed at higher (or lower) levels in PDXs compared to primary HNSCC. These findings indicate that the proteome is generally conserved in PDXs, but mechanisms for both positive and negative model selection and/or differences in the stromal components exist. Implications Proteomic characterization of HNSCC PDXs demonstrates potential drivers for model selection and provides a framework for improved utilization of this expanding model system.

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JAK Kinase Inhibition Abrogates STAT3 Activation and Head and Neck Squamous Cell Carcinoma Tumor Growth

Cited by 64 publications

References 34 publications

Genomic, Pathway Network, and Immunologic Features Distinguishing Squamous Carcinomas

Genomic, Pathway Network, and Immunologic Features Distinguishing Squamous Carcinomas

Identification of the Cell-Intrinsic and -Extrinsic Pathways Downstream of EGFR and IFNγ That Induce PD-L1 Expression in Head and Neck Cancer

Proteomic Characterization of Head and Neck Cancer Patient–Derived Xenografts

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