Notch activity regulates tumor biology in a context-dependent and complex manner. Notch may act as an oncogene or a tumor suppressor gene even within the same tumor type. Recently, Notch signaling has been implicated in cellular senescence. Yet, it remains unclear as to how cellular senescence checkpoint functions may interact with Notch-mediated oncogenic and tumor suppressor activities. Herein, we used genetically engineered human esophageal keratinocytes and esophageal squamous cell carcinoma cells to delineate the functional consequences of Notch activation and inhibition along with pharmacological intervention and RNA interference (RNAi) experiments. When expressed in a tetracycline-inducible manner, the ectopically expressed activated form of Notch1 (ICN1) displayed oncogene-like characteristics inducing cellular senescence corroborated by the induction of G0/G1 cell-cycle arrest, Rb dephosphorylation, flat and enlarged cell morphology and senescence-associated β-galactosidase activity. Notch-induced senescence involves canonical CSL/RBPJ-dependent transcriptional activity and the p16INK4A-Rb pathway. Loss of p16INK4A or the presence of human papilloma virus (HPV) E6/E7 oncogene products not only prevented ICN1 from inducing senescence, but permitted ICN1 to facilitate anchorage-independent colony formation and xenograft tumor growth with increased cell proliferation and reduced squamous-cell differentiation. Moreover, Notch1 appears to mediate replicative senescence as well as TGF-β-induced cellular senescence in non-transformed cells and that HPV E6/E7 targets Notch1 for inactivation to prevent senescence, revealing a tumor suppressor attribute of endogenous Notch1. In aggregate, cellular senescence checkpoint functions may influence dichotomous Notch activities in the neoplastic context.

JARID1 proteins are histone demethylases that both regulate normal cell fates during development and contribute to the epigenetic plasticity that underlies malignant transformation. This H3K4 demethylase family participates in multiple repressive transcriptional complexes at promoters and has broader regulatory effects on chromatin that remain ill-defined. There is growing understanding of the oncogenic and tumor suppressive functions of JARID1 proteins, which are contingent on cell context and the protein isoform. Their contributions to stem cell-like de-differentiation, tumor aggressiveness, and therapy resistance in cancer have sustained interest in the development of JARID1 inhibitors. Here we review the diverse and context-specific functions of the JARID1 proteins that may impact the utilization of emerging targeted inhibitors of this histone demethylase family in cancer therapy.

Objectives/Hypothesis Delineate factors impacting creation and use of patient-derived xenografts (PDXs) of human papilloma virus-related (HPV+) head and neck squamous cell carcinomas (HNSCCs). Study Design Laboratory-based translational study. Methods 51 surgically resected HNSCCs, including 31 HPV+ cancers, were implanted into NOD/SCID/IL-2Rγ−/− (NSG) mice using standardized methodology. Clinical and pathologic factors were tested for association with engraftment. The gross, histologic, and molecular features of established HPV+ PDXs were analyzed in comparison to their tumors of origin. Results Negative HPV status and perineural invasion (PNI) were independent, additive factors associated with increased PDX formation. Epstein-Barr Virus-positive (EBV+) human large B-cell lymphomas grew from 32% of HPV+ HNSCC cases that failed to engraft. Successfully established HPV+ PDXs retained basaloid histology and often developed cystic growth patterns typical of HPV+ nodal metastases. They also maintained elevated p16INK4A levels and expression of E6/E7 viral oncogene transcripts. Conclusion Reduced engraftment by HPV+ tumors lacking PNI likely results in selection biases in HNSCC PDX models. Formation of EBV+ lymphomas in NSG mice further reduces generation of HPV+ models and must be ruled out before long-term use of PDXs. Nevertheless, retention of distinctive pathologic traits and viral oncogene expression by HPV+ PDXs provides a viable in vivo platform for basic and translational studies as well as a resource for generating advanced in vitro models.

The sperm protein fertilinbeta, a member of the ADAM family of proteins, is implicated in sperm-egg binding in all mammals studied to date. Multivalent inhibitors containing the three amino acid binding sequence of fertilinbeta, ECD, have been shown previously to be more effective inhibitors of fertilization than their monovalent counterparts. Here, we probed sperm-egg interactions with ruthenium-catalyzed ring-opening metathesis polymers that contained from 3 to 70 ECD pharmacophores in densities ranging from 10% to 100%. Evaluation of the polymer potencies, and synthesis of a triblock copolymer from two building blocks, revealed that two multivalent contacts are sufficient for maximal inhibition, and that the distance between ECD pharmacophores required is 7-9 monomers spanning 4-5 nm. We conclude that inhibition requires recruitment of two receptors on the egg surface into an inhibitory complex.