An NFATc1/SMAD3/cJUN Complex Restricted to SMAD4-Deficient Pancreatic Cancer Guides Rational Therapies.

BACKGROUND & AIMS: The highly heterogeneous cellular and molecular makeup of pancreatic ductal adenocarcinoma (PDAC) not only fosters exceptionally aggressive tumor biology, but contradicts the current concept of one-size-fits-all therapeutic strategies to combat PDAC. Therefore, we aimed to exploit the tumor biological implication and therapeutic vulnerabilities of a clinically relevant molecular PDAC subgroup characterized by SMAD4 deficiency and high expression of the nuclear factor of activated T cells (SMAD4-/-/NFATc1High). METHODS: Transcriptomic and clinical data were analyzed to determine the prognostic relevance of SMAD4-/-/NFATc1High cancers. In vitro and in vivo oncogenic transcription factor complex formation was studied by immunoprecipitation, proximity ligation assays, and validated cross model and species. The impact of SMAD4 status on therapeutically targeting canonical KRAS signaling was mechanistically deciphered and corroborated by genome-wide gene expression analysis and genetic perturbation experiments, respectively. Validation of a novel tailored therapeutic option was conducted in patient-derived organoids and cells and transgenic as well as orthotopic PDAC models. RESULTS: Our findings determined the tumor biology of an aggressive and chemotherapy-resistant SMAD4-/-/NFATc1High subgroup. Mechanistically, we identify SMAD4 deficiency as a molecular prerequisite for the formation of an oncogenic NFATc1/SMAD3/cJUN transcription factor complex, which drives the expression of RRM1/2. RRM1/2 replenishes nucleoside pools that directly compete with metabolized gemcitabine for DNA strand incorporation. Disassembly of the NFATc1/SMAD3/cJUN complex by mitogen-activated protein kinase signaling inhibition normalizes RRM1/2 expression and synergizes with gemcitabine treatment in vivo to reduce the proliferative index. CONCLUSIONS: Our results suggest that PDAC characterized by SMAD4 deficiency and oncogenic NFATc1/SMAD3/cJUN complex formation exposes sensitivity to a mitogen-activated protein kinase signaling inhibition and gemcitabine combination therapy.

Prevalence of high-risk human papillomavirus types and cervical squamous intraepithelial lesions in women over 30 years of age in St. Petersburg, Russia.

BACKGROUND: Cytology-based screening has significantly decreased incidence of and mortality from cervical cancer. High sensitivity of high-risk human papillomavirus (hrHPV) test for the detection of high-grade cervical intraepithelial neoplasia (CIN) makes it a useful screening tool, especially in settings where cytology is not available or not quality assured. The study aimed to determine the prevalence of hrHPV and associated cervical lesions in Russian women over 30 years of age and to assess usefulness of HPV test for cervical screening in Russia. METHODS: Consecutive women aged 30-65 years (n=823) receiving routine gynaecological care, not pregnant and not treated for high-grade CIN, were recruited. Oncogenic HPV types were detected using Hybrid Capture 2 (HC2) assay and genotyped with direct DNA sequencing. Women with cytological abnormalities higher than atypical squamous cells of undetermined significance (ASCUS) and women positive for hrHPV were referred to colposcopy. RESULTS: HPV infection was present in 107 (13%) women. Cytological abnormalities were found in 81 (9.8%) patients, including 59 (7.2%) with ASCUS, 21 (2.5%) with low-grade squamous intraepithelial lesions (LSIL), and one (0.1%) with high-grade SIL. Only 11 (18.6%) patients with ASCUS were positive for hrHPV. Histological diagnoses were obtained for 63 women. Relative sensitivities and positive predictive values of the HPV test and cytology for the detection of high-grade CIN were 100% (6/6) and 9.5% (6/63), and 83.3% (5/6) and 27.8% (5/18), respectively. The most prevalent hrHPV types were 16 (3.9%), 31 (2.8%), 52 (1.7%), and 33 (1.3%). Cytological abnormalities and symptoms of a urogenital infection were strongly associated with hrHPV infection. CONCLUSIONS: The study provides data on the prevalence of hrHPV types in association with cervical lesions, as well as on hrHPV determinants, in an unvaccinated population of Russian women. Our results indicate that HPV test might be a useful screening tool in Russia.