BackgroundPeriodontal disease in pregnancy is considered a risk factor for adverse birth outcomes. Periodontal disease has a microbial etiology, however, the current state of knowledge about the subgingival microbiome in pregnancy is not well understood.ObjectiveTo characterize the structure and diversity of the subgingival microbiome in early and late pregnancy and explore relationships between the subgingival microbiome and preterm birth among pregnant Black women.MethodsThis longitudinal descriptive study used 16S rRNA sequencing to profile the subgingival microbiome of 59 Black women and describe microbial ecology using alpha and beta diversity metrics. We also compared microbiome features across early (8-14 weeks) and late (24-30 weeks) gestation overall and according to gestational age at birth outcomes (spontaneous preterm, spontaneous early term, full term).ResultsIn this sample of Black pregnant women, the top twenty bacterial taxa represented in the subgingival microbiome included a spectrum representative of various stages of biofilm progression leading to periodontal disease, including known periopathogens Porphyromonas gingivalis and Tannerella forsythia. Other organisms associated with periodontal disease reflected in the subgingival microbiome included several Prevotella spp., and Campylobacter spp. Measures of alpha or beta diversity did not distinguish the subgingival microbiome of women according to early/late gestation or full term/spontaneous preterm birth; however, alpha diversity differences in late pregnancy between women who spontaneously delivered early term and women who delivered full term were identified. Several taxa were also identified as being differentially abundant according to early/late gestation, and full term/spontaneous early term births.ConclusionsAlthough the composition of the subgingival microbiome is shifted toward complexes associated with periodontal disease, the diversity of the microbiome remains stable throughout pregnancy. Several taxa were identified as being associated with spontaneous early term birth. Two, in particular, are promising targets of further investigation. Depletion of the oral commensal Lautropia mirabilis in early pregnancy and elevated levels of Prevotella melaninogenica in late pregnancy were both associated with spontaneous early term birth.

Oncogenic RAS mutations drive aggressive cancers that are difficult to treat in the clinic, and while direct inhibition of the most common KRAS variant in lung adenocarcinoma (G12C) is undergoing clinical evaluation, a wide spectrum of oncogenic RAS variants together make up a large percentage of untargetable lung and GI cancers. Here we report that loss-of-function alterations (mutations and deep deletions) in the gene that encodes HD-PTP (PTPN23) occur in up to 14% of lung cancers in the ORIEN Avatar lung cancer cohort, associate with adenosquamous histology, and occur alongside an altered spectrum of KRAS alleles. Furthermore, we show that in publicly available early-stage NSCLC studies loss of HD-PTP is mutually exclusive with loss of LKB1, which suggests they restrict a common oncogenic pathway in early lung tumorigenesis. In support of this, knockdown of HD-PTP in RAS-transformed lung cancer cells is sufficient to promote FAK-dependent invasion. Lastly, knockdown of the Drosophila homolog of HD-PTP (dHD-PTP/Myopic) synergizes to promote RAS-dependent neoplastic progression. Our findings highlight a novel tumor suppressor that can restrict RAS-driven lung cancer oncogenesis and identify a targetable pathway for personalized therapeutic approaches for adenosquamous lung cancer.

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The acquisition of invasive properties is a prerequisite for tumor progression and metastasis. Molecular subtypes of KRAS-driven lung cancer exhibit distinct modes of invasion that likely contribute to unique growth properties and therapeutic susceptibilities. Despite this, pre-clinical discovery strategies designed to exploit invasive phenotypes are lacking. To address this, we designed an experimental system to screen for targetable signaling pathways linked to active early invasion phenotypes in the two most prominent molecular subtypes, TP53 and LKB1, of KRAS-driven lung adenocarcinoma (LUAD). By combining live-cell imaging of human bronchial epithelial cells in a 3D invasion matrix with RNA transcriptome profiling, we identified the LKB1-specific upregulation of bone morphogenetic protein 6 (BMP6). Examination of early-stage lung cancer patients confirmed upregulation of BMP6 in LKB1-mutant lung tumors. At the molecular level, we find that the canonical iron regulatory hormone Hepcidin is induced via BMP6 signaling upon LKB1 loss, where intact LKB1 kinase activity is necessary to maintain signaling homeostasis. Furthermore, pre-clinical studies in a novel Kras/Lkb1-mutant syngeneic mouse model show that potent growth suppression was achieved by inhibiting the ALK2/BMP6 signaling axis with single agents that are currently in clinical trials. We show that alterations in the iron homeostasis pathway are accompanied by simultaneous upregulation of ferroptosis protection proteins. Thus, LKB1 is sufficient to regulate both the gas and breaks to finely tune iron-regulated tumor progression.