Three cytochrome P450 enzymes consecutively catalyze the biosynthesis of furanoclerodane precursors in Salvia species.

Salvia species native to the Americas are rich in valuable bioactive furanoclerodanes, like the psychoactive salvinorin A found in Salvia divinorum, which is used in treatment of opioid addiction. However, there is relatively little known about their biosynthesis. To address this, we investigated the biosynthesis of salviarin, the most abundant furanoclerodane structure in the ornamental sage Salvia splendens.

The genomes of medicinal skullcaps reveal the polyphyletic origins of clerodane diterpene biosynthesis in the family Lamiaceae.

The presence of anticancer clerodane diterpenoids is a chemotaxonomic marker for the traditional Chinese medicinal plant Scutellaria barbata, although the molecular mechanisms behind clerodane biosynthesis are unknown. Here, we report a high-quality assembly of the 414.98 Mb genome of S.

Deciphering and reprogramming the cyclization regioselectivity in bifurcation of indole alkaloid biosynthesis.

The metabolism of monoterpene indole alkaloids (MIAs) is an outstanding example of how plants shape chemical diversity from a single precursor. Here we report the discovery of novel enzymes from the tree, a cytochrome P450, an NADPH dependent oxidoreductase and a BAHD acyltransferase that together synthesize the indole alkaloid akuammiline with a unique methanoquinolizidine cage structure. The two paralogous cytochrome P450 enzymes rhazimal synthase (AsRHS) and geissoschizine oxidase (AsGO) catalyse the cyclization of the common precursor geissoschizine and they direct the MIA metabolism towards to the two structurally distinct and medicinally important MIA classes of and alkaloids, respectively.

Cancer-associated mesothelial cells promote ovarian cancer chemoresistance through paracrine osteopontin signaling.

Ovarian cancer is the leading cause of gynecological malignancy-related deaths, due to its widespread intraperitoneal metastases and acquired chemoresistance. Mesothelial cells are an important cellular component of the ovarian cancer microenvironment that promote metastasis. However, their role in chemoresistance is unclear.

Eliminating hypoxic tumor cells improves response to PARP inhibitors in homologous recombination-deficient cancer models.

Hypoxia, a hallmark feature of the tumor microenvironment, causes resistance to conventional chemotherapy, but was recently reported to synergize with poly(ADP-ribose) polymerase inhibitors (PARPis) in homologous recombination-proficient (HR-proficient) cells through suppression of HR. While this synergistic killing occurs under severe hypoxia (<0.5% oxygen), our study shows that moderate hypoxia (2% oxygen) instead promotes PARPi resistance in both HR-proficient and -deficient cancer cells.

Neutralization of PD-L2 is Essential for Overcoming Immune Checkpoint Blockade Resistance in Ovarian Cancer.

Purpose: Ovarian cancer represents a major clinical hurdle for immune checkpoint blockade (ICB), with reported low patient response rates. We found that the immune checkpoint ligand PD-L2 is robustly expressed in patient samples of ovarian cancers and other malignancies exhibiting suboptimal response to ICB but not in cancers that are ICB sensitive. Therefore, we hypothesize that PD-L2 can facilitate immune escape from ICB through incomplete blockade of the PD-1 signaling pathway.

The mA RNA demethylase FTO is a HIF-independent synthetic lethal partner with the VHL tumor suppressor.

Loss of the von Hippel-Lindau (VHL) tumor suppressor is a hallmark feature of renal clear cell carcinoma. VHL inactivation results in the constitutive activation of the hypoxia-inducible factors (HIFs) HIF-1 and HIF-2 and their downstream targets, including the proangiogenic factors VEGF and PDGF. However, antiangiogenic agents and HIF-2 inhibitors have limited efficacy in cancer therapy due to the development of resistance.

Metabolic Profiling Reveals a Dependency of Human Metastatic Breast Cancer on Mitochondrial Serine and One-Carbon Unit Metabolism.

Breast cancer is the most common cancer among American women and a major cause of mortality. To identify metabolic pathways as potential targets to treat metastatic breast cancer, we performed metabolomics profiling on the breast cancer cell line MDA-MB-231 and its tissue-tropic metastatic subclones. Here, we report that these subclones with increased metastatic potential display an altered metabolic profile compared with the parental population.

S100A10 Is a Critical Mediator of GAS6/AXL-Induced Angiogenesis in Renal Cell Carcinoma.

Angiogenesis is a hallmark of cancer that promotes tumor progression and metastasis. However, antiangiogenic agents have limited efficacy in cancer therapy due to the development of resistance. In clear cell renal cell carcinoma (ccRCC), AXL expression is associated with antiangiogenic resistance and poor survival.

Establishment of peripheral blood mononuclear cell-derived humanized lung cancer mouse models for studying efficacy of PD-L1/PD-1 targeted immunotherapy.

Animal models used to evaluate efficacies of immune checkpoint inhibitors are insufficient or inaccurate. We thus examined two xenograft models used for this purpose, with the aim of optimizing them. One method involves the use of peripheral blood mononuclear cells and cell line-derived xenografts (PBMCs-CDX model).

CD215+ Myeloid Cells Respond to Interleukin 15 Stimulation and Promote Tumor Progression.

Interleukin 15 (IL-15) regulates the development, survival, and functions of multiple innate and adaptive immune cells and plays a dual role in promoting both tumor cell growth and antitumor immunity. Here, we demonstrated that the injection of recombinant human IL-15 (200 µg/kg) or murine IL-15 (3 µg/kg) to tumor-bearing NOD- (NSI) mice resulted in increased tumor progression and CD45+ CD11b+ Gr-1+ CD215+ cell expansion in the tumors and spleen. In B16F10-bearing C57BL/6 mice model, we found that murine IL-15 has antitumoral effect since the activation and expansion of CD8+ T cells with murine IL-15 treatment.

Heterogeneity of CD34 and CD38 expression in acute B lymphoblastic leukemia cells is reversible and not hierarchically organized.

The existence and identification of leukemia-initiating cells in adult acute B lymphoblastic leukemia (B-ALL) remain controversial. We examined whether adult B-ALL is hierarchically organized into phenotypically distinct subpopulations of leukemogenic and non-leukemogenic cells or whether most B-ALL cells retain leukemogenic capacity, irrespective of their immunophenotype profiles. Our results suggest that adult B-ALL follows the stochastic stem cell model and that the expression of CD34 and CD38 in B-ALL is reversibly and not hierarchically organized.

GZD824 suppresses the growth of human B cell precursor acute lymphoblastic leukemia cells by inhibiting the SRC kinase and PI3K/AKT pathways.

Available therapeutic options for advanced B cell precursor acute lymphoblastic leukemia (pre-B ALL) are limited. Many lead to neutropenia, leaving patients at risk of life-threatening infections and result in bad outcomes. New treatment options are needed to improve overall survival.

Repulsive guidance molecule B inhibits metastasis and is associated with decreased mortality in non-small cell lung cancer.

Repulsive guidance molecules (RGMs) are co-receptors of bone morphogenetic proteins (BMPs) and programmed death ligand 2 (PD-L2), and might be involved in lung and other cancers. We evaluated repulsive guidance molecule B (RGMB) expression in 165 non-small cell lung cancer (NSCLC) tumors and 22 normal lung tissue samples, and validated the results in an independent series of 131 samples. RGMB was downregulated in NSCLC (P ≤ 0.

A New Strategy to Target Acute Myeloid Leukemia Stem and Progenitor Cells Using Chidamide, a Histone Deacetylase Inhibitor.

Leukemia stem cells (LSCs) are responsible for treatment failure and relapse in acute myeloid leukemia (AML). Therefore, development of novel LSCs-targeting therapeutic strategies is of crucial clinical importance to improve the treatment outcomes of AML. Histone deacetylase (HDAC) inhibitors have shown potent and specific anticancer stem cell activities in preclinical studies.

Quantitative evaluation of the immunodeficiency of a mouse strain by tumor engraftments.

Background: The mouse is an organism that is widely used as a mammalian model for studying human physiology or disease, and the development of immunodeficient mice has provided a valuable tool for basic and applied human disease research. Following the development of large-scale mouse knockout programs and genome-editing tools, it has become increasingly efficient to generate genetically modified mouse strains with immunodeficiency. However, due to the lack of a standardized system for evaluating the immuno-capacity that prevents tumor progression in mice, an objective choice of the appropriate immunodeficient mouse strains to be used for tumor engrafting experiments is difficult.

Loss of Angiopoietin-like 7 diminishes the regeneration capacity of hematopoietic stem and progenitor cells.

Successful expansion of hematopoietic stem cells (HSCs) would benefit the use of HSC transplants in the clinic. Angiopoietin-like 7 promotes the expansion of hematopoietic stem and progenitor cells (HSPC) in vitro and ex vivo. However, the impact of loss of Angptl7 on HSPCs in vivo has not been characterized.

ANGPTL7 regulates the expansion and repopulation of human hematopoietic stem and progenitor cells.

Successful expansion of hematopoietic stem cells would benefit the use of hematopoietic stem cell transplants in the clinic. Several angiopoietin-like proteins, including angiopoietin-like 7, can support the activity of hematopoietic stem cells. However, effects of ANGPTL7 on human hematopoietic stem cells and the downstream signaling cascade activated by ANGPTL7 are poorly understood.

Mechanisms determining the fate of hematopoietic stem cells.

Successful in vitro expansion of hematopoietic stem cells (HSCs) will facilitate the application of HSC transplantation for the treatment of various diseases, including hematological malignancies. To achieve this expansion, the molecular mechanisms that control the fate of HSCs must be deciphered. Leukemia-initiating cells (LICs) or leukemia stem cells (LSCs) may originate from normal HSCs, which suggest that the dysregulation of the mechanisms that regulate the cell fate of HSCs may underlie leukemogenesis.

Using mouse models to study function of transcriptional factors in T cell development.

Laboratory mice have widely been used as tools for basic biological research and models for studying human diseases. With the advances of genetic engineering and conditional knockout (CKO) mice, we now understand hematopoiesis is a dynamic stepwise process starting from hematopoietic stem cells (HSCs) which are responsible for replenishing all blood cells. Transcriptional factors play important role in hematopoiesis.