Embryonic stem cell factors and pancreatic cancer

Pancreatic ductal adenocarcinoma(PDAC),the most common type of pancreatic tumor,is a highly aggressive human cancer with the lowest five-year survival rate of any human maligancy primarily due to its earlymetastasis and lack of response to chemotherapy and radiation.Recent research suggests that PDAC cells comprise a hierarchy of tumor cells that develop around a population of cancer stem cells(CSCs),a small and distinct population of cancer cells that mediates tumoregenesis,metastasis and resistance to standard treatments.Thus,CSCs could be a target for more effective treatment options.Interestingly,pancreatic CSCs are subject to regulation by some of key embryonic stem cell(ESC)transctiption factors abberently expressed in PDAC,such as SOX2,OCT4 and NANOG.ESC transcription factors are important DNA-binding proteins present in both embryonic and adult somatic cells.The critical role of these factors in reprogramming processes makes them essential not only for embryonic development but also tumorigenesis.Here we provide an overview of stem cell transcription factors,particularly SOX2,OCT4,and NANOG,on their expression and function in pancreatic cancer.In contrast to embryonic stem cells,in which OCT4 and SOX2 are tightly regulated and physically interact to regulate a wide spectrum of target genes,de novo SOX2 expression alone in pancreatic cancer cells is sufficient to promote self-renewal,dedifferentiation and imparting stemness characteristics via impacting specific cell cycle regulatory genes and epithelial-mesnechymal transtion driver genes.Thus,targeting ESC factors,particularly SOX2,could be a worthy strategy for pancreatic cancer therapy.

A ribosomal gene panel predicting a novel synthetic lethality in non-BRCAness tumors

Poly(ADP-ribose)polymerase(PARP)inhibitors are one of the most exciting classes of targeted therapy agents for cancers with homologous recombination(HR)deficiency.However,many patients without apparent HR defects also respond well to PARP inhibitors/cisplatin.The biomarker responsible for this mechanism remains unclear.Here,we identified a set of ribosomal genes that predict response to PARP inhibitors/cisplatin in HR-proficient patients.PARP inhibitor/cisplatin selectively eliminates cells with high expression of the eight genes in the identified panel via DNA damage(ATM)signaling-induced pro-apoptotic ribosomal stress,which along with ATM signaling-induced pro-survival HR repair constitutes a new model to balance the cell fate in response to DNA damage.Therefore,the combined examination of the gene panel along with HR status would allow for more precise predictions of clinical response to PARP inhibitor/cisplatin.The gene panel as an independent biomarker was validated by multiple published clinical datasets,as well as by an ovarian cancer organoids library we established.More importantly,its predictive value was further verified in a cohort of PARP inhibitor-treated ovarian cancer patients with both RNA-seq and WGS data.Furthermore,we identified several marketed drugs capable of upregulating the expression of the genes in the panel without causing HR deficiency in PARP inhibitor/cisplatin-resistant cell lines.These drugs enhance PARP inhibitor/cisplatin sensitivity in both intrinsically resistant organoids and cell lines with acquired resistance.Together,our study identifies a marker gene panel for HR-proficient patients and reveals a broader application of PARP inhibitor/cisplatin in cancer therapy.

Evidence for lung repair and regeneration in humans: key stem cells and therapeutic functions of fibroblast growth factors

Regeneration carries the idea of regrowing partially or completely a missing organ.Repair,on the other hand,allows restoring the function of an existing but failing organ.The recognition that human lungs can both repair and regenerate is quite novel,the concept has not been widely used to treat patients.We present evidence that the human adult lung does repair and regenerate and introduce different ways to harness this power.Various types of lung stem cells are capable of proliferating and differentiating upon injury driving the repair/regeneration process.Injury models,primarily in mice,combined with lineage tracing studies,have allowed the identification of these important cells.Some of these cells,such as basal cells,broncho-alveolar stem cells,and alveolar type 2 cells,rely on fibroblast growth factor (FGF) signaling for their survival,proliferation and/or differentiation.While preclinical studies have shown the therapeutic benefits of FGFs,a recent clinical trial for acute respiratory distress syndrome (ARDS) using intravenous injection of FGF7 did not report the expected beneficial effects.We discuss the potential reasons for these negative results and propose the rationale for new approaches for future clinical trials,such as delivery of FGFs to the damaged lungs through efficient inhalation systems,which may be more promising than systemic exposure to FGFs.While this change in the administration route presents a challenge,the therapeutic promises displayed by FGFs are worth the effort.