Metastasis, the dissemination and growth of neoplastic cells in an organ distinct from that in which they originated, is the most common cause of death in cancer patients. This is particularly true for pancreatic cancers, where most patients are diagnosed with metastatic disease and few show a sustained response to chemotherapy or radiation therapy. Whether the dismal prognosis of patients with pancreatic cancer compared to patients with other types of cancer is a result of late diagnosis or early dissemination of disease to distant organs is not known. Here we rely on data generated by sequencing the genomes of seven pancreatic cancer metastases to evaluate the clonal relationships among primary and metastatic cancers. We find that clonal populations that give rise to distant metastases are represented within the primary carcinoma, but these clones are genetically evolved from the original parental, non-metastatic clone. Thus, genetic heterogeneity of metastases reflects that within the primary carcinoma. A quantitative analysis of the timing of the genetic evolution of pancreatic cancer was performed, indicating at least a decade between the occurrence of the initiating mutation and the birth of the parental, non-metastatic founder cell. At least five more years are required for the acquisition of metastatic ability and patients die an average of two years thereafter. These data provide novel insights into the genetic features underlying pancreatic cancer progression and define a broad time window of opportunity for early detection to prevent deaths from metastatic disease.

SF-010-4 Distant metastasis occurs late during the genetic evolution of pancreatic cancer

Low bone mass and strength lead to fragility fractures, for example, in elderly individuals affected by osteoporosis or children with osteogenesis imperfecta. A decade ago, rare human mutations affecting bone negatively (osteoporosis-pseudoglioma syndrome) or positively (high-bone mass phenotype, sclerosteosis and Van Buchem disease) have been identified and found to all reside in components of the canonical WNT signaling machinery. Mouse genetics confirmed the importance of canonical Wnt signaling in the regulation of bone homeostasis, with activation of the pathway leading to increased, and inhibition leading to decreased, bone mass and strength. The importance of WNT signaling for bone has also been highlighted since then in the general population in numerous genome-wide association studies. The pathway is now the target for therapeutic intervention to restore bone strength in millions of patients at risk for fracture. This paper reviews our current understanding of the mechanisms by which WNT signalng regulates bone homeostasis.

WNT signaling in bone homeostasis and disease: from human mutations to treatments

TNF is a pleiotropic cytokine with important functions in homeostasis and disease pathogenesis. Recent discoveries have provided insights into TNF biology that introduce new concepts for the development of therapeutics for TNF-mediated diseases. The model of TNF receptor signalling has been extended to include linear ubiquitination and the formation of distinct signalling complexes that are linked with different functional outcomes, such as inflammation, apoptosis and necroptosis. Our understanding of TNF-induced gene expression has been enriched by the discovery of epigenetic mechanisms and concepts related to cellular priming, tolerization and induction of 'short-term transcriptional memory'. Identification of distinct homeostatic or pathogenic TNF-induced signalling pathways has introduced the concept of selectively inhibiting the deleterious effects of TNF while preserving its homeostatic bioactivities for therapeutic purposes. In this Review, we present molecular mechanisms underlying the roles of TNF in homeostasis and inflammatory disease pathogenesis, and discuss novel strategies to advance therapeutic paradigms for the treatment of TNF-mediated diseases.

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TNF biology, pathogenic mechanisms and emerging therapeutic strategies

The Wnt/β-catenin signaling system plays essential roles in embryonic development and in the self-renewal and maintenance of adult stem cells. R-spondins (RSPOs) are a group of secreted proteins that enhance Wnt/β-catenin signaling and have pleiotropic functions in development and stem cell growth. LGR5, an orphan receptor of the G protein-coupled receptor (GPCR) superfamily, is specifically expressed in stem cells of the intestinal crypt and hair follicle. Knockout of LGR5 in the mouse results in neonatal lethality. LGR4, a receptor closely related to LGR5, also has essential roles in development, as its knockout leads to reduced viability and retarded growth. Overexpression of both receptors has been reported in several types of cancer. Here we demonstrate that LGR4 and LGR5 bind the R-spondins with high affinity and mediate the potentiation of Wnt/β-catenin signaling by enhancing Wnt-induced LRP6 phosphorylation. Interestingly, neither receptor is coupled to heterotrimeric G proteins or to β-arrestin when stimulated by the R-spondins, indicating a unique mechanism of action. The findings provide a basis for stem cell-specific effects of Wnt/β-catenin signaling and for the broad range of functions LGR4, LGR5, and the R-spondins have in normal and malignant growth.

https://www.pnas.org/content/pnas/108/28/11452.full.pdf

R-spondins function as ligands of the orphan receptors LGR4 and LGR5 to regulate Wnt/β-catenin signaling

Medulloblastoma, the most common malignant paediatric brain tumour, is currently treated with nonspecific cytotoxic therapies including surgery, whole-brain radiation, and aggressive chemotherapy. As medulloblastoma exhibits marked intertumoural heterogeneity, with at least four distinct molecular variants, previous attempts to identify targets for therapy have been underpowered because of small samples sizes. Here we report somatic copy number aberrations (SCNAs) in 1,087 unique medulloblastomas. SCNAs are common in medulloblastoma, and are predominantly subgroup-enriched. The most common region of focal copy number gain is a tandem duplication of SNCAIP, a gene associated with Parkinson's disease, which is exquisitely restricted to Group 4α. Recurrent translocations of PVT1, including PVT1-MYC and PVT1-NDRG1, that arise through chromothripsis are restricted to Group 3. Numerous targetable SCNAs, including recurrent events targeting TGF-β signalling in Group 3, and NF-κB signalling in Group 4, suggest future avenues for rational, targeted therapy.

/pdf/subgroup-specific-structural-variation-across-1-000-ipevvapbfn.pdf

Subgroup-specific structural variation across 1,000 medulloblastoma genomes

The selection of relevant genes for breast cancer metastasis is critical for the treatment and prognosis of cancer patients. Although much effort has been devoted to the gene selection procedures by use of different statistical analysis methods or computational techniques, the interpretation of the variables in the resulting survival models has been limited so far. This article proposes a new Random Forest (RF)-based algorithm to identify important variables highly related with breast cancer metastasis, which is based on the important scores of two variable selection algorithms, including the mean decrease Gini (MDG) criteria of Random Forest and the GeneRank algorithm with protein–protein interaction (PPI) information. The new gene selection algorithm can be called PPIRF. The improved prediction accuracy fully illustrated the reliability and high interpretability of gene list selected by the PPIRF approach.

Identification of Genes Involved in Breast Cancer Metastasis by Integrating Protein-Protein Interaction Information with Expression Data.

The invention relates to 16alpha-methyl-3-hydroxyl-19-norpregnane-1, 3, 5-triene-20-ketone and a preparation method thereof. In the invention, degraded product of natural diosgenine petunidin 3-acetoxyl group-pregnane-5, 16-diene-20-ketone is used as the raw material, the raw material is methylated by aluminum methide before hydrolization, 1-dehydrogenation and A aromaticcyclizationofparaflins to prepare 16alpha-methyl estrone steroid compound 16alpha-methyl-3-hydroxyl-19-norpregnane-1, 3, 5-triene-20-ketone. The compound has activity suppression effect for breast cancer cellbeads MDA-MB-231, and the preparation method is characterized by easily available raw material and high yield.

16alpha-methyl-3-hydroxyl-19-norpregnane-1, 3, 5-triene-20-ketone and preparation method thereof

Using effective computer methods to infer potential drug-disease relationships can provide clues for the discovery new uses of old drugs. This paper introduced a Ranking-based k-Nearest Neighbor (Re-KNN) method to drug repositioning for cardiovascular diseases. The main characteristic of the Re-KNN lies in combining conventional KNN algorithm with Ranking SVM (Support Vector Machine) algorithm to get neighbors that are more trustable. By integrating the chemical structural similarity, target-based similarity, side-effect similarity and topological similarity information, Re-KNN method can obtain an improved AUC (Area under ROC Curve) and AUPR (Area under Precision-Recall curve) compared with other methods, which prove the validity and efficiency of multiple features integration.

Using the Ranking-Based KNN Approach for Drug Repositioning Based on Multiple Information

Compared with traditional cytotoxic cancer therapy, therapy-induced cancer cell senescence represents a novel promising strategy because it has similar efficacy, but fewer side effects. In this chapter, we briefly review the basic concept of cellular senescence and therapy-induced senescence and discuss the signalling pathway of cellular senescence, especially, Ras and Twist signalling. Moreover, we focus on Caffeic Acid 3,4-Dihydroxy-Phenethyl Ester (CADPE), a natural compound from the medicinal plants Sarcandra Glabra (Sarcandra) and Teucrium pilosum (Decne), that suppresses human cancer cell growth and colony formation by the induction of cellular senescence, not by apoptosis or autophagy. Furthermore, we discussed the underlying mechanisms and show that CADPE suppressed the Twist1-related senescence signaling pathways. Together, our results demonstrate that CADPE induces human cancer cell senescence by suppressing Twist expression and that CADPE could be a novel effective agent in the treatment of tumors.

Jian Luo

Papers

Identification of Genes Involved in Breast Cancer Metastasis by Integrating Protein-Protein Interaction Information with Expression Data.

16alpha-methyl-3-hydroxyl-19-norpregnane-1, 3, 5-triene-20-ketone and preparation method thereof

Using the Ranking-Based KNN Approach for Drug Repositioning Based on Multiple Information

Induction of Cancer Cell Senescence: Role of Caffeic Acid 3,4-Dihydroxy-Phenethyl Ester

Inactivation of G-protein coupled receptor 48 impairs definitive erythropoiesis at midgestation through downregulation of ATF4 pathway