Early Proterozoic calc-alkaline and Middle Proterozoic tholeiitic dyke swarms from Central-Eastern Argentina: Petrology, geochemistry, Sr-Nd isotopes and tectonic implications

The Rio de La Plata craton in Argentina (Azul and Tandil regions) is characterized by Early Proterozoic (2·0 Ga) calc-alkaline and Middle Proterozoic (1·6 Ga) tholeiitic dyke swarms intruding the crystalline basement involved in the Transamazonian Orogeny (2·2-1·9 Ga). The calc-alkaline dykes have andesitic and rhyolitic compositions and trend east-west, whereas the tholeiitic dykes mainly trend N30°W and are represented by basalts with low (0·9-1·7 wt %) and high TiO2 (up to 3·7 wt %). The calc-alkaline dykes have primitive mantle (PM)-normalized trace element patterns enriched in Rb, Ba, K, La, Ce and Nd, and significant negative Nb and Ti anomalies. These dykes are characterized by εt(Nd) values of - 3 to - 4, similar to those of the EMI mantle component. Low-TiO2 tholeiitic dykes have low incompatible-element (IE) contents and PM-IE patterns with slightly positive or negative Nb spikes. They have variable εt(Nd) values (-0·5 to 12·1), which mainly reflect derivation from a depleted source mantle. High-TiO2 tholeiitic dykes have more enriched IE-PM patterns and are characterized by εt(Nd) values (-1·4 to -7·5) typical of an enriched source mantle. Chemical and isotopic data and melting modelling indicate that both calc-alkaline and tholeiitic dykes originated by different melting degrees of a heterogeneous source mantle, the variable IE enrichment of which may have occured in Late Archaean to Early Proterozoic times. The emplacement of the calc-alkaline dykes is associated with the transtensional stage of the Transamazonian Orogeny, whereas the tholeiitic dykes reflect extensional tectonics succeeding the Transamazonian event. The calc-alkaline and tholeiitic dykes are similar in emplacement age and characteristics to metamorphosed granites and volcanic rocks outcropping within the Namaqua fold belts of southwestern Africa (Richtersveld and Witberg-Aggeneys-Gamsberg provinces); this may indicate that the Rio de La Plata craton and southwestern Africa were contiguous in Early-Middle Proterozoic times.Facultad de Ciencias Naturales y MuseoLaboratorio de Entrenamiento Multidisciplinario para la Investigación Tecnológic

SerpinB2 regulates stromal remodelling and local invasion in pancreatic cancer

Pancreatic cancer has a devastating prognosis, with an overall 5-year survival rate of ~8%, restricted treatment options and characteristic molecular heterogeneity. SerpinB2 expression, particularly in the stromal compartment, is associated with reduced metastasis and prolonged survival in pancreatic ductal adenocarcinoma (PDAC) and our genomic analysis revealed that SERPINB2 is frequently deleted in PDAC. We show that SerpinB2 is required by stromal cells for normal collagen remodelling in vitro, regulating fibroblast interaction and engagement with collagen in the contracting matrix. In a pancreatic cancer allograft model, co-injection of PDAC cancer cells and SerpinB2(-/-) mouse embryonic fibroblasts (MEFs) resulted in increased tumour growth, aberrant remodelling of the extracellular matrix (ECM) and increased local invasion from the primary tumour. These tumours also displayed elevated proteolytic activity of the primary biochemical target of SerpinB2-urokinase plasminogen activator (uPA). In a large cohort of patients with resected PDAC, we show that increasing uPA mRNA expression was significantly associated with poorer survival following pancreatectomy. This study establishes a novel role for SerpinB2 in the stromal compartment in PDAC invasion through regulation of stromal remodelling and highlights the SerpinB2/uPA axis for further investigation as a potential therapeutic target in pancreatic cancer

Early Proterozoic calc-alkaline and Middle Proterozoic tholeiitic dyke swarms from Central-Eastern Argentina: Petrology, geochemistry, Sr-Nd isotopes and tectonic implications

The Rio de La Plata craton in Argentina (Azul and Tandil regions) is characterized by Early Proterozoic (2·0 Ga) calc-alkaline and Middle Proterozoic (1·6 Ga) tholeiitic dyke swarms intruding the crystalline basement involved in the Transamazonian Orogeny (2·2-1·9 Ga). The calc-alkaline dykes have andesitic and rhyolitic compositions and trend east-west, whereas the tholeiitic dykes mainly trend N30°W and are represented by basalts with low (0·9-1·7 wt %) and high TiO2 (up to 3·7 wt %). The calc-alkaline dykes have primitive mantle (PM)-normalized trace element patterns enriched in Rb, Ba, K, La, Ce and Nd, and significant negative Nb and Ti anomalies. These dykes are characterized by εt(Nd) values of - 3 to - 4, similar to those of the EMI mantle component. Low-TiO2 tholeiitic dykes have low incompatible-element (IE) contents and PM-IE patterns with slightly positive or negative Nb spikes. They have variable εt(Nd) values (-0·5 to 12·1), which mainly reflect derivation from a depleted source mantle. High-TiO2 tholeiitic dykes have more enriched IE-PM patterns and are characterized by εt(Nd) values (-1·4 to -7·5) typical of an enriched source mantle. Chemical and isotopic data and melting modelling indicate that both calc-alkaline and tholeiitic dykes originated by different melting degrees of a heterogeneous source mantle, the variable IE enrichment of which may have occured in Late Archaean to Early Proterozoic times. The emplacement of the calc-alkaline dykes is associated with the transtensional stage of the Transamazonian Orogeny, whereas the tholeiitic dykes reflect extensional tectonics succeeding the Transamazonian event. The calc-alkaline and tholeiitic dykes are similar in emplacement age and characteristics to metamorphosed granites and volcanic rocks outcropping within the Namaqua fold belts of southwestern Africa (Richtersveld and Witberg-Aggeneys-Gamsberg provinces); this may indicate that the Rio de La Plata craton and southwestern Africa were contiguous in Early-Middle Proterozoic times.Facultad de Ciencias Naturales y MuseoLaboratorio de Entrenamiento Multidisciplinario para la Investigación Tecnológic

Transient tissue priming via ROCK inhibition uncouples pancreatic cancer progression, sensitivity to chemotherapy, and metastasis

The emerging standard of care for patients with inoperable pancreatic cancer is a combination of cytotoxic drugs gemcitabine and Abraxane, but patient response remains moderate. Pancreatic cancer development and metastasis occur in complex settings, with reciprocal feedback from microenvironmental cues influencing both disease progression and drug response. Little is known about how sequential dual targeting of tumor tissue tension and vasculature before chemotherapy can affect tumor response. We used intravital imaging to assess how transient manipulation of the tumor tissue, or "priming," using the pharmaceutical Rho kinase inhibitor Fasudil affects response to chemotherapy. Intravital Förster resonance energy transfer imaging of a cyclin-dependent kinase 1 biosensor to monitor the efficacy of cytotoxic drugs revealed that priming improves pancreatic cancer response to gemcitabine/Abraxane at both primary and secondary sites. Transient priming also sensitized cells to shear stress and impaired colonization efficiency and fibrotic niche remodeling within the liver, three important features of cancer spread. Last, we demonstrate a graded response to priming in stratified patient-derived tumors, indicating that fine-tuned tissue manipulation before chemotherapy may offer opportunities in both primary and metastatic targeting of pancreatic cancer

Recruitment and Activation of Pancreatic Stellate Cells from the Bone Marrow in Pancreatic Cancer: A Model of Tumor-Host Interaction

BACKGROUND AND AIMS: Chronic pancreatitis and pancreatic cancer are characterised by extensive stellate cell mediated fibrosis, and current therapeutic development includes targeting pancreatic cancer stroma and tumor-host interactions. Recent evidence has suggested that circulating bone marrow derived stem cells (BMDC) contribute to solid organs. We aimed to define the role of circulating haematopoietic cells in the normal and diseased pancreas. METHODS: Whole bone marrow was harvested from male β-actin-EGFP donor mice and transplanted into irradiated female recipient C57/BL6 mice. Chronic pancreatitis was induced with repeat injections of caerulein, while carcinogenesis was induced with an intrapancreatic injection of dimethylbenzanthracene (DMBA). Phenotype of engrafted donor-derived cells within the pancreas was assessed by immunohistochemistry, immunofluorescence and in situ hybridisation. RESULTS: GFP positive cells were visible in the exocrine pancreatic epithelia from 3 months post transplantation. These exhibited acinar morphology and were positive for amylase and peanut agglutinin. Mice administered caerulein developed chronic pancreatitis while DMBA mice exhibited precursor lesions and pancreatic cancer. No acinar cells were identified to be donor-derived upon cessation of cerulein treatment, however rare occurrences of bone marrow-derived acinar cells were observed during pancreatic regeneration. Increased recruitment of BMDC was observed within the desmoplastic stroma, contributing to the activated pancreatic stellate cell (PaSC) population in both diseases. Expression of stellate cell markers CELSR3, PBX1 and GFAP was observed in BMD cancer-associated PaSCs, however cancer-associated, but not pancreatitis-associated BMD PaSCs, expressed the cancer PaSC specific marker CELSR3. CONCLUSIONS: This study demonstrates that BMDC can incorporate into the pancreas and adopt the differentiated state of the exocrine compartment. BMDC that contribute to the activated PaSC population in chronic pancreatitis and pancreatic cancer have different phenotypes, and may play important roles in these diseases. Further, bone marrow transplantation may provide a useful model for the study of tumor-host interactions in cancer and pancreatitis

Identification of Functional Networks of Estrogen- and c-Myc-Responsive Genes and Their Relationship to Response to Tamoxifen Therapy in Breast Cancer

BACKGROUND: Estrogen is a pivotal regulator of cell proliferation in the normal breast and breast cancer. Endocrine therapies targeting the estrogen receptor are effective in breast cancer, but their success is limited by intrinsic and acquired resistance. METHODOLOGY/PRINCIPAL FINDINGS: With the goal of gaining mechanistic insights into estrogen action and endocrine resistance, we classified estrogen-regulated genes by function, and determined the relationship between functionally-related genesets and the response to tamoxifen in breast cancer patients. Estrogen-responsive genes were identified by transcript profiling of MCF-7 breast cancer cells. Pathway analysis based on functional annotation of these estrogen-regulated genes identified gene signatures with known or predicted roles in cell cycle control, cell growth (i.e. ribosome biogenesis and protein synthesis), cell death/survival signaling and transcriptional regulation. Since inducible expression of c-Myc in antiestrogen-arrested cells can recapitulate many of the effects of estrogen on molecular endpoints related to cell cycle progression, the estrogen-regulated genes that were also targets of c-Myc were identified using cells inducibly expressing c-Myc. Selected genes classified as estrogen and c-Myc targets displayed similar levels of regulation by estrogen and c-Myc and were not estrogen-regulated in the presence of siMyc. Genes regulated by c-Myc accounted for 50% of all acutely estrogen-regulated genes but comprised 85% (110/129 genes) in the cell growth signature. siRNA-mediated inhibition of c-Myc induction impaired estrogen regulation of ribosome biogenesis and protein synthesis, consistent with the prediction that estrogen regulates cell growth principally via c-Myc. The 'cell cycle', 'cell growth' and 'cell death' gene signatures each identified patients with an attenuated response in a cohort of 246 tamoxifen-treated patients. In multivariate analysis the cell death signature was predictive independent of the cell cycle and cell growth signatures. CONCLUSIONS/SIGNIFICANCE: These functionally-based gene signatures can stratify patients treated with tamoxifen into groups with differing outcome, and potentially identify distinct mechanisms of tamoxifen resistance

Pan-cancer analysis of whole genomes

Cancer is driven by genetic change, and the advent of massively parallel sequencing has enabled systematic documentation of this variation at the whole-genome scale(1-3). Here we report the integrative analysis of 2,658 whole-cancer genomes and their matching normal tissues across 38 tumour types from the Pan-Cancer Analysis of Whole Genomes (PCAWG) Consortium of the International Cancer Genome Consortium (ICGC) and The Cancer Genome Atlas (TCGA). We describe the generation of the PCAWG resource, facilitated by international data sharing using compute clouds. On average, cancer genomes contained 4-5 driver mutations when combining coding and non-coding genomic elements; however, in around 5% of cases no drivers were identified, suggesting that cancer driver discovery is not yet complete. Chromothripsis, in which many clustered structural variants arise in a single catastrophic event, is frequently an early event in tumour evolution; in acral melanoma, for example, these events precede most somatic point mutations and affect several cancer-associated genes simultaneously. Cancers with abnormal telomere maintenance often originate from tissues with low replicative activity and show several mechanisms of preventing telomere attrition to critical levels. Common and rare germline variants affect patterns of somatic mutation, including point mutations, structural variants and somatic retrotransposition. A collection of papers from the PCAWG Consortium describes non-coding mutations that drive cancer beyond those in the TERT promoter(4); identifies new signatures of mutational processes that cause base substitutions, small insertions and deletions and structural variation(5,6); analyses timings and patterns of tumour evolution(7); describes the diverse transcriptional consequences of somatic mutation on splicing, expression levels, fusion genes and promoter activity(8,9); and evaluates a range of more-specialized features of cancer genomes(8,10-18).Peer reviewe

Identification of unique neoantigen qualities in long-term survivors of pancreatic cancer

Pancreatic ductal adenocarcinoma is a lethal cancer with fewer than 7% of patients surviving past 5 years. T-cell immunity has been linked to the exceptional outcome of the few long-term survivors1,2, yet the relevant antigens remain unknown. Here we use genetic, immunohistochemical and transcriptional immunoprofiling, computational biophysics, and functional assays to identify T-cell antigens in long-term survivors of pancreatic cancer. Using whole-exome sequencing and in silico neoantigen prediction, we found that tumours with both the highest neoantigen number and the most abundant CD8+ T-cell infiltrates, but neither alone, stratified patients with the longest survival. Investigating the specific neoantigen qualities promoting T-cell activation in long-term survivors, we discovered that these individuals were enriched in neoantigen qualities defined by a fitness model, and neoantigens in the tumour antigen MUC16 (also known as CA125). A neoantigen quality fitness model conferring greater immunogenicity to neoantigens with differential presentation and homology to infectious disease-derived peptides identified long-term survivors in two independent datasets, whereas a neoantigen quantity model ascribing greater immunogenicity to increasing neoantigen number alone did not. We detected intratumoural and lasting circulating T-cell reactivity to both high-quality and MUC16 neoantigens in long-term survivors of pancreatic cancer, including clones with specificity to both high-quality neoantigens and predicted cross-reactive microbial epitopes, consistent with neoantigen molecular mimicry. Notably, we observed selective loss of high-quality and MUC16 neoantigenic clones on metastatic progression, suggesting neoantigen immunoediting. Our results identify neoantigens with unique qualities as T-cell targets in pancreatic ductal adenocarcinoma. More broadly, we identify neoantigen quality as a biomarker for immunogenic tumours that may guide the application of immunotherapies