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Salt diapirs are prominent features in the Zagros fold-and-thrust belt displaying complex interplay between the buoyant forces driving the rock salt to the surface, distribution of the caprock and erosion. The caprock represents the solid residue of salt dissolution in the apical part of the diapir. Understanding the dynamics of subaerial spreading of salt in salt glaciers therefore requires knowledge about the spatiotemporal surface deformation and the underlying controlling factors. However, the contemporary vertical surface-deformation pattern across salt diapirs is difficult to detect and interpret along disciplinary boundaries. Therefore, our goal is to analyse the active surface-deformation patterns of diapir-caprock systems in the Zagros, where diapirs and their caprocks are well exposed and accessible for field mapping. We primarily integrate high-resolution Persistent Scatterer Interferometry (PSI) and field mapping. We used Persistent Scatterer Interferometry (PSI) to obtain the highest available spatiotemporal resolution (on the range of mm/yr, ~12-day repeat cycle) of the vertical surface-deformation pattern across the Karmostaj and Siah Taq salt diapirs for which previous knowledge from detailed geological field mapping is available. Both diapirs contain a thick and deformed caprock layer on top or in the surroundings of the salt cupolas and are located 20 km south from the Lar city in southern Iran. We analysed the PSI-data using Sentinel-1 images acquired between October 2014 and December 2018 using the German Aerospace Center’s (DLR) Integrated Wide Area Processor (IWAP). First, the time-series analysis of the deformation signal in the line-of-sight is investigated for seasonal effects correlations, such as precipitation and heat. Second, the line-of-sight signal is split into vertical and horizontal components. In the next step, geological observations from field mapping provide the context to interpret the geodetic data. Preliminary results indicate that the deformation identified from PSI signal decreases outwards from the apical part for salt diapirs with thick caprock, as the caprocks and other residuals get relatively thicker above the underlying viscous salt. We postulate that the extra load the caprock body exerts on the underlying ductile salt drives subsidence in the crestal portion of the diapir. Understanding the spatiotemporal deformation pattern helps to recognize the impact of dissolution/erosion mechanisms and the distribution of caprock on salt diapirs. Therefore, careful analysis of geodetic signals, which requires contextual integration with geological field observations, reveals the influence of caprock on salt movement.

In the emergent (subaerial) salt diapirs, the salt faces negative buoyancy when extruded to the surface, and flows outward around their vent by gravity spreading. It also faces dissolution and erosion. Salt supply, salt flow, dissolution, and erosion also influence the diapir’s shape. Although satellite geodesy monitors the surface deformation of the salt-caprock glacier system, the interpretation of the resulting deformation pattern in terms of salt supply, dissolution, and erosion is not straightforward. To overcome these shortcomings, we analyze surface deformation pattern of a fountain-shaped and nearly symmetrical diapir (Finu) within the Zagros Belt of Iran using Persistent Scatterer Interferometry (PSI). The PSI data are extracted from the Sentinel-1 SAR images using the Integrated Wide Area Processor (IWAP) at the German Aerospace Center (DLR) covering four years from October 2014 to December 2018. The line-of-sight signal from the PSI data is decomposed into the vertical and horizontal deformation signals. Within the diapir, the deformation signal is then spatially correlated with the influencing factors, including local position within the diapir, slope, karstification, and drainage. Along an E-W profile across the diapir, two-dimensional deformation vectors reflect salt supply and spreading; therefore, the magnitude and direction of these vectors are influenced by their local position within the diapir and the slope. There is a slight uplift in the central part of the salt domes with active salt extrusion. The deformation vectors divert outward in the slope direction, and the deformation reaches its maximum magnitude at the upper flanks of the central dome. The deformation decreases in the outer flat plateau regions of the extrusions and continues to decrease in the steep slopes at their lateral terminations. Along the same profile, relatively higher subsidence is detected in areas where sinkholes are abundant. In these regions, salt is removed in the subsurface by dissolution-driven karst development in contrast to areas where the surface drainage system is developed, and fluvial erosion is dominant. In the future, a better understanding of the factors controlling salt spreading around the vent and the impacts of dissolution/erosion mechanisms on the deformation will improve our ability to interpret surface deformation of the salt-caprock system at unprecedented spatial and temporal resolution.

In emergent salt diapirs, the volume of the salt at the surface represents an equilibrium state between the salt supplied from the underlying orifice and that lost by dissolution and erosion at the surface. Therefore, the salt volume at the surface represents the surplus of the salt supply over the dissolution and erosion neglecting any volume changes from the decompaction. Both dissolution and erosion processes occur at or near surface and can be estimated, while estimating salt supply remains challenging because it occurs at depth. At the surface, the salt moves away from the central dome above the diapir’s orifice toward the flanks by gravity spreading in the direction of the slope.In this work, the salt volume change at the surface was estimated using Persistent Scatterer Interferometry (PSI) data to estimate the salt supply into the surface. While the salt tends to move in the direction of slopes, maximum deformation signal can be detected from the PSI data where the slope direction aligns with the line-of-sight (LOS) of satellite in the east- and west-facing slopes of salt diapirs. The salt deformation was estimated from both the east-west and up-down components of the decomposed PSI data along an east-west trending swath profile across the symmetrical Finu salt diapir to obtain salt gain (surplus) along this profile. During the PSI processing, areas with surface erosion and dissolution (sinkholes) were mostly filtered out, and the relevant salt loss was already accounted when analyzing the salt deformation. However, the down (subsidence) signal of the analyzed PSI data in nearly horizontal areas in the flanks of the Finu diapir, where salt movement is expected to be horizontal, is assumed to be associated with the subsurface salt dissolution. The used PSI data cover a period of four years from October 2014 to December 2018.Our results show that salt area surplus is c. 14 m2 a-1 along the profile crossing the Finu diapir. With the profile length of 4.6 km, the surplus rates along it are c. 3.1 mm a-1. The average subsidence rate on the diapirs flat flanks, which is supposed to be associated with the subsurface dissolution, was estimated at c. 1.0 mm a-1. Thus, the total supply rate along the profile is c. 4.1 mm a-1. Along the profile length, these rates mean that a total section area of c. 19 m2 a-1 of salt is added to the profile. Considering the semi-circular and symmetrical shape of the diapir and assuming uniform salt supply rates, the total volume of the salt delivered to the surface is in the order of c. 70,000 m3 a-1 from the underlying orifice. The orifice is approximately circular with a diameter of c. 1.7 km and an aperture covering c. 2.3 km2 area. This means the salt is extruded at a rate of c. 30 mm a-1 averaged over the period of four years.

Tumor-infiltrating immune cells comprise various cells of the innate and the adaptive immune system, which influence tumor growth and response to immunotherapy by exerting anti- and protumorigenic functions. Therefore, the quantification of tumor immune infiltrates is of paramount importance for cancer immunology and immunotherapy. We recently developed quanTIseq, a computational pipeline for the quantification of immune-cell fractions from bulk RNA sequencing (RNA-seq) data from blood or tumor samples. In this chapter, we show the capabilities of quanTIseq by analyzing two publicly available data sets. In the first example, we demonstrate how quanTIseq can be used to quantify circulating immune cells from preprocessed RNA-seq data and how to validate the results using matched flow cytometry data. In the second example, we analyze raw RNA-seq data from bulk tumor samples of melanoma patients collected before and on-treatment with kinase inhibitors to show how quanTIseq can be used to reveal the immunological effects of targeted and conventional drugs.

Tumor-infiltrating immune cells comprise various cells of the innate and the adaptive immune system, which influence tumor growth and response to immunotherapy by exerting anti- and protumorigenic functions. Therefore, the quantification of tumor immune infiltrates is of paramount importance for cancer immunology and immunotherapy. We recently developed quanTIseq, a computational pipeline for the quantification of immune-cell fractions from bulk RNA sequencing (RNA-seq) data from blood or tumor samples. In this chapter, we show the capabilities of quanTIseq by analyzing two publicly available data sets. In the first example, we demonstrate how quanTIseq can be used to quantify circulating immune cells from preprocessed RNA-seq data and how to validate the results using matched flow cytometry data. In the second example, we analyze raw RNA-seq data from bulk tumor samples of melanoma patients collected before and on-treatment with kinase inhibitors to show how quanTIseq can be used to reveal the immunological effects of targeted and conventional drugs.

Background & Aims Throughout life, the intestinal epithelium undergoes constant self-renewal from intestinal stem cells. Together with genotoxic stressors and failing DNA repair, this self-renewal causes susceptibility toward malignant transformation. X-box binding protein 1 (XBP1) is a stress sensor involved in the unfolded protein response (UPR). We hypothesized that XBP1 acts as a signaling hub to regulate epithelial DNA damage responses. Methods Data from The Cancer Genome Atlas were analyzed for association of XBP1 with colorectal cancer (CRC) survival and molecular interactions between XBP1 and p53 pathway activity. The role of XBP1 in orchestrating p53-driven DNA damage response was tested in vitro in mouse models of chronic intestinal epithelial cell (IEC) DNA damage (Xbp1/H2bfl/fl, Xbp1ΔIEC, H2bΔIEC, H2b/Xbp1ΔIEC) and via orthotopic tumor organoid transplantation. Transcriptome analysis of intestinal organoids was performed to identify molecular targets of Xbp1-mediated DNA damage response. Results In The Cancer Genome Atlas data set of CRC, low XBP1 expression was significantly associated with poor overall survival and reduced p53 pathway activity. In vivo, H2b/Xbp1ΔIEC mice developed spontaneous intestinal carcinomas. Orthotopic tumor organoid transplantation revealed a metastatic potential of H2b/Xbp1ΔIEC-derived tumors. RNA sequencing of intestinal organoids (H2b/Xbp1fl/fl, H2bΔIEC, H2b/Xbp1ΔIEC, and H2b/p53ΔIEC) identified a transcriptional program downstream of p53, in which XBP1 directs DNA-damage-inducible transcript 4-like (Ddit4l) expression. DDIT4L inhibits mechanistic target of rapamycin-mediated phosphorylation of 4E-binding protein 1. Pharmacologic mechanistic target of rapamycin inhibition suppressed epithelial hyperproliferation via 4E-binding protein 1. Conclusions Our data suggest a crucial role for XBP1 in coordinating epithelial DNA damage responses and stem cell function via a p53-DDIT4L–dependent feedback mechanism.

It was highlighted that the original article [1] contained a typesetting mistake in the name of Noel Filipe da Cunha Carvalho de Miranda. This was incorrectly captured as Noel Filipe da Cunha Carvahlo de Miranda. It was also highlighted that in Fig. 3C the left panels Y-axis were cropped and in Fig. 5C, CD8 bar was cropped. This Correction article shows the correct Figs. 3 and 5. The original article has been updated.

Mutations in KRAS are often associated with resistance to EGFR‐targeting antibody therapy. Using comprehensive systems analyses, GNB5 has been identified as a potential target to overcome therapy resistance targeting the EGFR signaling pathways, whereby the AKT signaling pathway (PI3K) rather than the ERK signaling pathway (RAS) might be dominantly affected. Personalized mathematical modeling and simulations of this signaling pathway/network and respective perturbations are of great utility to customize therapy for patients.

Colorectal cancer (CRC), a cancer with 1.4 million new cases diagnosed annually worldwide, is refractory to immunotherapy (with the exception of a minority of tumors with microsatellite instability). This is somehow paradoxical as CRC is a cancer which we have shown is under immunologic control and that tumor-infiltrating lymphocytes represent a strong independent predictor of survival (1). Based on our previous work showing that the immunophenotypes are determined by the genotypes (2), we hypothesized that mutations are rewiring signaling pathways and thereby modulate the recognition of tumor cells by T cells. In order to investigate rewiring of signaling networks and their interference with immunity for individual patients, we developed an experimental-computational concept using perturbation experiments with patient-derived tumor organoids. A biobank of CRC organoids was generated from histologically verified tumor samples, normal tissue, and liver metastases obtained from CRC patients (n=22). Comprehensive characterization of the organoids (exome sequencing, RNA sequencing, and proteomics) and of the tumors (multiplexed immunofluorescence for 6 immune cell types) was carried out and the resulting data were used to prioritize perturbation experiments. Patient-derived organoids were then perturbed with kinase inhibitors (MEKi, PI3Ki, mTORi, TBK1i, IKKi, BRAFi, and TAKi) and large-scale phosphoproteomic profiling using data-independent acquisition (SWATH-MS) was carried out. Deep phosphoproteomic profiling of perturbed organoids enabled reconstruction of patient-specific signaling networks and revealed profound rewiring by targeted drugs and interference with immune-related pathways, suggesting possible pharmacologic modulation by approved targeted agents to induce immunogenic effects. We show for the first time that systematic and comprehensive analysis of the signaling rewiring can provide a mechanistic rationale for immunotherapy-based combination regimens in CRC. This work is an important step towards the development of a precision immuno-oncology platform that integrates tumor organoids with high-throughput and high-content data for making therapeutic recommendations for individual patients. References 1. Galon J, Costes A, Sanchez-Cabo F, Kirilovsky A, Mlecnik B, Lagorce-Pages C, Tosolini M, Camus M, Berger A, Wind P, et al. Type, density, and location of immune cells within human colorectal tumors predict clinical outcome. Science 2006;313:1960-1964. 2. Angelova M, Charoentong P, Hackl H, Fischer ML, Snajder R, Krogsdam AM, Waldner MJ, Bindea G, Mlecnik B, Galon J, Trajanoski Z: Characterization of the immunophenotypes and antigenomes of colorectal cancers reveals distinct tumor escape mechanisms and novel targets for immunotherapy. Genome Biol 2015;16:64. Citation Format: Giorgia Lamberti, Christina Plattner, Peter Blattner, Stefan Scheidl, Francesca Finotello, Dietmar Rieder, Anne Krogsdam, Henner Farin, Florian Greten, Dietmar Öfner-Velano, Noel de Miranda, Ruedi Aebersold, Lukas Huber, Zlatko Trajanoski. Perturbation biology of colorectal cancer organoids reveals patient-specific signaling rewiring and interference with immunity [abstract]. In: Proceedings of the AACR Special Conference on Tumor Immunology and Immunotherapy; 2019 Nov 17-20; Boston, MA. Philadelphia (PA): AACR; Cancer Immunol Res 2020;8(3 Suppl):Abstract nr B60.

The immune contexture has a prognostic value in several cancers and the study of its pharmacological modulation could identify drugs acting synergistically with immune checkpoint blockers. However, the quantification of the immune contexture is hampered by the lack of simple and efficient methods. We developed quanTIseq, a deconvolution method that quantifies the densities of ten immune cell types from bulk RNA sequencing data and tissue imaging data. We performed extensive validation using simulated data, flow cytometry data, and immunohistochemistry data from three cancer cohorts.Analysis of 8,000 samples showed that the activation of the CXCR3/CXCL9 axis, rather than the mutational load is associated with cytotoxic T cell infiltration. We also show the prognostic value of deconvolution-based immunoscore and T cell/B cell score in several solid cancers. Finally, we used quanTIseq to show how kinase inhibitors modulate the immune contexture, and we suggest that it might have predictive value for immunotherapy.

Introduction Signalling pathway Hedgehog-Gli (Hh-Gli) is involved in embryonal ovarian development, but its atypical activation can lead to different types of ovarian tumours. Our previous studies showed aberrant Hh-Gli activity in some ovarian tumour types and hypermethylation in a promoter of tumour suppressor gene PTCH1 in the CpG islands near the GLI-binding site (Sabol et al. Int J Oncol 2012, 2017;Musani et al. Gene 2013; Maurac et al. Int J Gynecol Pathol 2012). We and other are aware that various genetic and epigenetic alterations contribute to aberrant Hh-Gli pathway activity in ovarian cancer, which could serve as interesting targets for cancer treatment and therapy, especially if can be used to bypass resistance and to target cancer in more efficient way. We hypothesise that changes in the expression of miRNA molecules related to the Hh-Gli signalling pathway genes contribute to the development of high-grade serous ovarian carcinoma (HGSOC). Material and methods We conducted a miRNA profiling of HGSOC and healthy Fallopian tube control samples with Agilent SurePrint G3 Human miRNA 8 × 60K Microarray Kit containing probes for 2549 human miRNAs. Gene expression profiling was preformed using Agilent SurePrint G3 Human Gene Expression v3 8 × 60K Microarray Kit, which covers 37 756 known RefSeq coding transcripts. Data were analysed using R/Bioconductor packages AgiMicroRna and limma. On-line DIANA Tools (TarBase, microT-CDS and miRPath) were used to find which Hh-Gli genes are targets of miRNAs differentially expressed in HGSOC. Results and discussions Data filtration gave 55 miRNAs: 32 up- and 23 down-regulated in HGSOC. Out of 47 genes involved in Hh-Gli pathway in humans (KEGG Pathway hsa04340), 35 are known targets for 27 over-expressed miRNAs, 22 are known targets for 16 under-expressed miRNAs, while 28 genes are potential targets for 26 up-regulated miRNAs and 24 are potential targets for 19 down-regulated miRNAs in HGSOC. In addition, 1090 genes were significantly over-expressed and 1692 were under-expressed in HGSOC. Further analysis revealed a couple of potential combinations of miRNAs and their target genes which are members of Hh-Gli pathway: ADRBK2/hsa-miR-96–5 p, BCL2/hsa-miR-16–5 p and hsa-miR-96–5 p, BOC/hsa-miR-224–5 p, and IHH/hsa-miR-16–5 p, hsa-miR-107 and hsa-miR-103a-3p. Conclusion Our results highlighted several candidate miRNAs targeting Hh-Gli signalling pathway genes, which, when additionally verified, could be potentially used for better therapeutic and early prevention approaches for HGSOC.

We introduce quanTIseq, a method to quantify the fractions of ten immune cell types from bulk RNA-sequencing data. quanTIseq was extensively validated in blood and tumor samples using simulated, flow cytometry, and immunohistochemistry data. quanTIseq analysis of 8000 tumor samples revealed that cytotoxic T cell infiltration is more strongly associated with the activation of the CXCR3/CXCL9 axis than with mutational load and that deconvolution-based cell scores have prognostic value in several solid cancers. Finally, we used quanTIseq to show how kinase inhibitors modulate the immune contexture and to reveal immune-cell types that underlie differential patients’ responses to checkpoint blockers. Availability: quanTIseq is available at http://icbi.at/quantiseq. Electronic supplementary material The online version of this article (10.1186/s13073-019-0638-6) contains supplementary material, which is available to authorized users.