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Purpose:Pancreatic ductal adenocarcinoma (PDAC) is a lethal cancer with a survival rate less than 5%. Multiple chemotherapeutic drugs have been tested to improve patient prognosis; however, the clinical efficacy of these treatments is low. One of the most controversial family of drugs are the proteasome inhibitors, which have displayed promising effects in preclinical studies, but low clinical performance. Here, we unravel a specific transcriptomic signature that discriminates a subgroup of patients sensitive to the proteasome inhibitor carfilzomib.Experimental Design:First, we identified a subpopulation of PDAC-derived primary cells cultures (PDPCC) sensitive to the proteasome inhibitor carfilzomib. Then, we selected a transcriptomic signature that predicts carfilzomib chemosensitivity using independent component analysis on the transcriptome of PDPCC. Finally, we validated the signature in an independent cohort of PDAC biopsy-derived pancreatic organoids.Results:Sensitive phenotype was characterized by a high expression of genes related with a cornified/squamous pathway and a downregulation of epithelial–mesenchymal transition genes. Interestingly, carfilzomib-sensitive transcriptomic profile did not show any association with the proteasome activity but strongly correlates with ATF4 and CHOP expression, which are key markers of the unfolded protein response and critical to trigger the cell death program. Concordantly, sensitive phenotype showed a high level of the de novo RNA and protein synthesis compared with the resistant one and, most important, cell death induced by carfilzomib is dependent of the translational activity.Conclusions:We demonstrate the existence of a carfilzomib-sensitive PDAC subgroup with a specific transcriptomic phenotype that could explain the biological reason for this responsiveness.

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research support, non-u.s. gov't letter 2023 Mar 2022 12 07 imported

Purpose: Compare pancreatic ductal adenocarcinoma (PDAC), preclinical models, by their transcriptome and drug response landscapes to evaluate their complementarity. Experimental Design: Three paired PDAC preclinical models—patient-derived xenografts (PDX), xenograft-derived pancreatic organoids (XDPO) and xenograft-derived primary cell cultures (XDPCC)—were derived from 20 patients and analyzed at the transcriptomic and chemosensitivity level. Transcriptomic characterization was performed using the basal-like/classical subtyping and the PDAC molecular gradient (PAMG). Chemosensitivity for gemcitabine, irinotecan, 5-fluorouracil and oxaliplatin was established and the associated biological pathways were determined using independent component analysis (ICA) on the transcriptome of each model. The selection criteria used to identify the different components was the chemosensitivity score (CSS) found for each drug in each model. Results: PDX was the most dispersed model whereas XDPO and XDPCC were mainly classical and basal-like, respectively. Chemosensitivity scoring determines that PDX and XDPO display a positive correlation for three out of four drugs tested, whereas PDX and XDPCC did not correlate. No match was observed for each tumor chemosensitivity in the different models. Finally, pathway analysis shows a significant association between PDX and XDPO for the chemosensitivity-associated pathways and PDX and XDPCC for the chemoresistance-associated pathways. Conclusions:&nbsp, Each PDAC preclinical model possesses a unique basal-like/classical transcriptomic phenotype that strongly influences their global chemosensitivity. Each preclinical model is imperfect but complementary, suggesting that a more representative approach of the clinical reality could be obtained by combining them. Translational Relevance: The identification of molecular signatures that underpin drug sensitivity to chemotherapy in PDAC remains clinically challenging. Importantly, the vast majority of studies using preclinical in vivo and in vitro models fail when transferred to patients in a clinical setting despite initially promising results. This study presents for the first time a comparison between three preclinical models directly derived from the same patients. We show that their applicability to preclinical studies should be considered with a complementary focus, avoiding tumor-based direct extrapolations, which might generate misleading conclusions and consequently the overlook of clinically relevant features.

International audience; Pancreatic ductal adenocarcinoma (PDAC) is composed of stromal, immune, and cancerous epithelial cells. Transcriptomic analysis of the epithelial compartment allows classification into different phenotypic subtypes as classical and basal-like. However, little is known about the intra-tumor heterogeneity particularly in the epithelial compartment. Growing evidences suggest that this phenotypic segregation is not so precise and different cancerous cell types may coexist in a single tumor. To test this hypothesis, we performed single-cell transcriptomic analyses using combinational barcoding exclusively on epithelial cells from six different classical PDAC patients obtained by Endoscopic Ultrasound (EUS) with Fine Needle Aspiration (FNA). To purify the epithelial compartment, PDAC were grown as biopsy-derived pancreatic cancer organoids. Single-cell transcriptomic analysis allowed the identification of four main cell clusters present in different proportions in all tumors. Remarkably, although all these tumors were classified as classical, one cluster present in all corresponded to a basal-like phenotype. These results reveal an unanticipated high heterogeneity of pancreatic cancers and demonstrate that basal-like cells, which have a highly aggressive phenotype, are more widespread than expected.

Recent evidence has highlighted the presence of neuronal nerve processes in the tumor microenvironment. However, the origin of intra-tumoral nerves remains poorly known, in part because of technical difficulties in tracing nerve fibers via regular histological preparations. Here, we employed three-dimensional (3D) imaging of cleared tissues for a comprehensive analysis of sympathetic innervation in pancreatic ductal adenocarcinoma (PDAC). The results support two independent, but coexisting, mechanisms: passive engulfment of pre-existing nerves within tumors and active, localized sprouting of nerve terminals into non-neoplastic lesions and tumor periphery. Nerve ablation revealed an inverse correlation between sympathetic innervation and tumor growth and spread. Furthermore, sympathectomy increased CD163+macrophage levels, which contributed to worse outcomes. Altogether, our findings revealed protective properties of the sympathetic nervous system in PDAC immunity and progression that could pave the way for new treatments.

Purpose: Pancreatic ductal adenocarcinoma (PDAC) is a lethal cancer with a survival rate less than 5%. Multiple chemotherapeutic drugs have been tested to improve patient prognosis; however, the clinical efficacy of these treatments is low. One of the most controversial family of drugs are the proteasome inhibitors, which have displayed promising effects in preclinical studies, but low clinical performance. Here, we unravel a specific transcriptomic signature that discriminates a subgroup of patients sensitive to the proteasome inhibitor carfilzomib. Experimental Design: First, we identified a subpopulation of PDAC-derived primary cells cultures (PDPCC) sensitive to the proteasome inhibitor carfilzomib. Then, we selected a transcriptomic signature that predicts carfilzomib chemosensitivity using independent component analysis on the transcriptome of PDPCC. Finally, we validated the signature in an independent cohort of PDAC biopsy-derived pancreatic organoids. Results: Sensitive phenotype was characterized by a high expression of genes related with a cornified/squamous pathway and a downregulation of epithelial-mesenchymal transition genes. Interestingly, carfilzomib-sensitive transcriptomic profile did not show any association with the proteasome activity but strongly correlates with ATF4 and CHOP expression, which are key markers of the unfolded protein response and critical to trigger the cell death program. Concordantly, sensitive phenotype showed a high level of the de novo RNA and protein synthesis compared with the resistant one and, most important, cell death induced by carfilzomib is dependent of the translational activity. Conclusions: We demonstrate the existence of a carfilzomib-sensitive PDAC subgroup with a specific transcriptomic phenotype that could explain the biological reason for this responsiveness. Fil: Fraunhoffer Navarro, Nicolas Alejandro. Consejo Nacional de Investigaciones Científicas y Técnicas. Oficina de Coordinación Administrativa Houssay. Centro de Estudios Farmacológicos y Botánicos. Universidad de Buenos Aires. Facultad de Medicina. Centro de Estudios Farmacológicos y Botánicos; Argentina. Inserm; Francia Fil: Meilerman Abuelafia, Miriam Analia. Inserm; Francia Fil: Bigonnet, Martin. Inserm; Francia Fil: Gayet, Odile. Inserm; Francia Fil: Roque, Julie. Inserm; Francia Fil: Telle, Emmanuel. Inserm; Francia Fil: Santofimia-Castaño, Patricia. Inserm; Francia Fil: Borrello, Maria Teresa. Inserm; Francia Fil: Chuluyan, Hector Eduardo. Consejo Nacional de Investigaciones Científicas y Técnicas. Oficina de Coordinación Administrativa Houssay. Centro de Estudios Farmacológicos y Botánicos. Universidad de Buenos Aires. Facultad de Medicina. Centro de Estudios Farmacológicos y Botánicos; Argentina Fil: Dusetti, Nelson. Inserm; Francia Fil: Iovanna, Juan Lucio. Inserm; Francia

SummaryPancreatic ductal adenocarcinoma (PDAC) is composed of stromal, immune and epithelial cells. Transcriptomic analysis of the epithelial compartment allows a binary classification into mainly two phenotypic subtypes, classical and basal-like. However, little is known about the intra-tumor heterogeneity of the epithelial component. Growing evidences suggest that this two side phenotypic segregation is not so clear and that both could coexist in a single tumor. In order to elucidate this hypothesis, we performed single-cell transcriptomic analyses using combinational barcoding on epithelial cells from 6 different classical PDAC obtained by Endoscopic Ultrasound (EUS) with Fine Needle Aspiration (FNA). In order to purify the epithelial compartment, PDAC were grown as Biopsy Derived Pancreatic Cancer Organoids. Single cell transcriptomic analysis allowed the identification of 4 main cell clusters present in different proportions in all tumors. Remarkably, although these tumors were classified as Classical, one of the clusters corresponded to a basal-like. These results depict the unanticipated high heterogeneity of pancreatic cancers and demonstrated that basal-like cells with a high aggressive phenotype are more widespread than expected.

The dismal prognosis of pancreatic ductal adenocarcinoma (PDAC) is mainly due to its rapidly acquired resistance to all conventional treatments. Despite drug-specific mechanisms of resistance, none explains how these cells resist the stress induced by any kind of anticancer treatment. Activation of stress-response pathways relies on the post-translational modifications (PTMs) of involved proteins. Among all PTMs, those mediated by the ubiquitin family of proteins play a central role. Our aim was to identify alterations of ubiquitination, neddylation, and sumoylation associated with the multiresistant phenotype and demonstrate their implications in the survival of PDAC cells undergoing treatment. This approach pointed at an alteration of promyelocytic leukemia (PML) protein sumoylation associated with both gemcitabine and oxaliplatin resistance. We could show that this alteration of PML sumoylation is part of a general mechanism of drug resistance, which in addition involves the abnormal activation of NF-κB and cAMP response element binding pathways. Importantly, using patient-derived tumors and cell lines, we identified a correlation between the levels of PML expression and sumoylation and the sensitivity of tumors to anticancer treatments.-Swayden, M., Alzeeb, G., Masoud, R., Berthois, Y., Audebert, S., Camoin, L., Hannouche, L., Vachon, H., Gayet, O., Bigonnet, M., Roques, J., Silvy, F., Carrier, A., Dusetti, N., Iovanna, J. L., Soubeyran, P. PML hyposumoylation is responsible for the resistance of pancreatic cancer.

Recent studies have offered ample insight into genome-wide expression patterns to define pancreatic ductal adenocarcinoma (PDAC) subtypes, although there remains a lack of knowledge regarding the underlying epigenomics of PDAC. Here we perform multi-parametric integrative analyses of chromatin immunoprecipitation-sequencing (ChIP-seq) on multiple histone modifications, RNA-sequencing (RNA-seq), and DNA methylation to define epigenomic landscapes for PDAC subtypes, which can predict their relative aggressiveness and survival. Moreover, we describe the state of promoters, enhancers, super-enhancers, euchromatic, and heterochromatic regions for each subtype. Further analyses indicate that the distinct epigenomic landscapes are regulated by different membrane-to-nucleus pathways. Inactivation of a basal-specific super-enhancer associated pathway reveals the existence of plasticity between subtypes. Thus, our study provides new insight into the epigenetic landscapes associated with the heterogeneity of PDAC, thereby increasing our mechanistic understanding of this disease, as well as offering potential new markers and therapeutic targets., Pancreatic ductal adenocarcinoma (PDAC) is a complex disease and its underlying epigenomic heterogeneity is not fully understood. Here, the authors utilize patient-derived PDAC xenografts to define the epigenomic landscape of PDAC, highlighting chromatin states linked to differing disease aggressiveness and survival.

Treating pancreatic cancer is extremely challenging due to multiple factors, including chemoresistance and poor disease prognosis. Chemoresistance can be explained by: the presence of a dense stromal barrier leading to a lower vascularized condition, therefore limiting drug delivery; the huge intra-tumoral heterogeneity; and the status of epithelial-to-mesenchymal transition. These factors are highly variable between patients making it difficult to predict responses to chemotherapy. Nicotinamide phosphoribosyl transferase (NAMPT) is the main enzyme responsible for recycling cytosolic NAD+ in hypoxic conditions. FK866 is a noncompetitive specific inhibitor of NAMPT, which has proven anti-tumoral effects, although a clinical advantage has still not been demonstrated. Here, we tested the effect of FK866 on pancreatic cancer-derived primary cell cultures (PCCs), both alone and in combination with three different drugs typically used against this cancer: gemcitabine, 5-Fluorouracil (5FU) and oxaliplatin. The aims of this study were to evaluate the benefit of drug combinations, define groups of sensitivity, and identify a potential biomarker for predicting treatment sensitivity. We performed cell viability tests in the presence of either FK866 alone or in combination with the drugs above-mentioned. We confirmed both inter- and intra-tumoral heterogeneity. Interestingly, only the in vitro effect of gemcitabine was influenced by the addition of FK866. We also found that NAMPT mRNA expression levels can predict the sensitivity of cells to FK866. Overall, our results suggest that patients with tumors sensitive to FK866 can be identified using NAMPT mRNA levels as a biomarker and could therefore benefit from a co-treatment of gemcitabine plus FK866.

The main goal of this study was to find out strategies of clinical relevance to classify patients with a pancreatic ductal adenocarcinoma (PDAC) for individualized treatments. In the present study a set of 55 patient-derived xenografts (PDX) were obtained and their transcriptome were analyzed by using an Affymetrix approach. A supervised bioinformatics-based analysis let us to classify these PDX in two main groups named E2F-highly dependent and E2F-lowly dependent. Afterwards their characterization by using a Kaplan-Meier analysis demonstrated that E2F high patients survived significantly less than E2F low patients (9.5 months vs. 16.8 months; p = 0.0066). Then we tried to establish if E2F transcriptional target levels were associated to the response to cytotoxic treatments by comparing the IC50 values of E2F high and E2F low cells after gemcitabine, 5-fluorouracil, oxaliplatin, docetaxel or irinotecan treatment, and no association was found. Then we identified an E2F inhibitor compound, named ly101-4B, and we observed that E2F-higly dependent cells were more sensitive to its treatment (IC50 of 19.4 ± 1.8 µM vs. 44.1 ± 4.4 µM; p = 0.0061). In conclusion, in this work we describe an E2F target expression-based classification that could be predictive for patient outcome, but more important, for the sensitivity of tumors to the E2F inhibitors as a treatment. Finally, we can assume that phenotypic characterization, essentially by an RNA expression analysis of the PDAC, can help to predict their clinical outcome and their response to some treatments when are rationally selected.

SUMMARY Preclinical models based on patient-derived xenografts have remarkable specificity in distinguishing transformed human tumor cells from non-transformed murine stromal cells computationally. We obtained 29 pancreatic ductal adenocarcinoma (PDAC) xenografts from either resectable or non-resectable patients (surgery and endoscopic ultrasound-guided fine-needle aspirate, respectively). Extensive multiomic profiling revealed two subtypes with distinct clinical outcomes. These subtypes uncovered specific alterations in DNA methylation and transcription as well as in signaling pathways involved in tumor-stromal cross-talk. The analysis of these pathways indicates therapeutic opportunities for targeting both compartments and their interactions. In particular, we show that inhibiting NPC1L1 with Ezetimibe, a clinically available drug, might be an efficient approach for treating pancreatic cancers. These findings uncover the complex and diverse interplay between PDAC tumors and the stroma and demonstrate the pivotal role of xenografts for drug discovery and relevance to PDAC., In Brief Nicolle et al. present a genomic analysis of pancreatic cancer xenografts showing that tumor subtypes are defined by specific epigenetic, transcriptional, and stromal landscapes. They reveal potential therapeutic targets through analysis of signaling cross-talk between tumor and stromal cells.

Patient-derived xenografts (PDX) are appearing as a prime approach for preclinical studies despite being insufficiently characterized as a model of the human disease and its diversity. In this work, 29 PDX were obtained from either surgery or endoscopic ultrasound-guided fine needle aspirate of pancreatic adenocarcinoma. The extensive genomic profiling of these pancreatic PDX, revealed two clinically-relevant subtypes having broad similarities with human primary tumors. These subtypes are defined by highly specific DNA methylation and transcriptomic profiles (mRNA, miRNA or lncRNA) but are not distinguishable by exonic mutations or copy number aberrations. Moreover, by specifically analyzing the stroma transcriptome, as defined by the expression of murine transcripts, we found that it is able to stratify the patients with the same efficiency than the analysis of grafted human tumor cells. This finding suggest that transformed pancreatic cells drive the composition of their own stroma. Finally, the multiomics analysis pinpoints novel therapeutic targets, one of which we demonstrate to be an efficient method for treating pancreatic cancer. Overall, we show that PDX are trustworthy pre-clinical models of pancreatic adenocarcinoma including of unresectable tumors. Their multiomics profiling allow the independent analysis of the uncontaminated cancer or stromal compartments and discloses several original therapeutics targets. Citation Format: Remy Nicolle, Yuna Blum, Laetitia Marisa, Celine Loncle, Odile Gayet, Vincent Moutardier, Olivier Turrini, Marc Giovannini, Benjamin Bian, Martin Bigonnet, Marion Rubis, Nabila Elarouci, Lucile Armenoult, Mira Ayadi, Pauline Duconseil, Mohamed Gasmi, Mehdi Ouaissi, Aurélie Maignan, Gwen Lomberk, Jean-Marie Boher, Jacques Ewald, Erwan Bories, Jonathan Garnier, Anthony Goncalves, Flora Poizat, Jean-Luc Raoul, Veronique Secq, Stephane Garcia, Philippe Grandval, Marine Barraud-Blanc, Emmanuelle Norguet, Marine Gilabert, Jean-Robert Delpero, Julie Roques, Ezequiel Calvo, Fabienne Guillaumond, Sophie Vasseur, Raul Urrutia, Aurélien de Reyniès, Nelson Dusetti, Juan Iovanna. Multiomics assessment of the cancer and stromal compartments of patient-derived pancreatic xenografts reveals clinically-relevant subtypes and novel targeted therapies [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2017; 2017 Apr 1-5; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2017;77(13 Suppl):Abstract nr 4396. doi:10.1158/1538-7445.AM2017-4396

Genome-wide molecular profiles have been proven to be beneficial for the identification of clinically relevant tumor subtypes in many neoplastic diseases. While pancreatic ductal adenocarcinoma (PDAC) is the fourth leading cause of cancer-related death, very few genomic and transcriptomic studies have been conducted. This is mainly due to the difficulty to obtain a suitable cohort of PDAC tumor samples. The major obstacle is the usually high proportion of non-transformed stromal cells, which can greatly hinder the analysis of carcinogenic-specific processes. Moreover, tumor cohorts requiring resection samples can be biased by the exclusion of inoperable patients, representing 85% of all patients presenting PDAC. In this study, we generated Patient Derived Xenografts (PDX) with samples collected from 29 patients using either Endoscopic Ultrasound-Guided Fine-Needle Aspirates or, for operable patients, resections. The transcriptomic profiles, of both mRNA and miRNA, and the epigenetic landscape of early PDX passages consistently identified two tumor-specific molecular subtypes: a well differentiated group often referred to as classical, and an undifferentiated group previously recognized as Basal, Quasi-Mesenchymal or Squamous. Of all the genetic alterations determined by Copy Number analysis and exome sequencing, none were specific to any of the two subtypes, which therefore could not be discriminated solely on genetic basis. These two PDAC subtypes are characterized by distinct epigenetic and transcriptomic profiles of which the analysis revealed the deregulation of several pathways previously imputed in PDAC development and carcinogenesis in general. In particular, we showed that the Wnt pathway as well as several metabolic pathways, including cytochrome P450 genes recently implicated in drug resistance, are both epigenetically and transcriptionally deregulated. Altogether, our results provide new insights on pancreatic carcinogenesis and suggest that PDAC phenotypical heterogeneity is mainly driven by epigenetic rather than genetic events. Citation Format: Remy Nicolle, Yuna Blum, Laetitia Marisa, Jonathan Garnier, Benjamin Bian, Celine Loncle, Martin Bigonnet, Odile Gayet, Vincent Moutardier, Pauline Duconseil, Mohamed Gasmi, Mehdi Ouaissi, Olivier Turrini, Marc Giovannini, Aurélie Maignan, Jean-Marie Boher, Jacques Ewald, Erwan Bories, Marc Barthet, Anthony Goncalves, Flora Poizat, Jean-Luc Raoul, Veronique Secq, Stephane Garcia, Philippe Grandval, Marine Barraud-Blanc, Emmanuelle Norguet, Marine Gilabert, Jean-Robert Delpero, Ezequiel Calvo, Aurélien de Reyniès, Nelson Dusetti, Juan Iovanna.{Authors}. Multi-omics characterization of PDAC subtypes using PDX reveals that epigenetic but not genetic analysis permit a clinically relevant classification. [abstract]. In: Proceedings of the AACR Special Conference on Pancreatic Cancer: Advances in Science and Clinical Care; 2016 May 12-15; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2016;76(24 Suppl):Abstract nr A48.

The extensive desmoplasia in pancreatic ductal adenocarcinoma (PDAC) has raised major interrogations on its role and function in the carcinogenic process. Patient-derived xenograft (PDX) offers an ideal setting to distinguish and to study the interactions between the cancerous epithelial cells and its stroma. Indeed, sequencing profiles of a mix of cancerous/Human and stroma/Mouse cells can be analyzed separately in silico by unambiguously assigning each sequence to the human or mouse genome. Using RNA sequencing, we profiled 30 pancreatic tumor PDXs and extracted the transcriptome profiles of epithelial cancerous cells as well as their corresponding stroma. On average, 70% of RNA sequencing reads were specifically attributed to a human origin, and therefore an epithelial origin, while 22% of RNA sequencing reads were mouse-specific. Using the rate of mouse sequences as a surrogate of the proportion of non-transformed cells, we observe a high variability in the infiltration level from 7% to 60%. The estimation was also consistent in whole exome sequencing (using the same sequencing process) and with the histological quantification of fibrotic tissue. By specifically analyzing the gene expression in mouse-stromal cells, we show that their transcriptomic profile is consistent with the recent description of human PDAC in situ tumors with high levels of genes of the reported activated-stroma and normal-stroma signatures. We also show that stromal cells over-express genes involved in the SLIT/ROBO axon guidance signalling pathway, in angiogenesis as well as a large number of collagens, cytokines and ligands associated with growth and developmental pathways. Recent studies identified two major subtypes of PDAC from transcriptomic analysis: a well differentiated, often referred as classical, and an undifferentiated, previously recognized as Basal, Quasi-Mesenchymal or Squamous. The stroma characterized in this work broadly reflects this heterogeneity with stromal gene expression signatures predictive of each subtype. For instance, collagens are significantly over-expressed in the stroma of squamous tumors. The concomitant analysis of transcriptomic profiles of both subtypes shows potential cross-talks between cancerous and stromal cells. Particularly in Squamous tumors, genes implicated in the axon-guidance and Wnt pathways are significantly upregulated in both, stroma and transformed cells. On the other hand, the stroma and transformed cells of Classical tumors shows an upregulation of complementary genes associated with several metabolic pathways. Taken together, our transcriptomic analysis reveals that human transformed pancreatic cells determine the composition, quantitatively and qualitatively, of stroma mouse cells in a PDX model. This model also reveals a broad variability of PDAC stromas and highlights potential cross-talks between them through known and novel pathways. Citation Format: Rémy Nicolle, Yuna Blum, Laetitia Marisa, Jonathan Garnier, Benjamin Bian, Celine Loncle, Martin Bigonnet, Odile Gayet, Vincent Moutardier, Pauline Duconseil, Mohamed Gasmi, Mehdi Ouaissi, Olivier Turrini, Marc Giovannini, Aurélie Maignan, Jean-Marie Boher, Jacques Ewald, Erwan Bories, Marc Barthet, Anthony Goncalves, Flora Poizat, Jean-Luc Raoul, Veronique Secq, Stephane Garcia, Philippe Grandval, Marine Barraud-Blanc, Emmanuelle Norguet, Marine Gilabert, Jean-Robert Delpero, Ezequiel Calvo, Aurélien de Reyniès, Juan Iovanna, Nelson Dusetti.{Authors}. Pancreatic cancer cell drives stroma composition. [abstract]. In: Proceedings of the AACR Special Conference on Pancreatic Cancer: Advances in Science and Clinical Care; 2016 May 12-15; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2016;76(24 Suppl):Abstract nr B72.