Abstract PO-127: Proteome profiling of pancreatic Ductal Adenocarcinoma (PDAC) primary tumors in Caucasian, African Americans and Latinx patients

Background: Pancreatic ductal adenocarcinoma (PDAC) is one of the most lethal primary tumors in humans, with undetermined tumorigenesis. Although previous work by us, and by others, has clearly demonstrated an involvement of miR-21 in the growth of PDAC, the underlying mechanism has not been clarified. Methods: Here we analyzed the regulation of FoxO1 by miR-21 in vitro and in vivo, using luciferase-reporter assay and pancreatic intraductal infusion of antisense of miR-21, respectively. Results: We found that overexpression of miR-21 in PDAC cells decreased FoxO1 protein levels, whereas inhibition of miR-21 increased FoxO1 levels. Further, miR-21 bound to FoxO1 mRNA to prevent its translation through its 3'UTR. Moreover, administration of antisense of miR-21 through an intraductal infusion system significantly decreased miR-21 levels and increased FoxO1 levels in implanted PDAC, resulting in a significant decrease in PDAC growth. Conclusion: Taken together, our data highlight miR-21/FoxO1 axis as a novel therapeutic target for inhibiting the growth of PDAC.

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Pancreatic cancer is marked by complement-high blood monocytes and tumor-associated macrophages

Life Science Alliance ◽

10.26508/lsa.202000935 ◽

2021 ◽

Vol 4 (6) ◽

pp. e202000935

Author(s):

Samantha B Kemp ◽

Nina G Steele ◽

Eileen S Carpenter ◽

Katelyn L Donahue ◽

Grace G Bushnell ◽

...

Keyword(s):

Single Cell ◽

Pancreatic Ductal Adenocarcinoma ◽

Rna Sequencing ◽

Gene Expression Signature ◽

Ductal Adenocarcinoma ◽

Specific Gene ◽

Sequencing Analysis ◽

Tumor Associated Macrophages ◽

Primary Tumors ◽

Single Cell Rna Sequencing

Pancreatic ductal adenocarcinoma (PDA) is accompanied by reprogramming of the local microenvironment, but changes at distal sites are poorly understood. We implanted biomaterial scaffolds, which act as an artificial premetastatic niche, into immunocompetent tumor-bearing and control mice, and identified a unique tumor-specific gene expression signature that includes high expression of C1qa, C1qb, Trem2, and Chil3. Single-cell RNA sequencing mapped these genes to two distinct macrophage populations in the scaffolds, one marked by elevated C1qa, C1qb, and Trem2, the other with high Chil3, Ly6c2 and Plac8. In mice, expression of these genes in the corresponding populations was elevated in tumor-associated macrophages compared with macrophages in the normal pancreas. We then analyzed single-cell RNA sequencing from patient samples, and determined expression of C1QA, C1QB, and TREM2 is elevated in human macrophages in primary tumors and liver metastases. Single-cell sequencing analysis of patient blood revealed a substantial enrichment of the same gene signature in monocytes. Taken together, our study identifies two distinct tumor-associated macrophage and monocyte populations that reflects systemic immune changes in pancreatic ductal adenocarcinoma patients.

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High CXCR4 expression in pancreatic ductal adenocarcinoma as characterized by an inflammatory tumor phenotype with potential implications for an immunotherapeutic approach.

Journal of Clinical Oncology ◽

10.1200/jco.2021.39.15_suppl.4021 ◽

2021 ◽

Vol 39 (15_suppl) ◽

pp. 4021-4021

Author(s):

Andreas Seeber ◽

Florian Kocher ◽

Andreas Pircher ◽

Alberto Puccini ◽

Yasmine Baca ◽

...

Keyword(s):

Pancreatic Ductal Adenocarcinoma ◽

Immune Cell ◽

Tumor Regression ◽

Signal Transduction Pathway ◽

Cxcr4 Expression ◽

Ductal Adenocarcinoma ◽

Rna Expression ◽

Primary Tumors ◽

Pathway Gene ◽

Molecular Landscape

4021 Background: Immunotherapy is considered ineffective in the majority of patients with pancreatic ductal adenocarcinoma (PDAC), a consequence of a highly immunosuppressive tumor microenvironment (TME). However, treatment induced inhibition of CXC chemokine receptor 4 (CXCR4) and programmed cell death protein-1 (PD-1) in the COMBAT trial caused T cell infiltration and tumor regression in a subset of PDAC patients. Elucidating a phenotype that predicts response is clinically relevant. We performed a comprehensive molecular landscape study in PDAC evaluating CXCR4 RNA expression. Methods: 3,647 PDAC specimens were centrally analysed. NextGen DNA sequencing (NextSeq, 592 gene panel or NovaSeq, whole-exome sequencing), whole-transcriptome RNA sequencing (NovaSeq) and immunohistochemistry (Caris Life Sciences, Phoenix, AZ) were performed. Gene expression is reported as TPM (Transcripts per million). Pathway gene enrichment analyses were done using GSEA (Subramaniam 2015, PNAS). Immune cell fraction was calculated by QuantiSeq (Finotello 2019, Genome Medicine). The cohort was stratified in quartiles according to CXCR4 RNA expression status. Results: Overall, CXCR4 expression was higher in primary tumors compared to distant metastasis (38 vs. 28 TPM, p < 0.0001). CXCR4-high (top quartile: > 59 TPMs), when compared to CXCR4-low (bottom quartile: < 17 TPM) PDACs, were characterized by a high prevalence of mutations in signal transduction pathway genes (e.g. GNAS: 3.6 vs. 0.5%), an increased infiltration of immune cells (e.g. CD8+ T cells, M1 macrophages), and a higher expression of HLA-DRA and HLA-E (all p < 0.0001). We detected an upregulation of CXCL9, CXCL10, CXCL12, CCL5, IDO1 and LAG3 in CXCR4-high compared to CXCR4-low tumors. In contrast, lower PD-L1 expression (17.4 vs. 13.1%, p = 0.02), genomic loss of heterozygosity (17.4 vs. 10.8%), and a lower frequency of gene amplifications in ERBB2 (2.1 vs. 0.1%), TNFRSF14 (2.0 vs. 0.1%), and TP53 (82 vs. 73%, all p < 0.0001) were observed. Moreover, CXCR4-high expression was associated with a better survival (HR: 1.417, 95% CI [1.168-1.72], p < 0.001). Conclusions: This is the first study comprehensively investigating the molecular landscape of PDACs according to CXCR4 RNA expression. High CXCR4 expression is associated with an improved survival and a pro-inflammatory phenotype that may identify a subset of tumors with greater responsiveness to immunotherapeutic approaches.

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hENT1 Testing in Pancreatic Ductal Adenocarcinoma: Are We Ready? A Multimodal Evaluation of hENT1 Status

Cancers ◽

10.3390/cancers11111808 ◽

2019 ◽

Vol 11 (11) ◽

pp. 1808 ◽

Cited By ~ 8

Author(s):

Jerome Raffenne ◽

Remy Nicolle ◽

Francesco Puleo ◽

Delphine Le Corre ◽

Camille Boyez ◽

...

Keyword(s):

Pancreatic Ductal Adenocarcinoma ◽

Predictive Value ◽

Mrna Level ◽

Progression Free Survival ◽

Predictive Biomarker ◽

Nucleoside Transport ◽

Ductal Adenocarcinoma ◽

Primary Tumors ◽

Free Survival ◽

Multicenter Cohort

Gemcitabine is still one of the standard chemotherapy regimens for pancreatic ductal adenocarcinoma (PDAC). Gemcitabine uptake into tumor cells is mainly through the human equilibrative nucleoside transport 1 (hENT1). It was therefore proposed as a potential predictive biomarker of gemcitabine efficacy but reports are conflicting, with an important heterogeneity in methods to assess hENT1 expression. A multicenter cohort of 471 patients with a resected PDAC was used to assess simultaneously the predictive value of the 2 best described hENT1 antibodies (10D7G2 and SP120). Three additional antibodies and the predictive value of hENT1 mRNA were also tested on 251 and 302 patients, respectively. hENT1 expression was assessed in 54 patients with matched primary tumors and metastases samples. The 10D7G2 clone was the only hENT1 antibody whose high expression was associated with a prolonged progression free survival and overall survival in patients who received adjuvant gemcitabine. hENT1 mRNA level was also predictive of gemcitabine benefit. hENT1 status was concordant in 83% of the cases with the best concordance in synchronous metastases. The 10D7G2 clone has the best predictive value of gemcitabine benefit in PDAC patients. Since it is not commercially available, hENT1 mRNA level could represent an alternative to assess hENT1 status.

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African Americans with pancreatic ductal adenocarcinoma exhibit gender differences in Kaiso expression

Cancer Letters ◽

10.1016/j.canlet.2016.06.025 ◽

2016 ◽

Vol 380 (2) ◽

pp. 513-522 ◽

Cited By ~ 9

Author(s):

Jacqueline Jones ◽

Angana Mukherjee ◽

Balasubramanyam Karanam ◽

Melissa Davis ◽

Jesse Jaynes ◽

...

Keyword(s):

Gender Differences ◽

African Americans ◽

Pancreatic Ductal Adenocarcinoma ◽

Ductal Adenocarcinoma

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Molecular targets for diagnostic and intraoperative imaging of pancreatic ductal adenocarcinoma after neoadjuvant FOLFIRINOX treatment

Scientific Reports ◽

10.1038/s41598-020-73242-6 ◽

2020 ◽

Vol 10 (1) ◽

Author(s):

F. A. Vuijk ◽

L. D. A. N. de Muynck ◽

L. C. Franken ◽

O. R. Busch ◽

J. W. Wilmink ◽

...

Keyword(s):

Molecular Imaging ◽

Lymph Nodes ◽

Pancreatic Ductal Adenocarcinoma ◽

Metastatic Lymph Node ◽

Imaging Techniques ◽

Intraoperative Imaging ◽

Neoadjuvant Treatment ◽

Radical Resection ◽

Ductal Adenocarcinoma ◽

Primary Tumors

Abstract Neoadjuvant systemic treatment is increasingly being integrated in the standard treatment of pancreatic ductal adenocarcinoma (PDAC) patients to improve oncological outcomes. Current available imaging techniques remain unreliable in assessing response to therapies, as they cannot distinguish between (vital) tumor tissue and therapy induced fibrosis (TIF). Consequently, resections with tumor positive margins and subsequent early post-operative recurrences occur and patients eligible for potential radical resection could be missed. To optimize patient selection and monitor results of neoadjuvant treatment, PDAC-specific diagnostic and intraoperative molecular imaging methods are required. This study aims to evaluate molecular imaging targets for PDAC after neoadjuvant FOLFIRINOX treatment. Expression of integrin αvβ6, carcinoembryonic antigen cell adhesion molecule 5 (CEACAM5), mesothelin, prostate-specific membrane antigen (PSMA), urokinase-type plasminogen activator receptor, fibroblast activating receptor, integrin α5 subunit and epidermal growth factor receptor was evaluated using immunohistochemistry. Immunoreactivity was determined using the semiquantitative H-score. Resection specimens from patients after neoadjuvant FOLFIRINOX treatment containing PDAC (n = 32), tumor associated pancreatitis (TAP) and TIF (n = 15), normal pancreas parenchyma (NPP) (n = 32) and tumor positive (n = 24) and negative (n = 56) lymph nodes were included. Integrin αvβ6, CEACAM5, mesothelin and PSMA stainings showed significantly higher expression in PDAC compared to TAP and NPP. No expression of αvβ6, CEACAM5 and mesothelin was observed in TIF. Integrin αvβ6 and CEACAM5 allow for accurate metastatic lymph node detection. Targeting integrin αvβ6, CEA, mesothelin and PSMA has the potential to distinguish vital PDAC from fibrotic tissue after neoadjuvant FOLFIRINOX treatment. Integrin αvβ6 and CEACAM5 detect primary tumors and tumor positive lymph nodes.

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MYC controls metastatic heterogeneity in pancreatic cancer

10.1101/2021.01.30.428641 ◽

2021 ◽

Author(s):

Ravikanth Maddipati ◽

Robert J. Norgard ◽

Timour Baslan ◽

Komal S. Rathi ◽

Amy Zhang ◽

...

Keyword(s):

Pancreatic Cancer ◽

Mouse Model ◽

Pancreatic Ductal Adenocarcinoma ◽

Cancer Patients ◽

Ductal Adenocarcinoma ◽

Tumor Type ◽

Metastatic Progression ◽

Primary Tumors ◽

Functional Differences ◽

Metastatic Burden

AbstractThe degree of metastatic disease varies widely amongst cancer patients and impacts clinical outcomes. However, the biological and functional differences that drive the extent of metastasis are poorly understood. We analyzed primary tumors and paired metastases using a multi-fluorescent lineage-labeled mouse model of pancreatic ductal adenocarcinoma (PDAC) – a tumor type where most patients present with metastases. Genomic and transcriptomic analysis revealed an association between metastatic burden and gene amplification or transcriptional upregulation of MYC and its downstream targets. Functional experiments showed that MYC promotes metastasis by recruiting tumor associated macrophages (TAMs), leading to greater bloodstream intravasation. Consistent with these findings, metastatic progression in human PDAC was associated with activation of MYC signaling pathways and enrichment for MYC amplifications specifically in metastatic patients. Collectively, these results implicate MYC activity as a major determinant of metastatic burden in advanced PDAC.

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Integrated genomic and transcriptomic analysis reveals unique characteristics of hepatic metastases and pro-metastatic role of complement C1q in pancreatic ductal adenocarcinoma

Genome Biology ◽

10.1186/s13059-020-02222-w ◽

2021 ◽

Vol 22 (1) ◽

Author(s):

Jianyu Yang ◽

Ping Lin ◽

Minwei Yang ◽

Wei Liu ◽

Xueliang Fu ◽

...

Keyword(s):

Pancreatic Ductal Adenocarcinoma ◽

Molecular Mechanisms ◽

Hepatic Metastases ◽

Ductal Adenocarcinoma ◽

Migration And Invasion ◽

M2 Macrophage ◽

Gene Expressions ◽

Primary Tumors ◽

Mesenchymal Transition ◽

Molecular Features

Abstract Background Pancreatic ductal adenocarcinoma (PDAC) is one of the most lethal cancers due to its high metastasis rate in the liver. However, little is known about the molecular features of hepatic metastases due to difficulty in obtaining fresh tissues and low tumor cellularity. Results We conduct exome sequencing and RNA sequencing for synchronous surgically resected primary tumors and the paired hepatic metastases from 17 hepatic oligometastatic pancreatic ductal adenocarcinoma and validate our findings in specimens from 35 of such cases. The comprehensive analysis of somatic mutations, copy number alterations, and gene expressions show high similarity between primary tumors and hepatic metastases. However, hepatic metastases also show unique characteristics, such as a higher degree of 3p21.1 loss, stronger abilities of proliferation, downregulation of epithelial to mesenchymal transition activity, and metabolic rewiring. More interesting, altered tumor microenvironments are observed in hepatic metastases, especially a higher proportion of tumor infiltrating M2 macrophage and upregulation of complement cascade. Further experiments demonstrate that expression of C1q increases in primary tumors and hepatic metastases, C1q is mainly produced by M2 macrophage, and C1q promotes migration and invasion of PDAC cells. Conclusion Taken together, we find potential factors that contribute to different stages of PDAC metastasis. Our study broadens the understanding of molecular mechanisms driving PDAC metastasis.

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