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4 pages, 534 KiB

Open AccessEditorial

The Tumor Microenvironment of Pancreatic Cancer

by Eva Karamitopoulou

Cancers 2020, 12(10), 3076; https://doi.org/10.3390/cancers12103076 - 21 Oct 2020

Cited by 16 | Viewed by 4059

Abstract

Pancreatic ductal adenocarcinoma (PDAC) has a dismal prognosis along with rising incidence rates and will be responsible for many cancer deaths in the future [...] Full article

(This article belongs to the Special Issue Tumor Microenvironment of Pancreatic Cancer)

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Research

Jump to: Editorial, Review

20 pages, 2555 KiB

Open AccessArticle

Targeting FTO Suppresses Pancreatic Carcinogenesis via Regulating Stem Cell Maintenance and EMT Pathway

by Rachana Garg, Laleh Melstrom, Jianjun Chen, Chuan He and Ajay Goel

Cancers 2022, 14(23), 5919; https://doi.org/10.3390/cancers14235919 - 30 Nov 2022

Cited by 9 | Viewed by 2618

Abstract

N⁶-methyladenosine (m⁶A) is the most prevalent post-transcriptional RNA modification regulating cancer self-renewal. However, despite its functional importance and prognostic implication in tumorigenesis, the relevance of FTO, an m⁶A eraser, in pancreatic cancer (PC) remains elusive. Here, we [...] Read more.

N⁶-methyladenosine (m⁶A) is the most prevalent post-transcriptional RNA modification regulating cancer self-renewal. However, despite its functional importance and prognostic implication in tumorigenesis, the relevance of FTO, an m⁶A eraser, in pancreatic cancer (PC) remains elusive. Here, we establish the oncogenic role played by FTO overexpression in PC. FTO is upregulated in PC cells compared to normal human pancreatic ductal epithelial (HPDE) cells. Both RNAi depletion and CS1-mediated pharmacological inhibition of FTO caused a diminution of PC cell proliferation via cell cycle arrest in the G1 phase and p21cip1 and p27kip1 induction. While HPDE cells remain insensitive to CS1 treatment, FTO overexpression confers enhancements in growth, motility, and EMT transition, thereby inculcating tumorigenic properties in HPDE cells. Notably, shRNA-mediated FTO depletion in PC cells impairs their mobility and invasiveness, leading to EMT reversal. Mechanistically, this was associated with impaired tumorsphere formation and reduced expression of CSCs markers. Furthermore, FTO depletion in PC cells weakened their tumor-forming capabilities in nude mice; those tumors had increased apoptosis, decreased proliferation markers, and MET conversion. Collectively, our study demonstrates the functional importance of FTO in PC and the maintenance of CSCs via EMT regulation. Thus, FTO may represent an attractive therapeutic target for PC. Full article

(This article belongs to the Special Issue Tumor Microenvironment of Pancreatic Cancer)

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15 pages, 35821 KiB

Open AccessArticle

Differential Expression of Polyamine Pathways in Human Pancreatic Tumor Progression and Effects of Polyamine Blockade on Tumor Microenvironment

by Sai Preethi Nakkina, Sarah B. Gitto, Veethika Pandey, Jignesh G. Parikh, Dirk Geerts, Hans Carlo Maurer, Kenneth P. Olive, Otto Phanstiel IV and Deborah A. Altomare

Cancers 2021, 13(24), 6391; https://doi.org/10.3390/cancers13246391 - 20 Dec 2021

Cited by 16 | Viewed by 4073

Abstract

Pancreatic cancer is the fourth leading cause of cancer death. Existing therapies only moderately improve pancreatic ductal adenocarcinoma (PDAC) patient prognosis. The present study investigates the importance of the polyamine metabolism in the pancreatic tumor microenvironment. Relative mRNA expression analysis identified differential expression [...] Read more.

Pancreatic cancer is the fourth leading cause of cancer death. Existing therapies only moderately improve pancreatic ductal adenocarcinoma (PDAC) patient prognosis. The present study investigates the importance of the polyamine metabolism in the pancreatic tumor microenvironment. Relative mRNA expression analysis identified differential expression of polyamine biosynthesis, homeostasis, and transport mediators in both pancreatic epithelial and stromal cells from low-grade pancreatic intraepithelial neoplasia (PanIN-1) or primary PDAC patient samples. We found dysregulated mRNA levels that encode for proteins associated with the polyamine pathway of PDAC tumors compared to early lesions. Next, bioinformatic databases were used to assess expression of select genes involved in polyamine metabolism and their impact on patient survival. Higher expression of pro-polyamine genes was associated with poor patient prognosis, supporting the use of a polyamine blockade therapy (PBT) strategy for inhibiting pancreatic tumor progression. Moreover, PBT treatment of syngeneic mice injected intra-pancreatic with PAN 02 tumor cells resulted in increased survival and decreased tumor weights of PDAC-bearing mice. Histological assessment of PBT-treated tumors revealed macrophage presence and significantly increased expression of CD86, a T cell co-stimulatory marker. Collectively, therapies which target polyamine metabolism can be used to disrupt tumor progression, modulate tumor microenvironment, and extend overall survival. Full article

(This article belongs to the Special Issue Tumor Microenvironment of Pancreatic Cancer)

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18 pages, 3229 KiB

Open AccessArticle

TGFβ Drives Metabolic Perturbations during Epithelial Mesenchymal Transition in Pancreatic Cancer: TGFβ Induced EMT in PDAC

by Meena U. Rajagopal, Shivani Bansal, Prabhjit Kaur, Shreyans K. Jain, Tatiana Altadil, Charles P. Hinzman, Yaoxiang Li, Joanna Moulton, Baldev Singh, Sunil Bansal, Siddheshwar Kisan Chauthe, Rajbir Singh, Partha P. Banerjee, Mark Mapstone, Massimo S. Fiandaca, Howard J. Federoff, Keith Unger, Jill P. Smith and Amrita K. Cheema

Cancers 2021, 13(24), 6204; https://doi.org/10.3390/cancers13246204 - 9 Dec 2021

Cited by 11 | Viewed by 3984

Abstract

Pancreatic ductal adenocarcinoma (PDAC) is a highly lethal malignancy wherein a majority of patients present metastatic disease at diagnosis. Although the role of epithelial to mesenchymal transition (EMT), mediated by transforming growth factor beta (TGFβ), in imparting an aggressive phenotype to PDAC is [...] Read more.

Pancreatic ductal adenocarcinoma (PDAC) is a highly lethal malignancy wherein a majority of patients present metastatic disease at diagnosis. Although the role of epithelial to mesenchymal transition (EMT), mediated by transforming growth factor beta (TGFβ), in imparting an aggressive phenotype to PDAC is well documented, the underlying biochemical pathway perturbations driving this behaviour have not been elucidated. We used high-resolution mass spectrometry (HRMS) based molecular phenotyping approach in order to delineate metabolic changes concomitant to TGFβ-induced EMT in pancreatic cancer cells. Strikingly, we observed robust changes in amino acid and energy metabolism that may contribute to tumor invasion and metastasis. Somewhat unexpectedly, TGFβ treatment resulted in an increase in intracellular levels of retinoic acid (RA) that in turn resulted in increased levels of extracellular matrix (ECM) proteins including fibronectin (FN) and collagen (COL1). These findings were further validated in plasma samples obtained from patients with resectable pancreatic cancer. Taken together, these observations provide novel insights into small molecule dysregulation that triggers a molecular cascade resulting in increased EMT-like changes in pancreatic cancer cells, a paradigm that can be potentially targeted for better clinical outcomes. Full article

(This article belongs to the Special Issue Tumor Microenvironment of Pancreatic Cancer)

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20 pages, 9616 KiB

Open AccessArticle

Anti-Cancer Activity Profiling of Chemotherapeutic Agents in 3D Co-Cultures of Pancreatic Tumor Spheroids with Cancer-Associated Fibroblasts and Macrophages

by So-Dam Jang, Jeeyeun Song, Hyun-Ah Kim, Chang-Nim Im, Iftikhar Ali Khawar, Jong Kook Park and Hyo-Jeong Kuh

Cancers 2021, 13(23), 5955; https://doi.org/10.3390/cancers13235955 - 26 Nov 2021

Cited by 15 | Viewed by 4630

Abstract

Activated pancreatic stellate cells (aPSCs) and M2 macrophages modulate tumor progression and therapeutic efficacy in pancreatic ductal adenocarcinoma (PDAC) via epithelial-mesenchymal transition (EMT). Here, our aim was to analyze the anti-invasion effects of anti-cancer agents where EMT-inducing cancer-stroma interaction occurs under three-dimensional (3D) [...] Read more.

Activated pancreatic stellate cells (aPSCs) and M2 macrophages modulate tumor progression and therapeutic efficacy in pancreatic ductal adenocarcinoma (PDAC) via epithelial-mesenchymal transition (EMT). Here, our aim was to analyze the anti-invasion effects of anti-cancer agents where EMT-inducing cancer-stroma interaction occurs under three-dimensional (3D) culture conditions. We used microfluidic channel chips to co-culture pancreatic tumor spheroids (TSs) with aPSCs and THP-1-derived M2 macrophages (M2 THP-1 cells) embedded in type I collagen. Under stromal cell co-culture conditions, PANC-1 TSs displayed elevated expression of EMT-related proteins and increased invasion and migration. When PANC-1 TSs were exposed to gemcitabine, 5-fluorouracil, oxaliplatin, or paclitaxel, 30–50% cells were found unaffected, with no significant changes in the dose-response profiles under stromal cell co-culture conditions. This indicated intrinsic resistance to these drugs and no further induction of drug resistance by stromal cells. Paclitaxel had a significant anti-invasion effect; in contrast, oxaliplatin did not show such effect despite its specific cytotoxicity in M2 THP-1 cells. Overall, our findings demonstrate that the TS-stroma co-culture model of PDAC is useful for activity profiling of anti-cancer agents against cancer and stromal cells, and analyzing the relationship between anti-stromal activity and anti-invasion effects. Full article

(This article belongs to the Special Issue Tumor Microenvironment of Pancreatic Cancer)

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13 pages, 3340 KiB

Open AccessArticle

Histopathological Tumor and Normal Tissue Responses after 3D-Planned Arc Radiotherapy in an Orthotopic Xenograft Mouse Model of Human Pancreatic Cancer

by Sophie Dobiasch, Severin Kampfer, Katja Steiger, Daniela Schilling, Julius C. Fischer, Thomas E. Schmid, Wilko Weichert, Jan J. Wilkens and Stephanie E. Combs

Cancers 2021, 13(22), 5656; https://doi.org/10.3390/cancers13225656 - 12 Nov 2021

Cited by 2 | Viewed by 2685

Abstract

Pancreatic ductal adenocarcinoma (PDAC) is one of the most lethal human cancers. Innovative treatment concepts may enhance oncological outcome. Clinically relevant tumor models are essential in developing new therapeutic strategies. In the present study, we used two human PDAC cell lines for an [...] Read more.

Pancreatic ductal adenocarcinoma (PDAC) is one of the most lethal human cancers. Innovative treatment concepts may enhance oncological outcome. Clinically relevant tumor models are essential in developing new therapeutic strategies. In the present study, we used two human PDAC cell lines for an orthotopic xenograft mouse model and compared treatment characteristics between this in vivo tumor model and PDAC patients. Tumor-bearing mice received stereotactic high-precision irradiation using arc technique after 3D-treatment planning. Induction of DNA damage in tumors and organs at risk (OARs) was histopathologically analyzed by the DNA damage marker γH2AX and compared with results after unprecise whole-abdomen irradiation. Our mouse model and preclinical setup reflect the characteristics of PDAC patients and clinical RT. It was feasible to perform stereotactic high-precision RT after defining tumor and OARs by CT imaging. After stereotactic RT, a high rate of DNA damage was mainly observed in the tumor but not in OARs. The calculated dose distributions and the extent of the irradiation field correlate with histopathological staining and the clinical example. We established and validated 3D-planned stereotactic RT in an orthotopic PDAC mouse model, which reflects the human RT. The efficacy of the whole workflow of imaging, treatment planning, and high-precision RT was proven by longitudinal analysis showing a significant improved survival. Importantly, this model can be used to analyze tumor regression and therapy-related toxicity in one model and will allow drawing clinically relevant conclusions. Full article

(This article belongs to the Special Issue Tumor Microenvironment of Pancreatic Cancer)

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21 pages, 3432 KiB

Open AccessArticle

Cholecystokinin Receptor Antagonist Improves Efficacy of Chemotherapy in Murine Models of Pancreatic Cancer by Altering the Tumor Microenvironment

by Zoe X. Malchiodi, Hong Cao, Martha D. Gay, Anita Safronenka, Sunil Bansal, Robin D. Tucker, Benjamin A. Weinberg, Amrita Cheema, Narayan Shivapurkar and Jill P. Smith

Cancers 2021, 13(19), 4949; https://doi.org/10.3390/cancers13194949 - 30 Sep 2021

Cited by 9 | Viewed by 3178

Abstract

Pancreatic cancer is resistant to chemotherapy in part due to the dense desmoplastic fibrosis surrounding the tumor, the immunosuppressive cells in the tumor microenvironment (TME), and the early rate of metastases. In this study, we examined the effects of a CCK receptor antagonist, [...] Read more.

Pancreatic cancer is resistant to chemotherapy in part due to the dense desmoplastic fibrosis surrounding the tumor, the immunosuppressive cells in the tumor microenvironment (TME), and the early rate of metastases. In this study, we examined the effects of a CCK receptor antagonist, proglumide, alone and in combination with gemcitabine in murine models of pancreatic cancer. Tumor growth rate, metastases, and survival were assessed in mice bearing syngeneic murine or human pancreatic tumors treated with PBS (control), gemcitabine, proglumide, or the combination of gemcitabine and proglumide. Excised tumors were evaluated histologically for fibrosis, immune cells, molecular markers, and uptake of chemotherapy by mass spectroscopy. Peripheral blood was analyzed with a microRNAs biomarker panel associated with fibrosis and oncogenesis. Differentially expressed genes between tumors of mice treated with gemcitabine monotherapy and combination therapy were compared by RNAseq. When given in combination the two compounds exhibited inhibitory effects by decreasing tumor growth rate by 70%, metastases, and prolonging survival. Proglumide monotherapy altered the TME by decreasing fibrosis, increasing intratumoral CD8⁺ T-cells, and decreasing arginase-positive cells, thus rendering the tumor sensitive to chemotherapy. Proglumide altered the expression of genes involved in fibrosis, epithelial–mesenchymal transition, and invasion. CCK-receptor antagonism with proglumide renders pancreatic cancer susceptible to chemotherapy. Full article

(This article belongs to the Special Issue Tumor Microenvironment of Pancreatic Cancer)

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44 pages, 16805 KiB

Open AccessFeature PaperArticle

HGF/c-Met Inhibition as Adjuvant Therapy Improves Outcomes in an Orthotopic Mouse Model of Pancreatic Cancer

by Tony C. Y. Pang, Zhihong Xu, Alpha Raj Mekapogu, Srinivasa Pothula, Therese Becker, Susan Corley, Marc R. Wilkins, David Goldstein, Romano Pirola, Jeremy Wilson and Minoti Apte

Cancers 2021, 13(11), 2763; https://doi.org/10.3390/cancers13112763 - 2 Jun 2021

Cited by 8 | Viewed by 3753

Abstract

Background: Inhibition of hepatocyte growth factor (HGF)/c-MET pathway, a major mediator of pancreatic stellate cell (PSC)−PC cell interactions, retards local and distant cancer progression. This study examines the use of this treatment in preventing PC progression after resection. We further investigate the postulated [...] Read more.

Background: Inhibition of hepatocyte growth factor (HGF)/c-MET pathway, a major mediator of pancreatic stellate cell (PSC)−PC cell interactions, retards local and distant cancer progression. This study examines the use of this treatment in preventing PC progression after resection. We further investigate the postulated existence of circulating PSCs (cPSCs) as a mediator of metastatic PC. Methods: Two orthotopic PC mouse models, produced by implantation of a mixture of luciferase-tagged human pancreatic cancer cells (AsPC-1), and human PSCs were used. Model 1 mice underwent distal pancreatectomy 3-weeks post-implantation (n = 62). One-week post-resection, mice were randomised to four treatments of 8 weeks: (i) IgG, (ii) gemcitabine (G), (iii) HGF/c-MET inhibition (HiCi) and (iv) HiCi + G. Tumour burden was assessed longitudinally by bioluminescence. Circulating tumour cells and cPSCs were enriched by filtration. Tumours of Model 2 mice progressed for 8 weeks prior to the collection of primary tumour, metastases and blood for single-cell RNA-sequencing (scRNA-seq). Results: HiCi treatments: (1) reduced both the risk and rate of disease progression after resection; (2) demonstrated an anti-angiogenic effect on immunohistochemistry; (3) reduced cPSC counts. cPSCs were identified using immunocytochemistry (α-smooth muscle actin+, pan-cytokeratin−, CD45−), and by specific PSC markers. scRNA-seq confirmed the existence of cPSCs and identified potential genes associated with development into cPSCs. Conclusions: This study is the first to demonstrate the efficacy of adjuvant HGF/c-Met inhibition for PC and provides the first confirmation of the existence of circulating PSCs. Full article

(This article belongs to the Special Issue Tumor Microenvironment of Pancreatic Cancer)

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19 pages, 7251 KiB

Open AccessArticle

Expression of Immune Checkpoint Regulators IDO, VISTA, LAG3, and TIM3 in Resected Pancreatic Ductal Adenocarcinoma

by Felix C. Popp, Ingracia Capino, Joana Bartels, Alexander I. Damanakis, Jiahui Li, Rabi R. Datta, Heike Löser, Yue Zhao, Alexander Quaas, Philipp Lohneis, Christiane J. Bruns and on behalf of the PANCALYZE Study Group

Cancers 2021, 13(11), 2689; https://doi.org/10.3390/cancers13112689 - 29 May 2021

Cited by 16 | Viewed by 3629

Abstract

Pancreatic cancer features elaborate mechanisms of immune evasion. The potential of new immune molecules was explored to restore the antitumor immune response. If these immune molecules are associated with poor survival, specific drugs could take effect. Here, we analyze the expression of VISTA, [...] Read more.

Pancreatic cancer features elaborate mechanisms of immune evasion. The potential of new immune molecules was explored to restore the antitumor immune response. If these immune molecules are associated with poor survival, specific drugs could take effect. Here, we analyze the expression of VISTA, LAG3, IDO, and TIM3 on tumor-infiltrating lymphocytes (TILs) and its impact on patient survival. We analyzed 153 pancreatic cancer patients from the prospectively managed database of the multicentered PANCALYZE study. Immunohistochemistry on a tissue microarray assessed VISTA, LAG3, IDO, and TIM3 expression of TILs from the patients undergoing primary resection. Complementarily, we analyzed publicly available transcriptomic data (n = 903). Successful completion of chemotherapy, and lymph node status were independent predictors of survival in the multivariate analysis of the clinicopathologic parameters. Fifteen tumors were exclusively VISTA-positive, thirteen tumors expressed VISTA together with TIM3, and ten tumors expressed VISTA together with IDO. Patients featuring tumors with high numbers of IDO-positive TILs had better patient survival (p = 0.037). VISTA, LAG3, and TIM3 expression did not correlate with survival. The analysis of publicly available data did not show survival differences. Tumors rarely co-express more than two immune molecules at the same time, and VISTA is most frequently co-expressed. Although IDO generally inhibits T-cell proliferation, a high expression of IDO was associated with improved survival. We expect immune checkpoint inhibitors against VISTA, LAG3, and TIM3 to be inefficient in a clinical application. Full article

(This article belongs to the Special Issue Tumor Microenvironment of Pancreatic Cancer)

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17 pages, 2383 KiB

Open AccessArticle

Pancreatic Cancers with High Grade Tumor Budding Exhibit Hallmarks of Diminished Anti-Tumor Immunity

by Hassan Sadozai, Animesh Acharjee, Thomas Gruber, Beat Gloor and Eva Karamitopoulou

Cancers 2021, 13(5), 1090; https://doi.org/10.3390/cancers13051090 - 4 Mar 2021

Cited by 10 | Viewed by 4026

Abstract

Tumor budding is associated with epithelial-mesenchymal transition and diminished survival in a number of cancer types including pancreatic ductal adenocarcinoma (PDAC). In this study, we dissect the immune landscapes of patients with high grade versus low grade tumor budding to determine the features [...] Read more.

Tumor budding is associated with epithelial-mesenchymal transition and diminished survival in a number of cancer types including pancreatic ductal adenocarcinoma (PDAC). In this study, we dissect the immune landscapes of patients with high grade versus low grade tumor budding to determine the features associated with immune escape and disease progression in pancreatic cancer. We performed immunohistochemistry-based quantification of tumor-infiltrating leukocytes and tumor bud assessment in a cohort of n = 111 PDAC patients in a tissue microarray (TMA) format. Patients were divided based on the ITBCC categories of tumor budding as Low Grade (LG: categories 1 and 2) and High Grade (HG: category 3). Tumor budding numbers and tumor budding grade demonstrated a significant association with diminished overall survival (OS). HG cases exhibit notably reduced densities of stromal (S) and intratumoral (IT) T cells. HG cases also display lower M1 macrophages (S) and increased M2 macrophages (IT). These findings were validated using gene expression data from TCGA. A published tumor budding gene signature demonstrated a significant association with diminished survival in PDAC patients in TCGA. Immune-related gene expression revealed an immunosuppressive TME in PDAC cases with high expression of the budding signature. Our findings highlight a number of immune features that permit an improved understanding of disease progression and EMT in pancreatic cancer. Full article

(This article belongs to the Special Issue Tumor Microenvironment of Pancreatic Cancer)

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Review

Jump to: Editorial, Research

19 pages, 1652 KiB

Open AccessReview

The Homologous Recombination Deficiency Scar in Advanced Cancer: Agnostic Targeting of Damaged DNA Repair

by Vilma Pacheco-Barcia, Andrés Muñoz, Elena Castro, Ana Isabel Ballesteros, Gloria Marquina, Iván González-Díaz, Ramon Colomer and Nuria Romero-Laorden

Cancers 2022, 14(12), 2950; https://doi.org/10.3390/cancers14122950 - 15 Jun 2022

Cited by 15 | Viewed by 3424

Abstract

BRCA1 and BRCA2 are the most recognized tumor-suppressor genes involved in double-strand DNA break repair through the homologous recombination (HR) system. Widely known for its role in hereditary cancer, HR deficiency (HRD) has turned out to be critical beyond breast and ovarian cancer: [...] Read more.

BRCA1 and BRCA2 are the most recognized tumor-suppressor genes involved in double-strand DNA break repair through the homologous recombination (HR) system. Widely known for its role in hereditary cancer, HR deficiency (HRD) has turned out to be critical beyond breast and ovarian cancer: for prostate and pancreatic cancer also. The relevance for the identification of these patients exceeds diagnostic purposes, since results published from clinical trials with poly-ADP ribose polymerase (PARP) inhibitors (PARPi) have shown how this type of targeted therapy can modify the long-term evolution of patients with HRD. Somatic aberrations in other HRD pathway genes, but also indirect genomic instability as a sign of this DNA repair impairment (known as HRD scar), have been reported to be relevant events that lead to more frequently than expected HR loss of function in several tumor types, and should therefore be included in the current diagnostic and therapeutic algorithm. However, the optimal strategy to identify HRD and potential PARPi responders in cancer remains undefined. In this review, we summarize the role and prevalence of HRD across tumor types and the current treatment landscape to guide the agnostic targeting of damaged DNA repair. We also discuss the challenge of testing patients and provide a special insight for new strategies to select patients who benefit from PARPi due to HRD scarring. Full article

(This article belongs to the Special Issue Tumor Microenvironment of Pancreatic Cancer)

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25 pages, 2180 KiB

Open AccessReview

Tumor Microenvironment in Pancreatic Intraepithelial Neoplasia

by Friederike V. Opitz, Lena Haeberle, Alexandra Daum and Irene Esposito

Cancers 2021, 13(24), 6188; https://doi.org/10.3390/cancers13246188 - 8 Dec 2021

Cited by 16 | Viewed by 4949

Abstract

Pancreatic ductal adenocarcinoma (PDAC) is one of the most aggressive tumors with a poor prognosis. A characteristic of PDAC is the formation of an immunosuppressive tumor microenvironment (TME) that facilitates bypassing of the immune surveillance. The TME consists of a desmoplastic stroma, largely [...] Read more.

Pancreatic ductal adenocarcinoma (PDAC) is one of the most aggressive tumors with a poor prognosis. A characteristic of PDAC is the formation of an immunosuppressive tumor microenvironment (TME) that facilitates bypassing of the immune surveillance. The TME consists of a desmoplastic stroma, largely composed of cancer-associated fibroblasts (CAFs), immunosuppressive immune cells, immunoregulatory soluble factors, neural network cells, and endothelial cells with complex interactions. PDAC develops from various precursor lesions such as pancreatic intraepithelial neoplasia (PanIN), intraductal papillary mucinous neoplasms (IPMN), mucinous cystic neoplasms (MCN), and possibly, atypical flat lesions (AFL). In this review, we focus on the composition of the TME in PanINs to reveal detailed insights into the complex restructuring of the TME at early time points in PDAC progression and to explore ways of modifying the TME to slow or even halt tumor progression. Full article

(This article belongs to the Special Issue Tumor Microenvironment of Pancreatic Cancer)

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23 pages, 1616 KiB

Open AccessReview

Pancreatic Cancer Microenvironment and Cellular Composition: Current Understandings and Therapeutic Approaches

by Linh-Huyen Truong and Siim Pauklin

Cancers 2021, 13(19), 5028; https://doi.org/10.3390/cancers13195028 - 8 Oct 2021

Cited by 47 | Viewed by 8618

Abstract

Pancreatic ductal adenocarcinoma (PDAC) remains one of the most lethal human solid tumors, despite great efforts in improving therapeutics over the past few decades. In PDAC, the distinct characteristic of the tumor microenvironment (TME) is the main barrier for developing effective treatments. PDAC [...] Read more.

Pancreatic ductal adenocarcinoma (PDAC) remains one of the most lethal human solid tumors, despite great efforts in improving therapeutics over the past few decades. In PDAC, the distinct characteristic of the tumor microenvironment (TME) is the main barrier for developing effective treatments. PDAC TME is characterized by a dense stroma, cancer-associated fibroblasts, and immune cells populations that crosstalk to the subpopulations of neoplastic cells that include cancer stem cells (CSCs). The heterogeneity in TME is also exhibited in the diversity and dynamics of acellular components, including the Extracellular matrix (ECM), cytokines, growth factors, and secreted ligands to signaling pathways. These contribute to drug resistance, metastasis, and relapse in PDAC. However, clinical trials targeting TME components have often reported unexpected results and still have not benefited patients. The failures in those trials and various efforts to understand the PDAC biology demonstrate the highly heterogeneous and multi-faceted TME compositions and the complexity of their interplay within TME. Hence, further functional and mechanistic insight is needed. In this review, we will present a current understanding of PDAC biology with a focus on the heterogeneity in TME and crosstalk among its components. We also discuss clinical challenges and the arising therapeutic opportunities in PDAC research. Full article

(This article belongs to the Special Issue Tumor Microenvironment of Pancreatic Cancer)

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11 pages, 922 KiB

Open AccessReview

Using Organotypic Tissue Slices to Investigate the Microenvironment of Pancreatic Cancer: Pharmacotyping and Beyond

by Jonathan Robert Weitz, Herve Tiriac, Tatiana Hurtado de Mendoza, Alexis Wascher and Andrew M. Lowy

Cancers 2021, 13(19), 4991; https://doi.org/10.3390/cancers13194991 - 5 Oct 2021

Cited by 13 | Viewed by 3472

Abstract

Organotypic tissue slices prepared from patient tumors are a semi-intact ex vivo preparation that recapitulates many aspects of the tumor microenvironment (TME). While connections to the vasculature and nervous system are severed, the integral functional elements of the tumor remain intact for many [...] Read more.

Organotypic tissue slices prepared from patient tumors are a semi-intact ex vivo preparation that recapitulates many aspects of the tumor microenvironment (TME). While connections to the vasculature and nervous system are severed, the integral functional elements of the tumor remain intact for many days during the slice culture. During this window of time, the slice platforms offer a suite of molecular, biomechanical and functional tools to investigate PDAC biology. In this review, we first briefly discuss the development of pancreatic tissue slices as a model system. Next, we touch upon using slices as an orthogonal approach to study the TME as compared to other established 3D models, such as organoids. Distinct from most other models, the pancreatic slices contain autologous immune and other stromal cells. Taking advantage of the existing immune cells within the slices, we will discuss the breakthrough studies which investigate the immune compartment in the pancreas slices. These studies will provide an important framework for future investigations seeking to exploit or reprogram the TME for cancer therapy. Full article

(This article belongs to the Special Issue Tumor Microenvironment of Pancreatic Cancer)

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34 pages, 1462 KiB

Open AccessReview

The Heterogeneity of the Tumor Microenvironment as Essential Determinant of Development, Progression and Therapy Response of Pancreatic Cancer

by Group Young Researchers in Inflammatory Carcinogenesis, Anna Maxi Wandmacher, Anne-Sophie Mehdorn and Susanne Sebens

Cancers 2021, 13(19), 4932; https://doi.org/10.3390/cancers13194932 - 30 Sep 2021

Cited by 18 | Viewed by 4256

Abstract

Pancreatic ductal adenocarcinoma (PDAC) is commonly diagnosed at advanced stages and most anti-cancer therapies have failed to substantially improve prognosis of PDAC patients. As a result, PDAC is still one of the deadliest tumors. Tumor heterogeneity, manifesting at multiple levels, provides a conclusive [...] Read more.

Pancreatic ductal adenocarcinoma (PDAC) is commonly diagnosed at advanced stages and most anti-cancer therapies have failed to substantially improve prognosis of PDAC patients. As a result, PDAC is still one of the deadliest tumors. Tumor heterogeneity, manifesting at multiple levels, provides a conclusive explanation for divergent survival times and therapy responses of PDAC patients. Besides tumor cell heterogeneity, PDAC is characterized by a pronounced inflammatory stroma comprising various non-neoplastic cells such as myofibroblasts, endothelial cells and different leukocyte populations which enrich in the tumor microenvironment (TME) during pancreatic tumorigenesis. Thus, the stromal compartment also displays a high temporal and spatial heterogeneity accounting for diverse effects on the development, progression and therapy responses of PDAC. Adding to this heterogeneity and the impact of the TME, the microbiome of PDAC patients is considerably altered. Understanding this multi-level heterogeneity and considering it for the development of novel therapeutic concepts might finally improve the dismal situation of PDAC patients. Here, we outline the current knowledge on PDAC cell heterogeneity focusing on different stromal cell populations and outline their impact on PDAC progression and therapy resistance. Based on this information, we propose some novel concepts for treatment of PDAC patients. Full article

(This article belongs to the Special Issue Tumor Microenvironment of Pancreatic Cancer)

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27 pages, 689 KiB

Open AccessReview

Pancreatic Cancer Small Extracellular Vesicles (Exosomes): A Tale of Short- and Long-Distance Communication

by Mareike Waldenmaier, Tanja Seibold, Thomas Seufferlein and Tim Eiseler

Cancers 2021, 13(19), 4844; https://doi.org/10.3390/cancers13194844 - 28 Sep 2021

Cited by 16 | Viewed by 4023

Abstract

Even with all recent advances in cancer therapy, pancreatic cancer still has a dismal 5-year survival rate of less than 7%. The most prevalent tumor subtype is pancreatic ductal adenocarcinoma (PDAC). PDACs display an extensive crosstalk with their tumor microenvironment (TME), e.g., pancreatic [...] Read more.

Even with all recent advances in cancer therapy, pancreatic cancer still has a dismal 5-year survival rate of less than 7%. The most prevalent tumor subtype is pancreatic ductal adenocarcinoma (PDAC). PDACs display an extensive crosstalk with their tumor microenvironment (TME), e.g., pancreatic stellate cells, but also immune cells to regulate tumor growth, immune evasion, and metastasis. In addition to crosstalk in the local TME, PDACs were shown to induce the formation of pre-metastatic niches in different organs. Recent advances have attributed many of these interactions to intercellular communication by small extracellular vesicles (sEVs, exosomes). These nanovesicles are derived of endo-lysosomal structures (multivesicular bodies) with a size range of 30–150 nm. sEVs carry various bioactive cargos, such as proteins, lipids, DNA, mRNA, or miRNAs and act in an autocrine or paracrine fashion to educate recipient cells. In addition to tumor formation, progression, and metastasis, sEVs were described as potent biomarker platforms for diagnosis and prognosis of PDAC. Advances in sEV engineering have further indicated that sEVs might once be used as effective drug carriers. Thus, extensive sEV-based communication and applications as platform for biomarker analysis or vehicles for treatment suggest a major impact of sEVs in future PDAC research. Full article

(This article belongs to the Special Issue Tumor Microenvironment of Pancreatic Cancer)

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32 pages, 2038 KiB

Open AccessFeature PaperReview

The Extracellular Matrix in Pancreatic Cancer: Description of a Complex Network and Promising Therapeutic Options

by Benedetta Ferrara, Cataldo Pignatelli, Mélissande Cossutta, Antonio Citro, José Courty and Lorenzo Piemonti

Cancers 2021, 13(17), 4442; https://doi.org/10.3390/cancers13174442 - 3 Sep 2021

Cited by 49 | Viewed by 8678

Abstract

The stroma is a relevant player in driving and supporting the progression of pancreatic ductal adenocarcinoma (PDAC), and a large body of evidence highlights its role in hindering the efficacy of current therapies. In fact, the dense extracellular matrix (ECM) characterizing this tumor [...] Read more.

The stroma is a relevant player in driving and supporting the progression of pancreatic ductal adenocarcinoma (PDAC), and a large body of evidence highlights its role in hindering the efficacy of current therapies. In fact, the dense extracellular matrix (ECM) characterizing this tumor acts as a natural physical barrier, impairing drug penetration. Consequently, all of the approaches combining stroma-targeting and anticancer therapy constitute an appealing option for improving drug penetration. Several strategies have been adopted in order to target the PDAC stroma, such as the depletion of ECM components and the targeting of cancer-associated fibroblasts (CAFs), which are responsible for the increased matrix deposition in cancer. Additionally, the leaky and collapsing blood vessels characterizing the tumor might be normalized, thus restoring blood perfusion and allowing drug penetration. Even though many stroma-targeting strategies have reported disappointing results in clinical trials, the ECM offers a wide range of potential therapeutic targets that are now being investigated. The dense ECM might be bypassed by implementing nanoparticle-based systems or by using mesenchymal stem cells as drug carriers. The present review aims to provide an overview of the principal mechanisms involved in the ECM remodeling and of new promising therapeutic strategies for PDAC. Full article

(This article belongs to the Special Issue Tumor Microenvironment of Pancreatic Cancer)

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16 pages, 1223 KiB

Open AccessReview

KRAS Mutation Dictates the Cancer Immune Environment in Pancreatic Ductal Adenocarcinoma and Other Adenocarcinomas

by Meichen Gu, Yanli Gao and Pengyu Chang

Cancers 2021, 13(10), 2429; https://doi.org/10.3390/cancers13102429 - 18 May 2021

Cited by 17 | Viewed by 4448

Abstract

Generally, patients with pancreatic ductal adenocarcinoma, especially those with wide metastatic lesions, have a poor prognosis. Recently, a breakthrough in improving their survival has been achieved by using first-line chemotherapy, such as gemcitabine plus nab-paclitaxel or oxaliplatin plus irinotecan plus 5-fluorouracil plus calcium [...] Read more.

Generally, patients with pancreatic ductal adenocarcinoma, especially those with wide metastatic lesions, have a poor prognosis. Recently, a breakthrough in improving their survival has been achieved by using first-line chemotherapy, such as gemcitabine plus nab-paclitaxel or oxaliplatin plus irinotecan plus 5-fluorouracil plus calcium folinate. Unfortunately, regimens with high effectiveness are still absent in second- or later-line settings. In addition, although immunotherapy using checkpoint inhibitors definitively represents a novel method for metastatic cancers, monotherapy using checkpoint inhibitors is almost completely ineffective for pancreatic ductal adenocarcinomas largely due to the suppressive immune milieu in such tumors. Critically, the genomic alteration pattern is believed to impact cancer immune environment. Surprisingly, KRAS gene mutation is found in almost all pancreatic ductal adenocarcinomas. Moreover, KRAS mutation is indispensable for pancreatic carcinogenesis. On these bases, a relationship likely exists between this oncogene and immunosuppression in this cancer. During pancreatic carcinogenesis, KRAS mutation-driven events, such as metabolic reprogramming, cell autophagy, and persistent activation of the yes-associated protein pathway, converge to cause immune evasion. However, intriguingly, KRAS mutation can dictate a different immune environment in other types of adenocarcinoma, such as colorectal adenocarcinoma and lung adenocarcinoma. Overall, the KRAS mutation can drive an immunosuppression in pancreatic ductal adenocarcinomas or in colorectal carcinomas, but this mechanism is not true in KRAS-mutant lung adenocarcinomas, especially in the presence of TP53 inactivation. As a result, the response of these adenocarcinomas to checkpoint inhibitors will vary. Full article

(This article belongs to the Special Issue Tumor Microenvironment of Pancreatic Cancer)

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15 pages, 594 KiB

Open AccessReview

Understanding and Targeting Natural Killer Cell-Cancer-Associated Fibroblast Interactions in Pancreatic Ductal Adenocarcinoma

by Zoe X. Malchiodi and Louis M. Weiner

Cancers 2021, 13(3), 405; https://doi.org/10.3390/cancers13030405 - 22 Jan 2021

Cited by 17 | Viewed by 4738

Abstract

Interactions between natural killer (NK) cells and cancer-associated fibroblasts (CAFs) comprise a relevant but relatively understudied crosstalk relationship within the tumor microenvironment (TME). This review discusses the relevance of both natural killer cell and cancer-associated fibroblast function and activity in cancers, with an [...] Read more.

Interactions between natural killer (NK) cells and cancer-associated fibroblasts (CAFs) comprise a relevant but relatively understudied crosstalk relationship within the tumor microenvironment (TME). This review discusses the relevance of both natural killer cell and cancer-associated fibroblast function and activity in cancers, with an emphasis on pancreatic ductal adenocarcinoma (PDAC), incorporating additional insights from other malignancies to inform future directions for research. We describe what is currently known about NK cell-CAF crosstalk and their molecular interactions, how it is possible to exploit NK cell cytotoxicity in tumors and how to target CAFs to enhance efficacy of cancer therapies and cytotoxic immune cells. Although not previously tested in combination, there is an abundance of evidence demonstrating that targeting tumor-promoting CAFs and exploiting NK cells, separately, are beneficial as therapeutic strategies. This raises the possibility that a novel combination regimen addressing these two cell targets may be even more beneficial to eradicate PDAC and other solid tumors. Full article

(This article belongs to the Special Issue Tumor Microenvironment of Pancreatic Cancer)

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