International Journal of Molecular Sciences

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18 pages, 5637 KiB

Open AccessArticle

Inhibition of β-Catenin Activity Abolishes LKB1 Loss-Driven Pancreatic Cystadenoma in Mice

by Mei-Jen Hsieh, Ching-Chieh Weng, Yu-Chun Lin, Chia-Chen Wu, Li-Tzong Chen and Kuang-Hung Cheng

Int. J. Mol. Sci. 2021, 22(9), 4649; https://doi.org/10.3390/ijms22094649 - 28 Apr 2021

Cited by 2 | Viewed by 2288

Abstract

Pancreatic cancer (PC) is the seventh leading cause of cancer death worldwide, and remains one of our most recalcitrant and dismal diseases. In contrast to many other malignancies, there has not been a significant improvement in patient survival over the past decade. Despite [...] Read more.

Pancreatic cancer (PC) is the seventh leading cause of cancer death worldwide, and remains one of our most recalcitrant and dismal diseases. In contrast to many other malignancies, there has not been a significant improvement in patient survival over the past decade. Despite advances in our understanding of the genetic alterations associated with this disease, an incomplete understanding of the underlying biology and lack of suitable animal models have hampered efforts to develop more effective therapies. LKB1 is a tumor suppressor that functions as a primary upstream kinase of adenine monophosphate-activated protein kinase (AMPK), which is an important mediator in the regulation of cell growth and epithelial polarity pathways. LKB1 is mutated in a significant number of Peutz–Jeghers syndrome (PJS) patients and in a small proportion of sporadic cancers, including PC; however, little is known about how LKB1 loss contributes to PC development. Here, we report that a reduction in Wnt/β-catenin activity is associated with LKB1 tumor-suppressive properties in PC. Remarkably, in vivo functional analyses of β-catenin in the Pdx-1-Cre LKB1^L/L β-catenin^L/L mouse model compared to LKB1 loss-driven cystadenoma demonstrate that the loss of β-catenin impairs cystadenoma development in the pancreas of Pdx-1Cre LKB1^L/L mice and dramatically restores the normal development and functions of the pancreas. This study further determined the in vivo and in vitro therapeutic efficacy of the β-catenin inhibitor FH535 in suppressing LKB1 loss-driven cystadenoma and reducing PC progression that delineates the potential roles of Wnt/β-catenin signaling in PC harboring LKB1 deficiency. Full article

(This article belongs to the Special Issue Pancreatic Ductal Adenocarcinoma: Precursors and Variants)

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9 pages, 2714 KiB

Open AccessArticle

CD117 Is a Specific Marker of Intraductal Papillary Mucinous Neoplasms (IPMN) of the Pancreas, Oncocytic Subtype

by Paola Mattiolo, Seung-Mo Hong, Gaetano Paolino, Borislav C. Rusev, Giovanni Marchegiani, Roberto Salvia, Stefano Andrianello, Paola Capelli, Paola Piccoli, Claudia Parolini, Aldo Scarpa, Rita T. Lawlor and Claudio Luchini

Int. J. Mol. Sci. 2020, 21(16), 5794; https://doi.org/10.3390/ijms21165794 - 12 Aug 2020

Cited by 16 | Viewed by 2966

Abstract

The intraductal oncocytic papillary neoplasm (IOPN) of the pancreas has been recognized by WHO classification as a unique intraductal papillary mucinous neoplasm (IPMN) category. IOPN is composed of oxyphil cells, usually expressing MUC5AC, MUC6, and Hep Par-1, and harboring PRKACA/B fusion [...] Read more.

The intraductal oncocytic papillary neoplasm (IOPN) of the pancreas has been recognized by WHO classification as a unique intraductal papillary mucinous neoplasm (IPMN) category. IOPN is composed of oxyphil cells, usually expressing MUC5AC, MUC6, and Hep Par-1, and harboring PRKACA/B fusion genes as their genetic hallmark. Although IOPNs are associated with an infiltrative adenocarcinoma in up to 30% of cases, the survival rate after surgical resection approaches 100%. This highlights the importance of the correct IOPN diagnosis, above all in cases with an associated invasive component. In this study, the immunohistochemical expression of CD117 was investigated in 111 IPMNs, including 17 oncocytic, 45 gastric, 20 pancreatico-biliary, and 29 intestinal IPMNs. We also tested the expression of MUC5AC, MUC6, and Hep Par-1 in the IOPN cohort. CD117 positivity was significantly more frequent in IOPNs compared to the other IPMN subtypes (p < 0.0001). Furthermore, within IOPN, a lower or absent CD117, MUC5AC, MUC6, and Hep Par-1 expression tended to be associated with the presence of an infiltrative component. Our findings shed light into the biology of these complex lesions, which are confirmed to be a distinctive IPMN subtype; notably, CD117 emerged as a potential, additional tool in the differential diagnosis of IPMNs. Full article

(This article belongs to the Special Issue Pancreatic Ductal Adenocarcinoma: Precursors and Variants)

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Review

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9 pages, 1425 KiB

Open AccessReview

Undifferentiated Sarcomatoid Carcinoma of the Pancreas: From Histology and Molecular Pathology to Precision Oncology

by Anastasios Gkountakos, Michele Simbolo, Elena Bariani, Aldo Scarpa and Claudio Luchini

Int. J. Mol. Sci. 2022, 23(3), 1283; https://doi.org/10.3390/ijms23031283 - 24 Jan 2022

Cited by 4 | Viewed by 3370

Abstract

Undifferentiated sarcomatoid carcinoma of the pancreas (SCP) is a rare and aggressive subtype of pancreatic cancer. Histologically, SCP is a poorly differentiated tumor characterized by the lack of glandular differentiation and the presence of mesenchymal-like, spindle-shaped tumor cells. Due to its rarity, only [...] Read more.

Undifferentiated sarcomatoid carcinoma of the pancreas (SCP) is a rare and aggressive subtype of pancreatic cancer. Histologically, SCP is a poorly differentiated tumor characterized by the lack of glandular differentiation and the presence of mesenchymal-like, spindle-shaped tumor cells. Due to its rarity, only sporadic cases have been reported, while its molecular characterization has not been sufficiently described. Surgical resection with curative intent is the gold-standard of SCP management, but this strategy is possible only in a small proportion of cases due to SCP early metastasization. Although SCP is generally associated with a poor prognosis, some clinical cases amenable to surgical resection and followed by adjuvant chemotherapy have demonstrated a remarkably long survival. Preliminary molecular insights on the SCP molecular landscape have demonstrated the recurrent presence of KRAS and TP53 mutations, highlighting genetic similarities with conventional pancreatic ductal adenocarcinoma (PDAC). Although the use of immunotherapy in PDAC remains an unmet challenge, recent insights indicated a potentially significant role of the PD-L1/Notch3 axis in SCP, opening new horizons for immunotherapy in this cancer subtype. In this review, we described the most important clinic-pathologic features of SCP, with a specific focus on their molecular landscape and the potential targets for precision oncology. Full article

(This article belongs to the Special Issue Pancreatic Ductal Adenocarcinoma: Precursors and Variants)

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19 pages, 2249 KiB

Open AccessReview

Intraductal Papillary Mucinous Carcinoma Versus Conventional Pancreatic Ductal Adenocarcinoma: A Comprehensive Review of Clinical-Pathological Features, Outcomes, and Molecular Insights

by Léo Mas, Renato M. Lupinacci, Jérôme Cros, Jean-Baptiste Bachet, Florence Coulet and Magali Svrcek

Int. J. Mol. Sci. 2021, 22(13), 6756; https://doi.org/10.3390/ijms22136756 - 23 Jun 2021

Cited by 20 | Viewed by 4335

Abstract

Intraductal papillary mucinous neoplasms (IPMN) are common and one of the main precursor lesions of pancreatic ductal adenocarcinoma (PDAC). PDAC derived from an IPMN is called intraductal papillary mucinous carcinoma (IPMC) and defines a subgroup of patients with ill-defined specificities. As compared to [...] Read more.

Intraductal papillary mucinous neoplasms (IPMN) are common and one of the main precursor lesions of pancreatic ductal adenocarcinoma (PDAC). PDAC derived from an IPMN is called intraductal papillary mucinous carcinoma (IPMC) and defines a subgroup of patients with ill-defined specificities. As compared to conventional PDAC, IPMCs have been associated to clinical particularities and favorable pathological features, as well as debated outcomes. However, IPMNs and IPMCs include distinct subtypes of precursor (gastric, pancreato-biliary, intestinal) and invasive (tubular, colloid) lesions, also associated to specific characteristics. Notably, consistent data have shown intestinal IPMNs and associated colloid carcinomas, defining the “intestinal pathway”, to be associated with less aggressive features. Genomic specificities have also been uncovered, such as mutations of the GNAS gene, and recent data provide more insights into the mechanisms involved in IPMCs carcinogenesis. This review synthetizes available data on clinical-pathological features and outcomes associated with IPMCs and their subtypes. We also describe known genomic hallmarks of these lesions and summarize the latest data about molecular processes involved in IPMNs initiation and progression to IPMCs. Finally, potential implications for clinical practice and future research strategies are discussed. Full article

(This article belongs to the Special Issue Pancreatic Ductal Adenocarcinoma: Precursors and Variants)

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19 pages, 906 KiB

Open AccessReview

Pancreatic Ductal Adenocarcinoma: The Dawn of the Era of Nuclear Medicine?

by Christopher Montemagno, Shamir Cassim, Nicolas De Leiris, Jérôme Durivault, Marc Faraggi and Gilles Pagès

Int. J. Mol. Sci. 2021, 22(12), 6413; https://doi.org/10.3390/ijms22126413 - 15 Jun 2021

Cited by 13 | Viewed by 3374

Abstract

Pancreatic ductal adenocarcinoma (PDAC), accounting for 90–95% of all pancreatic tumors, is a highly devastating disease associated with poor prognosis. The lack of accurate diagnostic tests and failure of conventional therapies contribute to this pejorative issue. Over the last decade, the advent of [...] Read more.

Pancreatic ductal adenocarcinoma (PDAC), accounting for 90–95% of all pancreatic tumors, is a highly devastating disease associated with poor prognosis. The lack of accurate diagnostic tests and failure of conventional therapies contribute to this pejorative issue. Over the last decade, the advent of theranostics in nuclear medicine has opened great opportunities for the diagnosis and treatment of several solid tumors. Several radiotracers dedicated to PDAC imaging or internal vectorized radiotherapy have been developed and some of them are currently under clinical consideration. The functional information provided by Positron Emission Tomography (PET) or Single Photon Emission Computed Tomography (SPECT) could indeed provide an additive diagnostic value and thus help in the selection of patients for targeted therapies. Moreover, the therapeutic potential of β^-- and α-emitter-radiolabeled agents could also overcome the resistance to conventional therapies. This review summarizes the current knowledge concerning the recent developments in the nuclear medicine field for the management of PDAC patients. Full article

(This article belongs to the Special Issue Pancreatic Ductal Adenocarcinoma: Precursors and Variants)

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25 pages, 1214 KiB

Open AccessReview

Morphologic and Molecular Landscape of Pancreatic Cancer Variants as the Basis of New Therapeutic Strategies for Precision Oncology

by Chiara Bazzichetto, Claudio Luchini, Fabiana Conciatori, Vanja Vaccaro, Ilaria Di Cello, Paola Mattiolo, Italia Falcone, Gianluigi Ferretti, Aldo Scarpa, Francesco Cognetti and Michele Milella

Int. J. Mol. Sci. 2020, 21(22), 8841; https://doi.org/10.3390/ijms21228841 - 22 Nov 2020

Cited by 30 | Viewed by 5504

Abstract

To date, pancreatic cancer is still one of the most lethal cancers in the world, mainly due to the lack of early diagnosis and personalized treatment strategies. In this context, the possibility and the opportunity of identifying genetic and molecular biomarkers are crucial [...] Read more.

To date, pancreatic cancer is still one of the most lethal cancers in the world, mainly due to the lack of early diagnosis and personalized treatment strategies. In this context, the possibility and the opportunity of identifying genetic and molecular biomarkers are crucial to improve the feasibility of precision medicine. In 2019, the World Health Organization classified pancreatic ductal adenocarcinoma cancer (the most common pancreatic tumor type) into eight variants, according to specific histomorphological features. They are: colloid carcinoma, medullary carcinoma, adenosquamous carcinoma, undifferentiated carcinoma, including also rhabdoid carcinoma, undifferentiated carcinoma with osteoclast-like giant cells, hepatoid carcinoma, and signet-ring/poorly cohesive cells carcinoma. Interestingly, despite the very low incidence of these variants, innovative high throughput genomic/transcriptomic techniques allowed the investigation of both somatic and germline mutations in each specific variant, paving the way for their possible classification according also to specific alterations, along with the canonical mutations of pancreatic cancer (KRAS, TP53, CDKN2A, SMAD4). In this review, we aim to report the current evidence about genetic/molecular profiles of pancreatic cancer variants, highlighting their role in therapeutic and clinical impact. Full article

(This article belongs to the Special Issue Pancreatic Ductal Adenocarcinoma: Precursors and Variants)

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16 pages, 327 KiB

Open AccessReview

Intraductal Pancreatic Mucinous Neoplasms: A Tumor-Biology Based Approach for Risk Stratification

by Vincenzo Nasca, Marta Chiaravalli, Geny Piro, Annachiara Esposito, Lisa Salvatore, Giampaolo Tortora, Vincenzo Corbo and Carmine Carbone

Int. J. Mol. Sci. 2020, 21(17), 6386; https://doi.org/10.3390/ijms21176386 - 2 Sep 2020

Cited by 12 | Viewed by 3230

Abstract

Pancreatic ductal adenocarcinoma is one of the most lethal human cancers. Its precursor lesions include pancreatic intra-epithelial neoplasia, mucinous cystic neoplasm, and intraductal papillary mucinous neoplasm (IPMN). IPMNs usually present as an incidental finding at imaging in 2.6% of the population and, according [...] Read more.

Pancreatic ductal adenocarcinoma is one of the most lethal human cancers. Its precursor lesions include pancreatic intra-epithelial neoplasia, mucinous cystic neoplasm, and intraductal papillary mucinous neoplasm (IPMN). IPMNs usually present as an incidental finding at imaging in 2.6% of the population and, according to the degree of dysplasia, they are classified as low- or high-grade lesions. Since the risk of malignant transformation is not accurately predictable, the management of these lesions is based on morphological and clinical parameters, such as presence of mural nodule, main pancreatic duct dilation, presence of symptoms, or high-grade dysplasia. Although the main genetic alterations associated to IPMNs have been elucidated, they are still not helpful for disease risk stratification. The growing body of genomic and epigenomic studies along with the more recent development of organotypic cultures provide the opportunity to improve our understanding of the malignant transformation process, which will likely deliver biomarkers to help discriminate between low- and high-risk lesions. Recent insights on the topic are herein summarized. Full article

(This article belongs to the Special Issue Pancreatic Ductal Adenocarcinoma: Precursors and Variants)

18 pages, 1263 KiB

Open AccessReview

From Malignant Progression to Therapeutic Targeting: Current Insights of Mesothelin in Pancreatic Ductal Adenocarcinoma

by Christopher Montemagno, Shamir Cassim, Jacques Pouyssegur, Alexis Broisat and Gilles Pagès

Int. J. Mol. Sci. 2020, 21(11), 4067; https://doi.org/10.3390/ijms21114067 - 6 Jun 2020

Cited by 18 | Viewed by 4539

Abstract

Pancreatic ductal adenocarcinoma (PDAC), accounting for 90% of all pancreatic tumors, is a highly devastating disease with poor prognosis and rising incidence. The lack of available specific diagnostics tests and the limited treatment opportunities contribute to this pejorative issue. Over the last 10 [...] Read more.

Pancreatic ductal adenocarcinoma (PDAC), accounting for 90% of all pancreatic tumors, is a highly devastating disease with poor prognosis and rising incidence. The lack of available specific diagnostics tests and the limited treatment opportunities contribute to this pejorative issue. Over the last 10 years, a growing interest pointing towards mesothelin (MSLN) as a promising PDAC-associated antigen has emerged. The limited expression of MSLN in normal tissues (peritoneum, pleura and pericardium) and its overexpression in 80 to 90% of PDAC make it an attractive candidate for therapeutic management of PDAC patients. Moreover, its role in malignant progression related to its involvement in tumor cell proliferation and resistance to chemotherapy has highlighted the relevance of its targeting. Hence, several clinical trials are investigating anti-MSLN efficacy in PDAC. In this review, we provide a general overview of the different roles sustained by MSLN during PDAC progression. Finally, we also summarize the different MSLN-targeted therapies that are currently tested in the clinic. Full article

(This article belongs to the Special Issue Pancreatic Ductal Adenocarcinoma: Precursors and Variants)

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24 pages, 1562 KiB

Open AccessReview

Pancreatic Cancer Molecular Classifications: From Bulk Genomics to Single Cell Analysis

by Luca Pompella, Giuseppe Tirino, Annalisa Pappalardo, Marianna Caterino, Anna Ventriglia, Valeria Nacca, Michele Orditura, Fortunato Ciardiello and Ferdinando De Vita

Int. J. Mol. Sci. 2020, 21(8), 2814; https://doi.org/10.3390/ijms21082814 - 17 Apr 2020

Cited by 20 | Viewed by 6094

Abstract

Pancreatic cancer represents one of the most lethal disease worldwide but still orphan of a molecularly driven therapeutic approach, although many genomic and transcriptomic classifications have been proposed over the years. Clinical heterogeneity is a hallmark of this disease, as different patients show [...] Read more.

Pancreatic cancer represents one of the most lethal disease worldwide but still orphan of a molecularly driven therapeutic approach, although many genomic and transcriptomic classifications have been proposed over the years. Clinical heterogeneity is a hallmark of this disease, as different patients show different responses to the same therapeutic regimens. However, genomic analyses revealed quite a homogeneous disease picture, with very common mutations in four genes only (KRAS, TP53, CDKN2A, and SMAD4) and a long tail of other mutated genes, with doubtful pathogenic meaning. Even bulk transcriptomic classifications could not resolve this great heterogeneity, as many informations related to small cell populations within cancer tissue could be lost. At the same time, single cell analysis has emerged as a powerful tool to dissect intratumoral heterogeneity like never before, with possibility of generating a new disease taxonomy at unprecedented molecular resolution. In this review, we summarize the most relevant genomic, bulk and single-cell transcriptomic classifications of pancreatic cancer, and try to understand how novel technologies, like single cell analysis, could lead to novel therapeutic strategies for this highly lethal disease. Full article

(This article belongs to the Special Issue Pancreatic Ductal Adenocarcinoma: Precursors and Variants)

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