Tumor Microenvironment in Pancreatic Intraepithelial Neoplasia

Opitz, Friederike V.; Haeberle, Lena; Daum, Alexandra; Espósito, Irene

doi:10.3390/cancers13246188

Cited by 19 publications

(14 citation statements)

References 268 publications

(292 reference statements)

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“…PDAC is one of the most common malignant tumors in the world, with a 5-year survival rate of about 10%. By 2030, PDAC is projected to become the second leading cause of cancer-related deaths in the United States of America [ 75 ]. Moreover, PDAC possesses different molecular characteristics, biological behaviors, and therapeutic responses at different ages.…”

Section: The Role Of Senescence In Types Of Pancreatic Diseasesmentioning

confidence: 99%

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Changes in Pancreatic Senescence Mediate Pancreatic Diseases

Bian

Xiao

et al. 2023

IJMS

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In recent years, there has been a significant increase in age-related diseases due to the improvement in life expectancy worldwide. The pancreas undergoes various morphological and pathological changes with aging, such as pancreatic atrophy, fatty degeneration, fibrosis, inflammatory cell infiltration, and exocrine pancreatic metaplasia. Meanwhile, these may predispose the individuals to aging-related diseases, such as diabetes, dyspepsia, pancreatic ductal adenocarcinoma, and pancreatitis, as the endocrine and exocrine functions of the pancreas are significantly affected by aging. Pancreatic senescence is associated with various underlying factors including genetic damage, DNA methylation, endoplasmic reticulum (ER) stress, mitochondrial dysfunction, and inflammation. This paper reviews the alternations of morphologies and functions in the aging pancreas, especially β-cells, closely related to insulin secretion. Finally, we summarize the mechanisms of pancreatic senescence to provide potential targets for treating pancreatic aging-related diseases.

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Section: The Role Of Senescence In Types Of Pancreatic Diseasesmentioning

confidence: 99%

“…As we know, PDAC can arise from different precursor lesions, such as PanIN, intraductal papillary mucinous neoplasms (IPMNs), mucinous cystic neoplasms (MCN), and possibly, atypical flat lesions (AFL) [ 75 ]. The most frequent and characteristic precursor lesion among these is PanIN [ 80 ].…”

Section: The Role Of Senescence In Types Of Pancreatic Diseasesmentioning

confidence: 99%

Changes in Pancreatic Senescence Mediate Pancreatic Diseases

Bian

Xiao

et al. 2023

IJMS

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“…3 These include hotspot mutations in the oncogene KRAS, which are thought to initiate pancreatic ductal neoplasia and occur in more than 90% of invasive pancreatic cancers, as well as inactivating mutations in tumor suppressor genes, including CDKN2A and TP53, which occur at lower prevalence. 3,6,[11][12][13][14] Previous studies have reported heterogeneity in driver gene mutations in intraductal papillary mucinous neoplasms, large non-invasive cystic precursors to PDAC, using multi-region next generation sequencing, demonstrating the complex clonal evolution in these lesions. [15][16][17] When examined, such heterogeneity in driver gene mutations has not been identified in primary PDACs or metastases, but the presence of driver gene heterogeneity in PanINs has not been assessed.…”

Section: Introductionmentioning

confidence: 99%

Three-dimensional genomic mapping of human pancreatic tissue reveals striking multifocality and genetic heterogeneity in precancerous lesions

Braxton

Kiemen

Grahn

et al. 2023

Preprint

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Pancreatic intraepithelial neoplasia (PanIN) is a precursor to pancreatic cancer and represents a critical opportunity for cancer interception. However, the number, size, shape, and connectivity of PanINs in human pancreatic tissue samples are largely unknown. In this study, we quantitatively assessed human PanINs using CODA, a novel machine-learning pipeline for 3D image analysis that generates quantifiable models of large pieces of human pancreas with single-cell resolution. Using a cohort of 38 large slabs of grossly normal human pancreas from surgical resection specimens, we identified striking multifocality of PanINs, with a mean burden of 13 spatially separate PanINs per cm3 of sampled tissue. Extrapolating this burden to the entire pancreas suggested a median of approximately 1000 PanINs in an entire pancreas. In order to better understand the clonal relationships within and between PanINs, we developed a pipeline for CODA-guided multi-region genomic analysis of PanINs, including targeted and whole exome sequencing. Multi-region assessment of 37 PanINs from eight additional human pancreatic tissue slabs revealed that almost all PanINs contained hotspot mutations in the oncogene KRAS, but no gene other than KRAS was altered in more than 20% of the analyzed PanINs. PanINs contained a mean of 13 somatic mutations per region when analyzed by whole exome sequencing. The majority of analyzed PanINs originated from independent clonal events, with distinct somatic mutation profiles between PanINs in the same tissue slab. A subset of the analyzed PanINs contained multiple KRAS mutations, suggesting a polyclonal origin even in PanINs that are contiguous by rigorous 3D assessment. This study leverages a novel 3D genomic mapping approach to describe, for the first time, the spatial and genetic multifocality of human PanINs, providing important insights into the initiation and progression of pancreatic neoplasia.

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“…Besides the ECM components, tumor-infiltrating cells are key determinants of malignant advancement. Different cell types including regulatory T cells (Treg), cancer-associated fibroblasts (CAFs), tumor-associated macrophages (TAMs), mesenchymal stem cells, and endothelial cells can all contribute to tumor growth and escape from the host immune surveillance [ 20 , 21 , 22 ]. Therefore, to closely mimic in vitro the complex cancer dynamic environment, it is crucial to consider the tumor–stroma–immune cell interplays.…”

Section: Introductionmentioning

confidence: 99%

Tumor Microenvironment and Hydrogel-Based 3D Cancer Models for In Vitro Testing Immunotherapies

Vitale

Marzagalli²,

Scaglione

et al. 2022

Cancers

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In recent years, immunotherapy has emerged as a promising novel therapeutic strategy for cancer treatment. In a relevant percentage of patients, however, clinical benefits are lower than expected, pushing researchers to deeply analyze the immune responses against tumors and find more reliable and efficient tools to predict the individual response to therapy. Novel tissue engineering strategies can be adopted to realize in vitro fully humanized matrix-based models, as a compromise between standard two-dimensional (2D) cell cultures and animal tests, which are costly and hardly usable in personalized medicine. In this review, we describe the main mechanisms allowing cancer cells to escape the immune surveillance, which may play a significant role in the failure of immunotherapies. In particular, we discuss the role of the tumor microenvironment (TME) in the establishment of a milieu that greatly favors cancer malignant progression and impact on the interactions with immune cells. Then, we present an overview of the recent in vitro engineered preclinical three-dimensional (3D) models that have been adopted to resemble the interplays between cancer and immune cells and for testing current therapies and immunotherapeutic approaches. Specifically, we focus on 3D hydrogel-based tools based on different types of polymers, discussing the suitability of each of them in reproducing the TME key features based on their intrinsic or tunable characteristics. Finally, we introduce the possibility to combine the 3D models with technological fluid dynamics platforms, reproducing the dynamic complex interactions between tumor cells and immune effectors migrated in situ via the systemic circulation, pointing out the challenges that still have to be overcome for setting more predictive preclinical assays.

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Tumor Microenvironment in Pancreatic Intraepithelial Neoplasia

Cited by 19 publications

References 268 publications

Changes in Pancreatic Senescence Mediate Pancreatic Diseases

Changes in Pancreatic Senescence Mediate Pancreatic Diseases

Three-dimensional genomic mapping of human pancreatic tissue reveals striking multifocality and genetic heterogeneity in precancerous lesions

Tumor Microenvironment and Hydrogel-Based 3D Cancer Models for In Vitro Testing Immunotherapies

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