scholarly journals Unraveling Tumor Heterogeneity by Using DNA Barcoding Technologies to Develop Personalized Treatment Strategies in Advanced-Stage PDAC

Cancers ◽  
2021 ◽  
Vol 13 (16) ◽  
pp. 4187
Author(s):  
Philip Dujardin ◽  
Anna K. Baginska ◽  
Sebastian Urban ◽  
Barbara M. Grüner
Keyword(s):  
Dna Barcoding ◽  
Tumor Heterogeneity ◽  
Clonal Evolution ◽  
Treatment Strategies ◽  
Therapy Resistance ◽  
Personalized Treatment ◽  
Ductal Adenocarcinoma ◽  
Cell Pool ◽  
Study Heterogeneity ◽  
A Cell

Tumor heterogeneity is a hallmark of many solid tumors, including pancreatic ductal adenocarcinoma (PDAC), and an inherent consequence of the clonal evolution of cancers. As such, it is considered the underlying concept of many characteristics of the disease, including the ability to metastasize, adapt to different microenvironments, and to develop therapy resistance. Undoubtedly, the high mortality of PDAC can be attributed to a high extent to these properties. Despite its apparent importance, studying tumor heterogeneity has been a challenging task, mainly due to its complexity and lack of appropriate methods. However, in recent years molecular DNA barcoding has emerged as a sophisticated tool that allows mapping of individual cells or subpopulations in a cell pool to study heterogeneity and thus devise new personalized treatment strategies. In this review, we provide an overview of genetic and non-genetic inter- and intra-tumor heterogeneity and its impact on (personalized) treatment strategies in PDAC and address how DNA barcoding technologies work and can be applied to study this clinically highly relevant question.

scholarly journals The Role of Exosomes in Pancreatic Cancer From Bench to Clinical Application: An Updated Review

2021 ◽  
Vol 11 ◽  
Author(s):  
Kai Chen ◽  
Qi Wang ◽  
Marko Kornmann ◽  
Xiaodong Tian ◽  
Yinmo Yang
Keyword(s):  
Pancreatic Cancer ◽  
Tumor Heterogeneity ◽  
Cell Communication ◽  
Treatment Strategies ◽  
Drug Carriers ◽  
Clinical Applications ◽  
Ductal Adenocarcinoma ◽  
Gastrointestinal Malignancies ◽  
Growing Body

Pancreatic ductal adenocarcinoma (PDAC) remains one of the most dismal gastrointestinal malignancies with an overall 5-year survival rate of 8%–9%. The intra-tumor heterogeneity and special tumor microenvironment in PDAC make it challenging to develop effective treatment strategies. Exosomes are extracellular vesicles that originate from the endosomes and have a diameter of 40–160 nm. A growing body of evidence has shown that exosomes play vital roles in tumor initiation and development. Recently, extensive application of exosomes as biomarkers and drug carriers has rendered them attractive in the field of PDAC. This review summarizes the latest progress in the methodologies for isolation, modification, and tracking of exosomes, exosome-mediated cell-to-cell communication, clinical applications of exosome as minimally invasive liquid biopsy and drugs carriers, as well as their involvement in the angiogenic regulation in PDAC. In spite of these advancements, some obstacles are still required to be overcome to use the exosome-based technologies for early diagnosis or improvement of prognosis of patients with PDAC.

scholarly journals An enhanced genetic model of relapsed IGH-translocated multiple myeloma evolutionary dynamics

2020 ◽  
Vol 10 (10) ◽  
Author(s):  
Phuc H. Hoang ◽  
Alex J. Cornish ◽  
Amy L. Sherborne ◽  
Daniel Chubb ◽  
Scott Kimber ◽  
...  
Keyword(s):  
Multiple Myeloma ◽  
Evolutionary Dynamics ◽  
Genetic Model ◽  
Clonal Selection ◽  
Clonal Evolution ◽  
Point Mutations ◽  
Treatment Strategies ◽  
Therapy Resistance ◽  
Time To Relapse ◽  
Mutational Processes

Abstract Most patients with multiple myeloma (MM) die from progressive disease after relapse. To advance our understanding of MM evolution mechanisms, we performed whole-genome sequencing of 80 IGH-translocated tumour-normal newly diagnosed pairs and 24 matched relapsed tumours from the Myeloma XI trial. We identify multiple events as potentially important for survival and therapy-resistance at relapse including driver point mutations (e.g., TET2), translocations (MAP3K14), lengthened telomeres, and increased genomic instability (e.g., 17p deletions). Despite heterogeneous mutational processes contributing to relapsed mutations across MM subtypes, increased AID/APOBEC activity is particularly associated with shorter progression time to relapse, and contributes to higher mutational burden at relapse. In addition, we identify three enhanced major clonal evolution patterns of MM relapse, independent of treatment strategies and molecular karyotypes, questioning the viability of “evolutionary herding” approach in treating drug-resistant MM. Our data show that MM relapse is associated with acquisition of new mutations and clonal selection, and suggest APOBEC enzymes among potential targets for therapy-resistant MM.

scholarly journals Stem Cells in the Exocrine Pancreas during Homeostasis, Injury, and Cancer

Cancers ◽  
2021 ◽  
Vol 13 (13) ◽  
pp. 3295
Author(s):  
Sophie C. Lodestijn ◽  
Sanne M. van Neerven ◽  
Louis Vermeulen ◽  
Maarten F. Bijlsma
Keyword(s):  
Stem Cells ◽  
Stem Cell ◽  
Cellular Proliferation ◽  
Treatment Strategies ◽  
Cell Types ◽  
Therapy Resistance ◽  
Current Treatment ◽  
Ductal Adenocarcinoma ◽  
Metastasis Formation ◽  
Cell Dynamics

Cell generation and renewal are essential processes to develop, maintain, and regenerate tissues. New cells can be generated from immature cell types, such as stem-like cells, or originate from more differentiated pre-existing cells that self-renew or transdifferentiate. The adult pancreas is a dormant organ with limited regeneration capacity, which complicates studying these processes. As a result, there is still discussion about the existence of stem cells in the adult pancreas. Interestingly, in contrast to the classical stem cell concept, stem cell properties seem to be plastic, and, in circumstances of injury, differentiated cells can revert back to a more immature cellular state. Importantly, deregulation of the balance between cellular proliferation and differentiation can lead to disease initiation, in particular to cancer formation. Pancreatic ductal adenocarcinoma (PDAC) is a lethal disease with a 5-year survival rate of only ~9%. Unfortunately, metastasis formation often occurs prior to diagnosis, and most tumors are resistant to current treatment strategies. It has been proposed that a specific subpopulation of cells, i.e., cancer stem cells (CSCs), are responsible for tumor expansion, metastasis formation, and therapy resistance. Understanding the underlying mechanisms of pancreatic stem cells during homeostasis and injury might lead to new insights to understand the role of CSCs in PDAC. Therefore, in this review, we present an overview of the current literature regarding the stem cell dynamics in the pancreas during health and disease. Furthermore, we highlight the influence of the tumor microenvironment on the growth behavior of PDAC.

scholarly journals Immune Cell Modulation of the Extracellular Matrix Contributes to the Pathogenesis of Pancreatic Cancer

Biomolecules ◽  
2021 ◽  
Vol 11 (6) ◽  
pp. 901
Author(s):  
Ramiz S. Ahmad ◽  
Timothy D. Eubank ◽  
Slawomir Lukomski ◽  
Brian A. Boone
Keyword(s):  
Pancreatic Cancer ◽  
Extracellular Matrix ◽  
Immune Cells ◽  
Immune Cell ◽  
Treatment Strategies ◽  
Stellate Cells ◽  
Pancreatic Stellate Cells ◽  
Ductal Adenocarcinoma ◽  
Cellular Mechanisms ◽  
Novel Treatment Strategies

Pancreatic ductal adenocarcinoma (PDAC) is a highly lethal malignancy with a five-year survival rate of only 9%. PDAC is characterized by a dense, fibrotic stroma composed of extracellular matrix (ECM) proteins. This desmoplastic stroma is a hallmark of PDAC, representing a significant physical barrier that is immunosuppressive and obstructs penetration of cytotoxic chemotherapy agents into the tumor microenvironment (TME). Additionally, dense ECM promotes hypoxia, making tumor cells refractive to radiation therapy and alters their metabolism, thereby supporting proliferation and survival. In this review, we outline the significant contribution of fibrosis to the pathogenesis of pancreatic cancer, with a focus on the cross talk between immune cells and pancreatic stellate cells that contribute to ECM deposition. We emphasize the cellular mechanisms by which neutrophils and macrophages, specifically, modulate the ECM in favor of PDAC-progression. Furthermore, we investigate how activated stellate cells and ECM influence immune cells and promote immunosuppression in PDAC. Finally, we summarize therapeutic strategies that target the stroma and hinder immune cell promotion of fibrogenesis, which have unfortunately led to mixed results. An enhanced understanding of the complex interactions between the pancreatic tumor ECM and immune cells may uncover novel treatment strategies that are desperately needed for this devastating disease.

scholarly journals The Jekyll and Hyde of Cellular Senescence in Cancer

Cells ◽  
2021 ◽  
Vol 10 (2) ◽  
pp. 208
Author(s):  
Dilara Demirci ◽  
Bengisu Dayanc ◽  
Fatma Aybuke Mazi ◽  
Serif Senturk
Keyword(s):  
Cancer Cell ◽  
Cellular Senescence ◽  
Expression Profiles ◽  
Treatment Strategies ◽  
Gene Expression Profiles ◽  
Therapy Resistance ◽  
Disease Recurrence ◽  
Adverse Outcomes ◽  
Cell Senescence ◽  
Great Promise

Cellular senescence is a state of stable cell cycle arrest that can be triggered in response to various insults and is characterized by distinct morphological hallmarks, gene expression profiles, and the senescence-associated secretory phenotype (SASP). Importantly, cellular senescence is a key component of normal physiology with tumor suppressive functions. In the last few decades, novel cancer treatment strategies exploiting pro-senescence therapies have attracted considerable interest. Recent insight, however, suggests that therapy-induced senescence (TIS) elicits cell-autonomous and non-cell-autonomous implications that potentially entail detrimental consequences, reflecting the Jekyll and Hyde nature of cancer cell senescence. In essence, the undesirable manifestations that generally culminate in inflammation, cancer stemness, senescence reversal, therapy resistance, and disease recurrence are dictated by the persistent accumulation of senescent cells and the SASP. Thus, mitigating these pro-tumorigenic effects by eliminating these cells or inhibiting their SASP production holds great promise for developing innovative therapeutic strategies. In this review, we describe the fundamental aspects and dynamics of cancer cell senescence and summarize the comprehensive research on the adverse outcomes of TIS. Furthermore, we underline the rationale and motivation of emerging senotherapeutic modalities surrounding the removal of senescent cells and the SASP to help maximize the overall efficacy of cancer therapies.

scholarly journals Molecular Targeting of Cancer-Associated PCNA Interactions in Pancreatic Ductal Adenocarcinoma Using a Cell-Penetrating Peptide

2020 ◽  
Vol 17 ◽  
pp. 250-256
Author(s):  
Shanna J. Smith ◽  
Caroline M. Li ◽  
Robert G. Lingeman ◽  
Robert J. Hickey ◽  
Yilun Liu ◽  
...  
Keyword(s):  
Pancreatic Ductal Adenocarcinoma ◽  
Ductal Adenocarcinoma ◽  
Molecular Targeting ◽  
Cell Penetrating Peptide ◽  
Cell Penetrating ◽  
A Cell

scholarly journals Clonal Evolution Characteristics and Reduced Dimension Prognostic Model for Non-Metastatic Metachronous Bilateral Breast Cancer

2021 ◽  
Author(s):  
Lingyu Li ◽  
Jiaxuan Li ◽  
Jiwei Jia ◽  
Hua He ◽  
Mingyang Li ◽  
...  
Keyword(s):  
Breast Cancer ◽  
Clinical Features ◽  
Risk Model ◽  
Clonal Evolution ◽  
Bilateral Breast Cancer ◽  
Treatment Strategies ◽  
Significant Heterogeneity ◽  
Prognostic Evaluation ◽  
Interval Time ◽  
Time To Build

Abstract Background:How to evaluate the prognosis and develop overall treatment strategies of metachronous bilateral breast cancer (MBBC) remains confused in clinical practice.Methods:Data from Surveillance, Epidemiology, and End Results (SEER) database and the first hospital of Jilin university were analyzed for breast cancer-specific cumulative mortality (BCCM) by competing risk model. Whole-exome sequencing was applied for 10 lesions acquired at spatial-temporal distinct regions from 5 patients to reconstruct clonal evolutionary characteristics of MBBC. Dimensional reduction (DR) cumulative incidence function (CIF) curves of MBBC features were established on different point in diagnostic interval time, to build a novel DR nomogram.Results:Significant heterogeneity in genome and clinical features of MBBC was widespread. The mutational diversity of contralateral BC (CBC) was significantly higher than that in primary BC (PBC), and the most effective prognostic MATH ratio was significantly correlated with interval time (R2=0.85, p < .05). In SEER cohort study (n=13304), the interval time was not only significantly affected the BCCM by multivariate analysis (p < .000), but determined the weight of clinical features (T/N stage, grade and ER status) on PBC and CBC in prognostic evaluation. Thus, clinical parameters after DR based on interval time were incorporated into the nomogram for prognostic predicting BCCM. Concordance index was 0.773 (95% CI, 0.769 to 0.776) in training cohort (n=8869), and 0.819 (95% CI, 0.813 to 0.826) in validation cohort (n=4435).Conclusions:Bilateral heterogeneous characteristics and interval time were determinant prognostic factors of MBBC. The DR nomogram may help clinical prognostic evaluation.

scholarly journals Pancreatic Ductal Adenocarcinoma: Preclinical in vitro and ex vivo Models

2021 ◽  
Vol 9 ◽  
Author(s):  
Beate Gündel ◽  
Xinyuan Liu ◽  
Matthias Löhr ◽  
Rainer Heuchel
Keyword(s):  
Pancreatic Ductal Adenocarcinoma ◽  
Ex Vivo ◽  
Treatment Options ◽  
3D Cell Culture ◽  
Therapy Resistance ◽  
Ductal Adenocarcinoma ◽  
The Past ◽  
Slow Progress

Pancreatic ductal adenocarcinoma (PDAC) is one of the most overlooked cancers despite its dismal median survival time of 6 months. The biggest challenges in improving patient survival are late diagnosis due to lack of diagnostic markers, and limited treatment options due to almost complete therapy resistance. The past decades of research identified the dense stroma and the complex interplay/crosstalk between the cancer- and the different stromal cells as the main culprits for the slow progress in improving patient outcome. For better ex vivo simulation of this complex tumor microenvironment the models used in PDAC research likewise need to become more diverse. Depending on the focus of the investigation, several in vitro and in vivo models for PDAC have been established in the past years. Particularly, 3D cell culture such as spheroids and organoids have become more frequently used. This review aims to examine current PDAC in vitro models, their inherent limitations, and their successful implementations in research.

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