The Extinction and Persistence of Tumor Evolution Influenced by External Fluctuations and Periodic Treatment

Abstract Interrogation of hematopoietic tissue at the clonal level has a rich history spanning over 50 years, and has provided critical insights into both normal and malignant hematopoiesis. Characterization of chromosomes identified some of the first genetic links to cancer with the discovery of chromosomal translocations in association with many hematological neoplasms. The unique accessibility of hematopoietic tissue and the ability to clonally expand hematopoietic progenitors in vitro has provided fundamental insights into the cellular hierarchy of normal hematopoiesis, as well as the functional impact of driver mutations in disease. Transplantation assays in murine models have enabled cellular assessment of the functional consequences of somatic mutations in vivo. Most recently, next-generation sequencing–based assays have shown great promise in allowing multi-“omic” characterization of single cells. Here, we review how clonal approaches have advanced our understanding of disease development, focusing on the acquisition of somatic mutations, clonal selection, driver mutation cooperation, and tumor evolution.

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Amino Acid Transporters on the Guard of Cell Genome and Epigenome

Cancers ◽

10.3390/cancers13010125 ◽

2021 ◽

Vol 13 (1) ◽

pp. 125

Author(s):

Uğur Kahya ◽

Ayşe Sedef Köseer ◽

Anna Dubrovska

Keyword(s):

Amino Acid ◽

Cancer Metabolism ◽

Tumor Imaging ◽

Redox Homeostasis ◽

Amino Acid Uptake ◽

Metabolic Reprogramming ◽

Tumor Evolution ◽

Amino Acid Transporters ◽

Acid Uptake ◽

Growth And Survival

Tumorigenesis is driven by metabolic reprogramming. Oncogenic mutations and epigenetic alterations that cause metabolic rewiring may also upregulate the reactive oxygen species (ROS). Precise regulation of the intracellular ROS levels is critical for tumor cell growth and survival. High ROS production leads to the damage of vital macromolecules, such as DNA, proteins, and lipids, causing genomic instability and further tumor evolution. One of the hallmarks of cancer metabolism is deregulated amino acid uptake. In fast-growing tumors, amino acids are not only the source of energy and building intermediates but also critical regulators of redox homeostasis. Amino acid uptake regulates the intracellular glutathione (GSH) levels, endoplasmic reticulum stress, unfolded protein response signaling, mTOR-mediated antioxidant defense, and epigenetic adaptations of tumor cells to oxidative stress. This review summarizes the role of amino acid transporters as the defender of tumor antioxidant system and genome integrity and discusses them as promising therapeutic targets and tumor imaging tools.

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Enhanced Vasculogenic Capacity Induced by 5-Fluorouracil Chemoresistance in a Gastric Cancer Cell Line

International Journal of Molecular Sciences ◽

10.3390/ijms22147698 ◽

2021 ◽

Vol 22 (14) ◽

pp. 7698

Author(s):

Sara Peri ◽

Alessio Biagioni ◽

Giampaolo Versienti ◽

Elena Andreucci ◽

Fabio Staderini ◽

...

Keyword(s):

Gastric Cancer ◽

Cancer Cells ◽

Cell Line ◽

Cancer Cell ◽

Intracellular Signaling ◽

Gastric Cancer Cell ◽

Gastric Cancer Cell Line ◽

Cancer Cell Line ◽

Tumor Evolution ◽

Selective Growth Advantage

Chemotherapy is still widely used as a coadjutant in gastric cancer when surgery is not possible or in presence of metastasis. During tumor evolution, gatekeeper mutations provide a selective growth advantage to a subpopulation of cancer cells that become resistant to chemotherapy. When this phenomenon happens, patients experience tumor recurrence and treatment failure. Even if many chemoresistance mechanisms are known, such as expression of ATP-binding cassette (ABC) transporters, aldehyde dehydrogenase (ALDH1) activity and activation of peculiar intracellular signaling pathways, a common and universal marker for chemoresistant cancer cells has not been identified yet. In this study we subjected the gastric cancer cell line AGS to chronic exposure of 5-fluorouracil, cisplatin or paclitaxel, thus selecting cell subpopulations showing resistance to the different drugs. Such cells showed biological changes; among them, we observed that the acquired chemoresistance to 5-fluorouracil induced an endothelial-like phenotype and increased the capacity to form vessel-like structures. We identified the upregulation of thymidine phosphorylase (TYMP), which is one of the most commonly reported mutated genes leading to 5-fluorouracil resistance, as the cause of such enhanced vasculogenic ability.

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EPCO-31. EPIGENOMIC INTRATUMORAL HETEROGENEITY OF GLIOBLASTOMA IN THREE-DIMENSIONAL SPACE

Neuro-Oncology ◽

10.1093/neuonc/noaa215.310 ◽

2020 ◽

Vol 22 (Supplement_2) ◽

pp. ii76-ii76

Author(s):

Radhika Mathur ◽

Sriranga Iyyanki ◽

Stephanie Hilz ◽

Chibo Hong ◽

Joanna Phillips ◽

...

Keyword(s):

Spatial Organization ◽

Dimensional Space ◽

Three Dimensional ◽

Spatial Location ◽

Therapy Resistance ◽

Regulatory Elements ◽

Chromatin Accessibility ◽

Intratumoral Heterogeneity ◽

Tumor Evolution ◽

Open Chromatin

Abstract Treatment failure in glioblastoma is often attributed to intratumoral heterogeneity (ITH), which fosters tumor evolution and generation of therapy-resistant clones. While ITH in glioblastoma has been well-characterized at the genomic and transcriptomic levels, the extent of ITH at the epigenomic level and its biological and clinical significance are not well understood. In collaboration with neurosurgeons, neuropathologists, and biomedical imaging experts, we have established a novel topographical approach towards characterizing epigenomic ITH in three-dimensional (3-D) space. We utilize pre-operative MRI scans to define tumor volume and then utilize 3-D surgical neuro-navigation to intra-operatively acquire 10+ samples representing maximal anatomical diversity. The precise spatial location of each sample is mapped by 3-D coordinates, enabling tumors to be visualized in 360-degrees and providing unprecedented insight into their spatial organization and patterning. For each sample, we conduct assay for transposase-accessible chromatin using sequencing (ATAC-Seq), which provides information on the genomic locations of open chromatin, DNA-binding proteins, and individual nucleosomes at nucleotide resolution. We additionally conduct whole-exome sequencing and RNA sequencing for each spatially mapped sample. Integrative analysis of these datasets reveals distinct patterns of chromatin accessibility within glioblastoma tumors, as well as their associations with genetically defined clonal expansions. Our analysis further reveals how differences in chromatin accessibility within tumors reflect underlying transcription factor activity at gene regulatory elements, including both promoters and enhancers, and drive expression of particular gene expression sets, including neuronal and immune programs. Collectively, this work provides the most comprehensive characterization of epigenomic ITH to date, establishing its importance for driving tumor evolution and therapy resistance in glioblastoma. As a resource for further investigation, we have provided our datasets on an interactive data sharing platform – The 3D Glioma Atlas – that enables 360-degree visualization of both genomic and epigenomic ITH.

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The Emerging Role of Extracellular Vesicles in Endocrine Resistant Breast Cancer

Cancers ◽

10.3390/cancers13051160 ◽

2021 ◽

Vol 13 (5) ◽

pp. 1160

Author(s):

Giusi La Camera ◽

Luca Gelsomino ◽

Amanda Caruso ◽

Salvatore Panza ◽

Ines Barone ◽

...

Keyword(s):

Breast Cancer ◽

Endocrine Therapy ◽

Extracellular Vesicles ◽

Molecular Mechanisms ◽

Endocrine Resistance ◽

Disease Recurrence ◽

Estrogen Receptor Α ◽

Research Area ◽

Tumor Evolution

Breast cancer is the most common solid malignancy diagnosed in females worldwide, and approximately 70% of these tumors express estrogen receptor α (ERα), the main biomarker of endocrine therapy. Unfortunately, despite the use of long-term anti-hormone adjuvant treatment, which has significantly reduced patient mortality, resistance to the endocrine treatments often develops, leading to disease recurrence and limiting clinical benefits. Emerging evidence indicates that extracellular vesicles (EVs), nanosized particles that are released by all cell types and responsible for local and systemic intercellular communications, might represent a newly identified mechanism underlying endocrine resistance. Unraveling the role of EVs, released by transformed cells during the tumor evolution under endocrine therapy, is still an open question in the cancer research area and the molecular mechanisms involved should be better defined to discover alternative therapeutic approaches to overcome resistance. In this review, we will provide an overview of recent findings on the involvement of EVs in sustaining hormonal resistance in breast cancer and discuss opportunities for their potential use as biomarkers to monitor the therapeutic response and disease progression.

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LOX-1 and cancer: an indissoluble liaison

Cancer Gene Therapy ◽

10.1038/s41417-020-00279-0 ◽

2021 ◽

Author(s):

M. Murdocca ◽

C. De Masi ◽

S. Pucci ◽

R. Mango ◽

G. Novelli ◽

...

Keyword(s):

Tumor Progression ◽

Epithelial Mesenchymal Transition ◽

Vascular Endothelial Cells ◽

Transition Process ◽

Receptor Protein ◽

Pancreatic Tumors ◽

Tumor Evolution ◽

Mesenchymal Transition ◽

Angiogenic Proteins

AbstractRecently, a strong correlation between metabolic disorders, tumor onset, and progression has been demonstrated, directing new therapeutic strategies on metabolic targets. OLR1 gene encodes the LOX-1 receptor protein, responsible for the recognition, binding, and internalization of ox-LDL. In the past, several studied, aimed to clarify the role of LOX-1 receptor in atherosclerosis, shed light on its role in the stimulation of the expression of adhesion molecules, pro-inflammatory signaling pathways, and pro-angiogenic proteins, including NF-kB and VEGF, in vascular endothelial cells and macrophages. In recent years, LOX-1 upregulation in different tumors evidenced its involvement in cancer onset, progression and metastasis. In this review, we outline the role of LOX-1 in tumor spreading and metastasis, evidencing its function in VEGF induction, HIF-1alpha activation, and MMP-9/MMP-2 expression, pushing up the neoangiogenic and the epithelial–mesenchymal transition process in glioblastoma, osteosarcoma prostate, colon, breast, lung, and pancreatic tumors. Moreover, our studies contributed to evidence its role in interacting with WNT/APC/β-catenin axis, highlighting new pathways in sporadic colon cancer onset. The application of volatilome analysis in high expressing LOX-1 tumor-bearing mice correlates with the tumor evolution, suggesting a closed link between LOX-1 upregulation and metabolic changes in individual volatile compounds and thus providing a viable method for a simple, non-invasive alternative monitoring of tumor progression. These findings underline the role of LOX-1 as regulator of tumor progression, migration, invasion, metastasis formation, and tumor-related neo-angiogenesis, proposing this receptor as a promising therapeutic target and thus enhancing current antineoplastic strategies.

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