Drivers of dynamic intratumor heterogeneity and phenotypic plasticity

2021 ◽  
Vol 320 (5) ◽  
pp. C750-C760
Author(s):  
Antara Biswas ◽  
Subhajyoti De
Keyword(s):  
Phenotypic Plasticity ◽  
Tumor Cells ◽  
State Transition ◽  
Malignant Lesion ◽  
Genetic Alterations ◽  
Intratumor Heterogeneity ◽  
Genetic Mutations ◽  
Dynamic Heterogeneity ◽  
Cell State ◽  
Somatic Evolution

Cancer is a clonal disease, i.e., all tumor cells within a malignant lesion trace their lineage back to a precursor somatic cell that acquired oncogenic mutations during development and aging. And yet, those tumor cells tend to have genetic and nongenetic variations among themselves—which is denoted as intratumor heterogeneity. Although some of these variations are inconsequential, others tend to contribute to cell state transition and phenotypic heterogeneity, providing a substrate for somatic evolution. Tumor cell phenotypes can dynamically change under the influence of genetic mutations, epigenetic modifications, and microenvironmental contexts. Although epigenetic and microenvironmental changes are adaptive, genetic mutations are usually considered permanent. Emerging reports suggest that certain classes of genetic alterations show extensive reversibility in tumors in clinically relevant timescales, contributing as major drivers of dynamic intratumor heterogeneity and phenotypic plasticity. Dynamic heterogeneity and phenotypic plasticity can confer resistance to treatment, promote metastasis, and enhance evolvability in cancer. Here, we first highlight recent efforts to characterize intratumor heterogeneity at genetic, epigenetic, and microenvironmental levels. We then discuss phenotypic plasticity and cell state transition by tumor cells, under the influence of genetic and nongenetic determinants and their clinical significance in classification of tumors and therapeutic decision-making.

scholarly journals Generation of Non-Small Cell Lung Cancer Patient-Derived Xenografts to Study Intratumor Heterogeneity

Cancers ◽  
2021 ◽  
Vol 13 (10) ◽  
pp. 2446
Author(s):  
Zoi Kanaki ◽  
Alexandra Voutsina ◽  
Athina Markou ◽  
Ioannis S. Pateras ◽  
Konstantinos Potaris ◽  
...  
Keyword(s):  
Lung Cancer ◽  
Small Cell Lung Cancer ◽  
Tumor Cells ◽  
Cell Lung Cancer ◽  
Genetic Alterations ◽  
Small Cell ◽  
Intratumor Heterogeneity ◽  
Molecular Characteristics ◽  
Tumor Evolution ◽  
Small Cell Lung

Recent advances in sequencing technologies have allowed the in-depth molecular study of tumors, even at the single cell level. Sequencing efforts have uncovered a previously unappreciated heterogeneity among tumor cells, which has been postulated to be the driving force of tumor evolution and to facilitate recurrence, metastasis, and drug resistance. In the current study, focused on early-stage operable non-small cell lung cancer, we used tumor growth in patient-derived xenograft (PDX) models in mice as a fast-forward tumor evolution process to investigate the molecular characteristics of tumor cells that grow in mice, as well as the parameters that affect the grafting efficiency. We found that squamous cell carcinomas grafted significantly more efficiently compared with adenocarcinomas. Advanced stage, patient age and primary tumor size were positively correlated with grafting. Additionally, we isolated and characterized circulating tumor cells (CTC) from patients’ peripheral blood and found that the presence of CTCs expressing epithelial-to-mesenchymal (EMT) markers correlated with the grafting potential. Interestingly, exome sequencing of the PDX tumor identified genetic alterations in DNA repair and genome integrity genes that were under-represented in the human primary counterpart. In conclusion, through the generation of a PDX biobank of NSCLC, we identified the clinical and molecular properties of tumors that affected growth in mice.

scholarly journals TAMI-28. DIFFERENTIAL MIGRATION MECHANICS AND IMMUNE RESPONSES OF GLIOMA SUBTYPES

2020 ◽  
Vol 22 (Supplement_2) ◽  
pp. ii219-ii219
Author(s):  
Ghaidan Shamsan ◽  
Chao Liu ◽  
Brooke Braman ◽  
Susan Rathe ◽  
Aaron Sarver ◽  
...  
Keyword(s):  
Tumor Cells ◽  
Immune Cell ◽  
Molecular Subtypes ◽  
Ex Vivo ◽  
Brain Slices ◽  
Traction Force ◽  
Genetic Alterations ◽  
Sleeping Beauty ◽  
Brain Parenchyma ◽  
Biophysical Modeling

Abstract In Glioblastoma (GBM), tumor spreading is driven by tumor cells’ ability to infiltrate healthy brain parenchyma, which prevents complete surgical resection and contributes to tumor recurrence. GBM molecular subtypes, classical, proneural and mesenchymal, were shown to strongly correlate with specific genetic alterations (Mesenchymal: NF1; Classical: EGFRVIII; Proneural: PDGFRA). Here we tested the hypothesis that a key mechanistic difference between GBM molecular subtypes is that proneural cells are slow migrating and mesenchymal cells are fast migrating. Using Sleeping Beauty transposon system, immune-competent murine brain tumors were induced by SV40-LgT antigen in combination with either NRASG12V (NRAS) or PDGFB (PDGF) overexpression. Cross-species transcriptomic analysis revealed NRAS and PDGF-driven tumors correlate with human mesenchymal and proneural GBM, respectively. Similar to human GBM, CD44 expression was higher in NRAS tumors and, consistent with migration simulations of varying CD44 levels, ex vivo brain slice live imaging showed NRAS tumors cells migrate faster than PDGF tumors cells (random motility coefficient = 30µm2/hr vs. 2.5µm2/hr, p < 0.001). Consistent with CD44 function as an adhesion molecule, migration phenotype was independent of the tumor microenvironment. NRAS and human PDX/MES tumor cells were found to migrate faster and have larger cell spread area than PDGF and human PDX/PN tumors cells, respectively, in healthy mouse brain slices. Furthermore, traction force microscopy revealed NRAS tumor cells generate larger traction forces than PDGF tumors cells which further supports our theoretical mechanism driving glioma migration. Despite increased migration, NRAS cohort had better survival than PDGF which was attributed to enhanced antitumoral immune response in NRAS tumors, consistent with increased immune cell infiltration found in human mesenchymal GBM. Overall our work identified a potentially actionable difference in migration mechanics between GBM subtypes and establishes an integrated biophysical modeling and experimental approach to mechanically parameterize and simulate distinct molecular subtypes in preclinical models of cancer.

scholarly journals eIF5B regulates the expression of PD-L1 in prostate cancer cells by interacting with Wig1

BMC Cancer ◽  
2021 ◽  
Vol 21 (1) ◽  
Author(s):  
Qi Li ◽  
Mulun Xiao ◽  
Yibo Shi ◽  
Jinhao Hu ◽  
Tianxiang Bi ◽  
...  
Keyword(s):  
Prostate Cancer ◽  
Cancer Cells ◽  
Tumor Cells ◽  
Translation Initiation ◽  
Genetic Alterations ◽  
Cell Counting ◽  
Migration And Invasion ◽  
Cell Group ◽  
Prostate Cancer Cells ◽  
Normal Prostate

Abstract Background Eukaryotic translation initiation factors (eIFs) are the key factors to synthesize translation initiation complexes during the synthesis of eukaryotic proteins. Besides, eIFs are especially important in regulating the immune function of tumor cells. However, the effect mechanism of eIFs in prostate cancer remains to be studied, which is precisely the purpose of this study. Methods In this study, three groups of prostate cancer cells were investigated. One group had its eIF5B gene knocked down; another group had its Programmed death 1 (PD-L1) overexpressed; the final group had its Wild-type p53-induced gene 1 (Wig1) overexpressed. Genetic alterations of the cancer cells were performed by plasmid transfection. The expression of PD-L1 mRNA was detected by quantitative real-time PCR (qRT-PCR), and the expressions of PD-L1 and eIF5B proteins were observed by western blot assays. Cell Counting Kit-8 (CCK-8), flow cytometry, Transwell and Transwell martrigel were used to investigated cell proliferation, apoptosis, migration and invasion, respectively. The effect of peripheral blood mononuclear cells (PBMCs) on tumor cells was observed, and the interaction between eIF5B and Wig1 was revealed by co-immunoprecipitation (CoIP) assay. Finally, the effects of interference with eIF5B expression on the growth, morphology, and immunity of the tumor, as well as PD-L1 expression in the tumor, were verified by tumor xenograft assays in vivo. Results Compared with normal prostate epithelial cells, prostate cancer cells revealed higher expressions of eIF5B and PD-L1 interference with eIF-5B expression can inhibit the proliferation, migration, invasion and PD-L1 expression of prostate cancer cells. Meanwhile, the cancer cell group with interference with eIF5B expression also demonstrated greater, apoptosis and higher vulnerability to PBMCs. CoIP assays showed that Wig1 could bind to eIF5B in prostate cancer cells, and its overexpression can inhibit the proliferation, migration, invasion and PD-L1 expression of cancer cells while promoting apoptosis. Moreover, interference with eIF5B expression can inhibit tumor growth, destroy tumor morphology, and suppress the proliferation of tumor cells. Conclusion eIF5B can promote the expression of PD-L1 by interacting with Wig1. Besides, interference with eIF5B expression can inhibit the proliferation, migration, invasion and immunosuppressive response of prostate cancer cells. This study proposes a new target, eIF5B, for immunotherapy of prostate cancer.

scholarly journals Author response: A lncRNA fine tunes the dynamics of a cell state transition involving Lin28, let-7 and de novo DNA methylation

2017 ◽  
Author(s):  
Meng Amy Li ◽  
Paulo P Amaral ◽  
Priscilla Cheung ◽  
Jan H Bergmann ◽  
Masaki Kinoshita ◽  
...  
Keyword(s):  
Dna Methylation ◽  
State Transition ◽  
De Novo ◽  
Author Response ◽  
Cell State ◽  
A Cell

scholarly journals A Case Report of Incomplete Carney Complex With SMARCA4-Deficient Thoracic Sarcoma: Implications for the SLC7Aaa and ARID1A Expression

2021 ◽  
Author(s):  
yusuke kito ◽  
Keisuke Kawashima ◽  
Chiemi Saigo ◽  
Masayoshi Hasegawa ◽  
Shusuke Nomura ◽  
...  
Keyword(s):  
Tumor Cells ◽  
Epithelioid Sarcoma ◽  
Immunohistochemical Analysis ◽  
Large Cell Carcinoma ◽  
Large Cell ◽  
Large Mass ◽  
Soft Tissue Tumors ◽  
Genetic Alterations ◽  
Undifferentiated Carcinoma ◽  
Carney Complex

Abstract Background: SWI/SNF-related, matrix-associated, matrix-associated, actin-dependent regulator of chromatin, subfamily A, member (SMARCA4)-deficient thoracic sarcoma (SMARCA4-DTS) is a rare disease that has recently been described as an entity. It is characterized by an aggressive clinical course and specific genetic alterations. As an immunohistological feature, the tumors are deficient in SMARCA4 and SMARCA2 and express the sex-determining region Y-box 2 (SOX2). In contrast, Carney’s triad is a syndrome that combines three rare soft tissue tumors: gastric leiomyosarcoma, pulmonary chondroma, and extra-adrenal paraganglioma, of which at least two are required for diagnosis. Both diseases are valuable case, and there have been no previous reports of their coexistence.Case presentation: A 43-year-old man visited our hospital because of respiratory distress. Computed tomography revealed a large mass measuring 55 mm in the upper lobe of his right lung and front mediastinum, with metastases in the surrounding lymph nodes. Needle biopsy was performed for diagnosis, and histological examination of the samples revealed monotonous epithelioid-like cells with loose binding and sheet-form proliferation. The tumor cells had distinct nuclei, with rhabdoid-kile cells in some locations. Immunohistochemical analysis revealed that the tumor cells were positive for SOX2, CD34, and p53 and negative for SMARCA4 and SMARCA2. The patient died 6 months after admission without any treatment. Autopsy revealed ganglioneuroma and enchondroma, suggesting an incomplete Carney complex.Conclusion: SMARCA4-DTS is a rare and recently established disease. While it is difficult to siagnose, it is necessary to distinguish undifferentiated carcinoma, large cell carcinoma, Ewing sarcoma, epithelioid sarcoma, etc. when diagnosing tumors involving the mediastinum, In addition, case with both an incomplete Carney complex and SMARCA4-DTS are very rare. We discuss and report about SMARCA4-DTS by examining the expression of AT-rich interactive domain-containing protein 1A and solute carrier family 7 member 11.

scholarly journals Visualizing Cell State Transition Using Raman Spectroscopy

PLoS ONE ◽  
2014 ◽  
Vol 9 (1) ◽  
pp. e84478 ◽  
Author(s):  
Taro Ichimura ◽  
Liang-da Chiu ◽  
Katsumasa Fujita ◽  
Satoshi Kawata ◽  
Tomonobu M. Watanabe ◽  
...  
Keyword(s):  
Raman Spectroscopy ◽  
State Transition ◽  
Cell State

scholarly journals High Expression of Pd-1 in Circulating Cells of Patients With Advanced Colorectal Cancer Receiving Adjuvant Therapy

2020 ◽  
Vol 19 ◽  
pp. 153303382096944
Author(s):  
Muhammed A. Bakhrebah ◽  
Mohammad Nasrullah ◽  
Wesam H. Abdulaal ◽  
Mohammed A. Hassan ◽  
Halima Siddiqui ◽  
...  
Keyword(s):  
Colorectal Cancer ◽  
Immune Response ◽  
Adjuvant Therapy ◽  
Tumor Cells ◽  
Immune Cells ◽  
Human Leukocyte ◽  
Genetic Alterations ◽  
Programmed Death ◽  
Programmed Death 1 ◽  
Cancer Types

Among all cancer types, colorectal cancer is the third most common in men and the second most common in women globally. Generally, the risk of colorectal cancer increases with age, and colorectal cancer is modulated by various genetic alterations. Alterations in the immune response serve a significant role in the development of colorectal cancer. In primary cancer types, immune cells express a variety of inhibitory molecules that dampen the immune response against tumor cells. Additionally, few reports have demonstrated that classical chemotherapy promotes the immunosuppressive microenvironment in both tissues and immune cells. This study assessed the expression levels of genes using RT-qPCR associated with the immune system, including interferon-γ, programmed death-1, β2-microglobulin, human leukocyte antigen-A, CD3e, CD28 and intracellular adhesion molecule 1, in patients with colorectal cancer, as these genes are known to serve important roles in immune regulation during cancer incidence. Gene expression analysis was performed with the whole blood cells of patients with colorectal cancer and healthy volunteers. Compared with the normal controls, programmed death-1was highly expressed in patients with advanced-stage colorectal cancer. Furthermore, the expression of programmed death-1 was higher in patients receiving adjuvant therapy, which suggests the therapy dampened the immune response against tumor cells. The results of the present study indicate that classical adjuvant therapies, which are currently used for patients with colorectal cancer, should be modulated, and a combination of classical therapy with anti-programmed death-1 antibody should be conducted for improved management of patients with colorectal cancer.

scholarly journals Pancreatic cancer organoids recapitulate disease and allow personalized drug screening

2019 ◽  
Vol 116 (52) ◽  
pp. 26580-26590 ◽  
Author(s):  
Else Driehuis ◽  
Arne van Hoeck ◽  
Kat Moore ◽  
Sigrid Kolders ◽  
Hayley E. Francies ◽  
...  
Keyword(s):  
Pancreatic Cancer ◽  
Bile Duct ◽  
Tumor Cells ◽  
Drug Screening ◽  
Pancreatic Tumor ◽  
Genetic Alterations ◽  
Therapeutic Agents ◽  
In Vitro Testing ◽  
Distal Bile Duct

We report the derivation of 30 patient-derived organoid lines (PDOs) from tumors arising in the pancreas and distal bile duct. PDOs recapitulate tumor histology and contain genetic alterations typical of pancreatic cancer. In vitro testing of a panel of 76 therapeutic agents revealed sensitivities currently not exploited in the clinic, and underscores the importance of personalized approaches for effective cancer treatment. The PRMT5 inhibitor EZP015556, shown to targetMTAP(a gene commonly lost in pancreatic cancer)-negative tumors, was validated as such, but also appeared to constitute an effective therapy for a subset of MTAP-positive tumors. Taken together, the work presented here provides a platform to identify novel therapeutics to target pancreatic tumor cells using PDOs.

scholarly journals Dissecting Mechanisms of Melanoma Resistance to BRAF and MEK Inhibitors Revealed Genetic and Non-Genetic Patient- and Drug-Specific Alterations and Remarkable Phenotypic Plasticity

Cells ◽  
2020 ◽  
Vol 9 (1) ◽  
pp. 142 ◽  
Author(s):  
Mariusz L. Hartman ◽  
Malgorzata Sztiller-Sikorska ◽  
Anna Gajos-Michniewicz ◽  
Malgorzata Czyz
Keyword(s):  
Phenotypic Plasticity ◽  
Cell Lines ◽  
Mapk Pathway ◽  
Acquired Resistance ◽  
Resistance Mechanisms ◽  
Genetic Alterations ◽  
Resistant Cell ◽  
Cross Resistance ◽  
Preclinical Model ◽  
Development Of Resistance

The clinical benefit of MAPK pathway inhibition in BRAF-mutant melanoma patients is limited by the development of acquired resistance. Using drug-naïve cell lines derived from tumor specimens, we established a preclinical model of melanoma resistance to vemurafenib or trametinib to provide insight into resistance mechanisms. Dissecting the mechanisms accompanying the development of resistance, we have shown that (i) most of genetic and non-genetic alterations are triggered in a cell line- and/or drug-specific manner; (ii) several changes previously assigned to the development of resistance are induced as the immediate response to the extent measurable at the bulk levels; (iii) reprogramming observed in cross-resistance experiments and growth factor-dependence restricted by the drug presence indicate that phenotypic plasticity of melanoma cells largely contributes to the sustained resistance. Whole-exome sequencing revealed novel genetic alterations, including a frameshift variant of RBMX found exclusively in phospho-AKThigh resistant cell lines. There was no similar pattern of phenotypic alterations among eleven resistant cell lines, including expression/activity of crucial regulators, such as MITF, AXL, SOX, and NGFR, which suggests that patient-to-patient variability is richer and more nuanced than previously described. This diversity should be considered during the development of new strategies to circumvent the acquired resistance to targeted therapies.

Potential Role of Dual NF-κB and Oxidative Stress Pathway Inhibitor, OT-304 as a Novel Drug Resistance-Reversing Agent.

Blood ◽  
2007 ◽  
Vol 110 (11) ◽  
pp. 4211-4211
Author(s):  
Shaker A. Mousa ◽  
Ghanshyam Patil ◽  
Abdelhadi Rebbaa
Keyword(s):  
Oxidative Stress ◽  
Drug Resistance ◽  
Tumor Cells ◽  
Genetic Alterations ◽  
Potential Candidate ◽  
Drug Resistant ◽  
P Glycoprotein ◽  
And Oxidative Stress

Abstract The development of resistance to chemotherapy represents an adaptive biological response by tumor cells that leads to treatment failure and patient relapse. During the course of their evolution (intrinsic resistance) or in response to chemotherapy (acquired resistance), tumor cells may undergo genetic alterations to possess a drug resistant phenotype. Dysregulation of membrane transport proteins and cellular enzymes, as well as altered susceptibility to commit to apoptosis are among the mechanisms that contribute to the genesis of acquired drug resistance. Recently, the development of approaches to prevent and/or to reverse this phenomenon has attracted special interest and a number of drug candidates have been identified. Despite strong effects observed for these candidates in vitro, however, most of them fail in vivo. In the present study, we have identified a novel small molecule inhibitor of dual NF-κB and oxidative stress pathways, OT-304, as a potential candidate to reverse drug resistance. Initial investigations indicate that this compound effectively inhibits proliferation of doxorubicin-sensitive and doxorubicin-resistant cells to the same extent, suggesting that it is capable of bypassing the development of drug resistance. Additional experiments reveal that OT-304 enhances cancer cell sensitivity to doxorubicin and to etoposide, particularly in cells characterized by the over-expression of the drug transporter P-glycoprotein. These findings suggest that either the expression/and or the function of P-glycoprotein could be affected by OT-304. In vivo studies using tumor xenografts in nude mice showed that OT-304 is also capable of preventing the growth of drug resistant cancer cells. This later finding further confirms the role of OT-304 as a drug resistance-reversing agent and warrants further pre-clinical and clinical investigation to determine its efficacy in treating aggressive tumors.

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