Tumor Heterogeneity

A special issue of Cancers (ISSN 2072-6694).

Deadline for manuscript submissions: closed (30 September 2021) | Viewed by 17202

Special Issue Editor


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Guest Editor
Departments Dermatology, Oncological Sciences and Genetics & Genome Sciences, Icahn School of Medicine at Mount Sinai, New York, NY, USA
Interests: cancer genetics; tumor evolution; chromosomal alterations; mutation; chromatin; tumor resistance; copy number alterations; epigenetics; genetic predisposition; inflammation

Special Issue Information

Dear Colleagues,

Tumors can show differences in morphology, inflammatory infiltrate, mutational status, gene expression, epigenetic profiles, and response to treatment (inter-tumor heterogeneity). These differences can sometimes also be seen within a single tumor (intra-tumor heterogeneity). However, the effect of this heterogeneity upon treatment response, metastasis, drug resistance, relapse, and even tumor dormancy are not well understood.

The origin of intra-tumoral heterogeneity is not clear. At the DNA level, it can range from a single point mutation to catastrophic chromosomal or intra-chromosomal alterations. Evidence of chromosomal instability can be a prognostic predictor. Studies incorporating longitudinal tissue sampling, integrating genomic and clinical data, can reveal the sub-clonal composition of a tumor and track its evolution. This type of studies have been facilitated in recent years by advances in next-generation sequencing, which have led to fundamental insights into cancer genomes at the chromatin and nucleic acid levels.

Tumor heterogeneity can impact treatment response. The identification of major driver genes or gene expression profiles of a subset of tumors can permit stratification of patients into different therapeutic and prognostic subgroups. There can also be heterogeneity with respect to inflammatory infiltrate, and this can contribute to the efficacy of immune checkpoint inhibitors. Intra-tumor heterogeneity of actionable mutations is also likely to impact targeted treatment and can contribute to drug resistance.  

This Special Issue will address aspects of inter- and intra-tumor heterogeneity, including the different types and levels of heterogeneity between and within different tumor types. Observations relating to tumor evolution are also of great interest, as are the effects of tumor heterogeneity on metastasis, treatment response, drug resistance, tumor dormancy, and relapse.

Prof. Anne M. Bowcock
Guest Editor

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Keywords

  • Tumor heterogeneity
  • Gene expression
  • Chromosomal instability
  • Immune infiltrate
  • Immune checkpoint inhibition
  • Actionable mutations
  • Tumor evolution
  • Drug resistance
  • Metastasis
  • Tumor Dormancy
  • Relapse
  • Epigenetics

Published Papers (6 papers)

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Research

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18 pages, 6998 KiB  
Article
Early-Stage Lung Adenocarcinoma MDM2 Genomic Amplification Predicts Clinical Outcome and Response to Targeted Therapy
by Abhilasha Sinha, Yong Zou, Ayushi S. Patel, Seungyeul Yoo, Feng Jiang, Takashi Sato, Ranran Kong, Hideo Watanabe, Jun Zhu, Pierre P. Massion, Alain C. Borczuk and Charles A. Powell
Cancers 2022, 14(3), 708; https://doi.org/10.3390/cancers14030708 - 29 Jan 2022
Cited by 9 | Viewed by 3292
Abstract
Lung cancer is the most common cause of cancer-related deaths in both men and women, accounting for one-quarter of total cancer-related mortality globally. Lung adenocarcinoma is the major subtype of non-small cell lung cancer (NSCLC) and accounts for around 40% of lung cancer [...] Read more.
Lung cancer is the most common cause of cancer-related deaths in both men and women, accounting for one-quarter of total cancer-related mortality globally. Lung adenocarcinoma is the major subtype of non-small cell lung cancer (NSCLC) and accounts for around 40% of lung cancer cases. Lung adenocarcinoma is a highly heterogeneous disease and patients often display variable histopathological morphology, genetic alterations, and genomic aberrations. Recent advances in transcriptomic and genetic profiling of lung adenocarcinoma by investigators, including our group, has provided better stratification of this heterogeneous disease, which can facilitate devising better treatment strategies suitable for targeted patient cohorts. In a recent study we have shown gene expression profiling identified novel clustering of early stage LUAD patients and correlated with tumor invasiveness and patient survival. In this study, we focused on copy number alterations in LUAD patients. SNP array data identified amplification at chromosome 12q15 on MDM2 locus and protein overexpression in a subclass of LUAD patients with an invasive subtype of the disease. High copy number amplification and protein expression in this subclass correlated with poor overall survival. We hypothesized that MDM2 copy number and overexpression predict response to MDM2-targeted therapy. In vitro functional data on a panel of LUAD cells showed that MDM2-targeted therapy effectively suppresses cell proliferation, migration, and invasion in cells with MDM2 amplification/overexpression but not in cells without MDM2 amplification, independent of p53 status. To determine the key signaling mechanisms, we used RNA sequencing (RNA seq) to examine the response to therapy in MDM2-amplified/overexpressing p53 mutant and wild-type LUAD cells. RNA seq data shows that in MDM2-amplified/overexpression with p53 wild-type condition, the E2F → PEG10 → MMPs pathway is operative, while in p53 mutant genetic background, MDM2-targeted therapy abrogates tumor progression in LUAD cells by suppressing epithelial to mesenchymal transition (EMT) signaling. Our study provides a potentially clinically relevant strategy of selecting LUAD patients for MDM2-targeted therapy that may provide for increased response rates and, thus, better survival. Full article
(This article belongs to the Special Issue Tumor Heterogeneity)
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18 pages, 12632 KiB  
Article
Intra-Tumour Genetic Heterogeneity and Prognosis in High-Risk Neuroblastoma
by Amparo López-Carrasco, Ana P. Berbegall, Susana Martín-Vañó, Maite Blanquer-Maceiras, Victoria Castel, Samuel Navarro and Rosa Noguera
Cancers 2021, 13(20), 5173; https://doi.org/10.3390/cancers13205173 - 15 Oct 2021
Cited by 9 | Viewed by 1514
Abstract
Spatial ITH is defined by genomic and biological variations within a tumour acquired by tumour cell evolution under diverse microenvironments, and its role in NB patient prognosis is understudied. In this work, we applied pangenomic techniques to detect chromosomal aberrations in at least [...] Read more.
Spatial ITH is defined by genomic and biological variations within a tumour acquired by tumour cell evolution under diverse microenvironments, and its role in NB patient prognosis is understudied. In this work, we applied pangenomic techniques to detect chromosomal aberrations in at least two different areas of each tumour and/or in simultaneously obtained solid and liquid biopsies, detecting ITH in the genomic profile of almost 40% of HR-NB. ITH was better detected when comparing one or more tumour pieces and liquid biopsy (50%) than between different tumour pieces (21%). Interestingly, we found that patients with ITH analysed by pangenomic techniques had a significantly better survival rate that those with non-heterogeneous tumours, especially in cases without MYCN amplification. Moreover, all patients in the studied cohort with high ITH (defined as 50% or more genomic aberration differences between areas of a tumour or simultaneously obtained samples) survived after 48 months. These results clearly support analysing at least two solid tumour areas (separately or mixed) and liquid samples to provide more accurate genomic diagnosis, prognosis and therapy options in HR-NB. Full article
(This article belongs to the Special Issue Tumor Heterogeneity)
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19 pages, 1908 KiB  
Article
Low Doses of Silver Nanoparticles Selectively Induce Lipid Peroxidation and Proteotoxic Stress in Mesenchymal Subtypes of Triple-Negative Breast Cancer
by Christina M. Snyder, Monica M. Rohde, Cale D. Fahrenholtz, Jessica Swanner, John Sloop, George L. Donati, Cristina M. Furdui and Ravi Singh
Cancers 2021, 13(16), 4217; https://doi.org/10.3390/cancers13164217 - 22 Aug 2021
Cited by 7 | Viewed by 2907
Abstract
Molecular profiling of tumors shows that triple-negative breast cancer (TNBC) can be stratified into mesenchymal (claudin-low breast cancer; CLBC) and epithelial subtypes (basal-like breast cancer; BLBC). Subtypes differ in underlying genetics and in response to therapeutics. Several reports indicate that therapeutic strategies that [...] Read more.
Molecular profiling of tumors shows that triple-negative breast cancer (TNBC) can be stratified into mesenchymal (claudin-low breast cancer; CLBC) and epithelial subtypes (basal-like breast cancer; BLBC). Subtypes differ in underlying genetics and in response to therapeutics. Several reports indicate that therapeutic strategies that induce lipid peroxidation or proteotoxicity may be particularly effective for various cancers with a mesenchymal phenotype such as CLBC, for which no specific treatment regimens exist and outcomes are poor. We hypothesized that silver nanoparticles (AgNPs) can induce proteotoxic stress and cause lipid peroxidation to a greater extent in CLBC than in BLBC. We found that AgNPs were lethal to CLBCs at doses that had little effect on BLBCs and were non-toxic to normal breast epithelial cells. Analysis of mRNA profiles indicated that sensitivity to AgNPs correlated with expression of multiple CLBC-associated genes. There was no correlation between sensitivity to AgNPs and sensitivity to silver cations, uptake of AgNPs, or proliferation rate, indicating that there are other molecular factors driving sensitivity to AgNPs. Mechanistically, we found that the differences in sensitivity of CLBC and BLBC cells to AgNPs were driven by peroxidation of lipids, protein oxidation and aggregation, and subsequent proteotoxic stress and apoptotic signaling, which were induced in AgNP-treated CLBC cells, but not in BLBC cells. This study shows AgNPs are a specific treatment for CLBC and indicates that stratification of TNBC subtypes may lead to improved outcomes for other therapeutics with similar mechanisms of action. Full article
(This article belongs to the Special Issue Tumor Heterogeneity)
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13 pages, 1708 KiB  
Article
Phosphorous Magnetic Resonance Spectroscopy to Detect Regional Differences of Energy and Membrane Metabolism in Naïve Glioblastoma Multiforme
by Lisa Maria Walchhofer, Ruth Steiger, Andreas Rietzler, Johannes Kerschbaumer, Christian Franz Freyschlag, Günther Stockhammer, Elke Ruth Gizewski and Astrid Ellen Grams
Cancers 2021, 13(11), 2598; https://doi.org/10.3390/cancers13112598 - 26 May 2021
Cited by 12 | Viewed by 2207
Abstract
Background: Glioblastoma multiforme (GBM) is a highly malignant primary brain tumor with infiltration of, on conventional imaging, normal-appearing brain parenchyma. Phosphorus magnetic resonance spectroscopy (31P-MRS) enables the investigation of different energy and membrane metabolites. The aim of this study is to investigate [...] Read more.
Background: Glioblastoma multiforme (GBM) is a highly malignant primary brain tumor with infiltration of, on conventional imaging, normal-appearing brain parenchyma. Phosphorus magnetic resonance spectroscopy (31P-MRS) enables the investigation of different energy and membrane metabolites. The aim of this study is to investigate regional differences of 31P-metabolites in GBM brains. Methods: In this study, we investigated 32 patients (13 female and 19 male; mean age 63 years) with naïve GBM using 31P-MRS and conventional MRI. Contrast-enhancing (CE), T2-hyperintense, adjacent and distant ipsilateral areas of the contralateral brain and the brains of age- and gender-matched healthy volunteers were assessed. Moreover, the 31P-MRS results were correlated with quantitative diffusion parameters. Results: Several metabolite ratios between the energy-dependent metabolites and/or the membrane metabolites differed significantly between the CE areas, the T2-hyperintense areas, the more distant areas, and even the brains of healthy volunteers. pH values and Mg2+ concentrations were highest in visible tumor areas and decreased with distance from them. These results are in accordance with the literature and correlated with quantitative diffusion parameters. Conclusions: This pilot study shows that 31P-MRS is feasible to show regional differences of energy and membrane metabolism in brains with naïve GBM, particularly between the different “normal-appearing” regions and between the contralateral hemisphere and healthy controls. Differences between various genetic mutations or clinical applicability for follow-up monitoring have to be assessed in a larger cohort. Full article
(This article belongs to the Special Issue Tumor Heterogeneity)
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Review

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16 pages, 1574 KiB  
Review
Intratumor Heterogeneity in Hepatocellular Carcinoma: Challenges and Opportunities
by Sharanya Maanasi Kalasekar, Chad H. VanSant-Webb and Kimberley J. Evason
Cancers 2021, 13(21), 5524; https://doi.org/10.3390/cancers13215524 - 03 Nov 2021
Cited by 14 | Viewed by 2787
Abstract
Hepatocellular carcinoma (HCC) represents a leading cause of cancer-related death, but it remains difficult to treat. Intratumor genetic and phenotypic heterogeneity are inherent properties of breast, skin, lung, prostate, and brain tumors, and intratumor heterogeneity (ITH) helps define prognosis and therapeutic response in [...] Read more.
Hepatocellular carcinoma (HCC) represents a leading cause of cancer-related death, but it remains difficult to treat. Intratumor genetic and phenotypic heterogeneity are inherent properties of breast, skin, lung, prostate, and brain tumors, and intratumor heterogeneity (ITH) helps define prognosis and therapeutic response in these cancers. Several recent studies estimate that ITH is inherent to HCC and attribute the clinical intractability of HCC to this heterogeneity. In this review, we examine the evidence for genomic, phenotypic, and tumor microenvironment ITH in HCC, with a focus on two of the top molecular drivers of HCC: β-catenin (CTNNB1) and Telomerase reverse transcriptase (TERT). We discuss the influence of ITH on HCC diagnosis, prognosis, and therapy, while highlighting the gaps in knowledge and possible future directions. Full article
(This article belongs to the Special Issue Tumor Heterogeneity)
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Other

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13 pages, 960 KiB  
Perspective
Stem Cell Theory of Cancer: Origin of Tumor Heterogeneity and Plasticity
by Shi-Ming Tu, Miao Zhang, Christopher G. Wood and Louis L. Pisters
Cancers 2021, 13(16), 4006; https://doi.org/10.3390/cancers13164006 - 09 Aug 2021
Cited by 17 | Viewed by 3418
Abstract
In many respects, heterogeneity is one of the most striking revelations and common manifestations of a stem cell origin of cancer. We observe heterogeneity in myriad mixed tumors including testicular, lung, and breast cancers. We recognize heterogeneity in diverse tumor subtypes in prostate [...] Read more.
In many respects, heterogeneity is one of the most striking revelations and common manifestations of a stem cell origin of cancer. We observe heterogeneity in myriad mixed tumors including testicular, lung, and breast cancers. We recognize heterogeneity in diverse tumor subtypes in prostate and kidney cancers. From this perspective, we illustrate that one of the main stem-ness characteristics, i.e., the ability to differentiate into diverse and multiple lineages, is central to tumor heterogeneity. We postulate that cancer subtypes can be meaningless and useless without a proper theory about cancer’s stem cell versus genetic origin and nature. We propose a unified theory of cancer in which the same genetic abnormalities, epigenetic defects, and microenvironmental aberrations cause different effects and lead to different outcomes in a progenitor stem cell versus a mature progeny cell. We need to recognize that an all-encompassing genetic theory of cancer may be incomplete and obsolete. A stem cell theory of cancer provides greater universality, interconnectivity, and utility. Although genetic defects are pivotal, cellular context is paramount. When it concerns tumor heterogeneity, perhaps we need to revisit the conventional wisdom of precision medicine and revise our current practice of targeted therapy in cancer care. Full article
(This article belongs to the Special Issue Tumor Heterogeneity)
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