bims-tumhet Biomed News
on Tumor Heterogeneity
Issue of 2024–10–06
fiveteen papers selected by
Sergio Marchini, Humanitas Research
  1. Crosstalk of T cells within the ovarian cancer microenvironment.
  2. Cell-Free DNA Hydroxymethylation in Cancer: Current and Emerging Detection Methods and Clinical Applications.
  3. Exploring public cancer gene expression signatures across bulk, single-cell and spatial transcriptomics data with signifinder Bioconductor package.
  4. The Role of Circulating Tumor DNA in Ovarian Cancer.
  5. Mimicking and analyzing the tumor microenvironment.
  6. Spatial oncology: Translating contextual biology to the clinic.
  7. Early detection of ovarian cancer using cell-free DNA fragmentomes and protein biomarkers.
  8. Pre-ciliated tubal epithelial cells are prone to initiation of high-grade serous ovarian carcinoma.
  9. When is prostate cancer really cancer?
  10. Aneuploidy as a driver of human cancer.
  11. The Epigenetic Hallmarks of Cancer.
  12. Single-cell sequencing to multi-omics: technologies and applications.
  13. Reconstructing oral cavity tumor evolution through brush biopsy.
  14. Screening Strategies to Improve Early Diagnosis in Endometrial Cancer.
  15. The Role of ctDNA and Liquid Biopsy in the Diagnosis and Monitoring of Head and Neck Cancer: Towards Precision Medicine.
  1. Trends Cancer. 2024 Sep 27. pii: S2405-8033(24)00190-0. [Epub ahead of print]
    Crosstalk of T cells within the ovarian cancer microenvironment.
    Bovannak S Chap, Nicolas Rayroux, Alizée J Grimm, Eleonora Ghisoni, Denarda Dangaj Laniti.
      Ovarian cancer (OC) represents ecosystems of highly diverse tumor microenvironments (TMEs). The presence of tumor-infiltrating lymphocytes (TILs) is linked to enhanced immune responses and long-term survival. In this review we present emerging evidence suggesting that cellular crosstalk tightly regulates the distribution of TILs within the TME, underscoring the need to better understand key cellular networks that promote or impede T cell infiltration in OC. We also capture the emergent methodologies and computational techniques that enable the dissection of cell-cell crosstalk. Finally, we present innovative ex vivo TME models that can be leveraged to map and perturb cellular communications to enhance T cell infiltration and immune reactivity.
    Keywords:  3D tumor models; T cell; cellular crosstalk; ovarian cancer; spatial omics; tumor microenvironment
    DOI:  https://doi.org/10.1016/j.trecan.2024.09.001
  2. Genes (Basel). 2024 Sep 03. pii: 1160. [Epub ahead of print]15(9):
    Cell-Free DNA Hydroxymethylation in Cancer: Current and Emerging Detection Methods and Clinical Applications.
    Janice J N Li, Geoffrey Liu, Benjamin H Lok.
      In the era of precision oncology, identifying abnormal genetic and epigenetic alterations has transformed the way cancer is diagnosed, managed, and treated. 5-hydroxymethylcytosine (5hmC) is an emerging epigenetic modification formed through the oxidation of 5-methylcytosine (5mC) by ten-eleven translocase (TET) enzymes. DNA hydroxymethylation exhibits tissue- and cancer-specific patterns and is essential in DNA demethylation and gene regulation. Recent advancements in 5hmC detection methods and the discovery of 5hmC in cell-free DNA (cfDNA) have highlighted the potential for cell-free 5hmC as a cancer biomarker. This review explores the current and emerging techniques and applications of DNA hydroxymethylation in cancer, particularly in the context of cfDNA.
    Keywords:  5-hydroxymethylcytosine; DNA hydroxymethylation; cancer biomarker; cell-free DNA; epigenetics; liquid biopsy
    DOI:  https://doi.org/10.3390/genes15091160
  3. NAR Genom Bioinform. 2024 Sep;6(4): lqae138
    Exploring public cancer gene expression signatures across bulk, single-cell and spatial transcriptomics data with signifinder Bioconductor package.
    Stefania Pirrotta, Laura Masatti, Anna Bortolato, Anna Corrà, Fabiola Pedrini, Martina Aere, Giovanni Esposito, Paolo Martini, Davide Risso, Chiara Romualdi, Enrica Calura.
      Understanding cancer mechanisms, defining subtypes, predicting prognosis and assessing therapy efficacy are crucial aspects of cancer research. Gene-expression signatures derived from bulk gene expression data have played a significant role in these endeavors over the past decade. However, recent advancements in high-resolution transcriptomic technologies, such as single-cell RNA sequencing and spatial transcriptomics, have revealed the complex cellular heterogeneity within tumors, necessitating the development of computational tools to characterize tumor mass heterogeneity accurately. Thus we implemented signifinder, a novel R Bioconductor package designed to streamline the collection and use of cancer transcriptional signatures across bulk, single-cell, and spatial transcriptomics data. Leveraging publicly available signatures curated by signifinder, users can assess a wide range of tumor characteristics, including hallmark processes, therapy responses, and tumor microenvironment peculiarities. Through three case studies, we demonstrate the utility of transcriptional signatures in bulk, single-cell, and spatial transcriptomic data analyses, providing insights into cell-resolution transcriptional signatures in oncology. Signifinder represents a significant advancement in cancer transcriptomic data analysis, offering a comprehensive framework for interpreting high-resolution data and addressing tumor complexity.
    DOI:  https://doi.org/10.1093/nargab/lqae138
  4. Cancers (Basel). 2024 Sep 10. pii: 3117. [Epub ahead of print]16(18):
    The Role of Circulating Tumor DNA in Ovarian Cancer.
    Anna Golara, Mateusz Kozłowski, Aneta Cymbaluk-Płoska.
      Ovarian cancer is the deadliest of all gynecological diseases because its diagnosis and treatment still pose many problems. Surgical excision, hormone therapy, radiation, chemotherapy, or targeted therapy for eradicating the main tumor and halting the spread of metastases are among the treatment options available to individuals with ovarian cancer, depending on the disease's stage. Tumor DNA that circulates in a patient's bodily fluids has been studied recently as a possible novel biomarker for a number of cancers, as well as a means of quantifying tumor size and evaluating the efficacy of cancer therapy. The most significant alterations that we could find in the ctDNA of ovarian cancer patients-such as chromosomal instability, somatic mutations, and methylation-are discussed in this review. Additionally, we talk about the utility of ctDNA in diagnosis, prognosis, and therapy response prediction for these patients.
    Keywords:  chromosomal instability; ctDNA; methylation; ovarian cancer; somatic mutations
    DOI:  https://doi.org/10.3390/cancers16183117
  5. Cell Rep Methods. 2024 Sep 25. pii: S2667-2375(24)00244-3. [Epub ahead of print] 100866
    Mimicking and analyzing the tumor microenvironment.
    Roxane Crouigneau, Yan-Fang Li, Jamie Auxillos, Eliana Goncalves-Alves, Rodolphe Marie, Albin Sandelin, Stine Falsig Pedersen.
      The tumor microenvironment (TME) is increasingly appreciated to play a decisive role in cancer development and response to therapy in all solid tumors. Hypoxia, acidosis, high interstitial pressure, nutrient-poor conditions, and high cellular heterogeneity of the TME arise from interactions between cancer cells and their environment. These properties, in turn, play key roles in the aggressiveness and therapy resistance of the disease, through complex reciprocal interactions between the cancer cell genotype and phenotype, and the physicochemical and cellular environment. Understanding this complexity requires the combination of sophisticated cancer models and high-resolution analysis tools. Models must allow both control and analysis of cellular and acellular TME properties, and analyses must be able to capture the complexity at high depth and spatial resolution. Here, we review the advantages and limitations of key models and methods in order to guide further TME research and outline future challenges.
    Keywords:  CP: Biotechnology; CP: Cancer biology; cancer; heterogeneity; metabolism; microfluidics; organoids; tumor microenvironment; tumor models
    DOI:  https://doi.org/10.1016/j.crmeth.2024.100866
  6. Cancer Cell. 2024 Sep 20. pii: S1535-6108(24)00349-0. [Epub ahead of print]
    Spatial oncology: Translating contextual biology to the clinic.
    Dennis Gong, Jeanna M Arbesfeld-Qiu, Ella Perrault, Jung Woo Bae, William L Hwang.
      Microscopic examination of cells in their tissue context has been the driving force behind diagnostic histopathology over the past two centuries. Recently, the rise of advanced molecular biomarkers identified through single cell profiling has increased our understanding of cellular heterogeneity in cancer but have yet to significantly impact clinical care. Spatial technologies integrating molecular profiling with microenvironmental features are poised to bridge this translational gap by providing critical in situ context for understanding cellular interactions and organization. Here, we review how spatial tools have been used to study tumor ecosystems and their clinical applications. We detail findings in cell-cell interactions, microenvironment composition, and tissue remodeling for immune evasion and therapeutic resistance. Additionally, we highlight the emerging role of multi-omic spatial profiling for characterizing clinically relevant features including perineural invasion, tertiary lymphoid structures, and the tumor-stroma interface. Finally, we explore strategies for clinical integration and their augmentation of therapeutic and diagnostic approaches.
    DOI:  https://doi.org/10.1016/j.ccell.2024.09.001
  7. Cancer Discov. 2024 Sep 30.
    Early detection of ovarian cancer using cell-free DNA fragmentomes and protein biomarkers.
    Jamie E Medina, Akshaya V Annapragada, Pien Lof, Sarah Short, Adrianna L Bartolomucci, Dimitrios Mathios, Shashikant Koul, Noushin Niknafs, Michael Noe, Zachariah H Foda, Daniel C Bruhm, Carolyn Hruban, Nicholas A Vulpescu, Euihye Jung, Renu Dua, Jenna V Canzoniero, Stephen Cristiano, Vilmos Adleff, Heather Symecko, Daan van den Broek, Lori J Sokoll, Stephen B Baylin, Michael F Press, Dennis J Slamon, Gottfried E Konecny, Christina Therkildsen, Beatriz Carvalho, Gerrit A Meijer, Claus Lindbjerg Andersen, Susan M Domchek, Ronny Drapkin, Robert B Scharpf, Jillian Phallen, Christine A R Lok, Victor E Velculescu.
      Ovarian cancer is a leading cause of death for women worldwide in part due to ineffective screening methods. In this study, we used whole-genome cell-free DNA (cfDNA) fragmentome and protein biomarker (CA-125 and HE4) analyses to evaluate 591 women with ovarian cancer, benign adnexal masses, or without ovarian lesions. Using a machine learning model with the combined features, we detected ovarian cancer with specificity >99% and sensitivity of 72%, 69%, 87%, and 100% for stages I-IV, respectively. At the same specificity, CA-125 alone detected 34%, 62%, 63%, and 100% of ovarian cancers for stages I-IV. Our approach differentiated benign masses from ovarian cancers with high accuracy (AUC=0.88, 95% CI=0.83-0.92). These results were validated in an independent population. These findings show that integrated cfDNA fragmentome and protein analyses detect ovarian cancers with high performance, enabling a new accessible approach for noninvasive ovarian cancer screening and diagnostic evaluation.
    DOI:  https://doi.org/10.1158/2159-8290.CD-24-0393
  8. Nat Commun. 2024 Oct 05. 15(1): 8641
    Pre-ciliated tubal epithelial cells are prone to initiation of high-grade serous ovarian carcinoma.
    Andrea Flesken-Nikitin, Coulter Q Ralston, Dah-Jiun Fu, Andrea J De Micheli, Daryl J Phuong, Blaine A Harlan, Christopher S Ashe, Amanda P Armstrong, David W McKellar, Sangeeta Ghuwalewala, Lora H Ellenson, John C Schimenti, Benjamin D Cosgrove, Alexander Yu Nikitin.
      The distal region of the uterine (Fallopian) tube is commonly associated with high-grade serous carcinoma (HGSC), the predominant and most aggressive form of ovarian or extra-uterine cancer. Specific cell states and lineage dynamics of the adult tubal epithelium (TE) remain insufficiently understood, hindering efforts to determine the cell of origin for HGSC. Here, we report a comprehensive census of cell types and states of the mouse uterine tube. We show that distal TE cells expressing the stem/progenitor cell marker Slc1a3 can differentiate into both secretory (Ovgp1+) and ciliated (Fam183b+) cells. Inactivation of Trp53 and Rb1, whose pathways are commonly altered in HGSC, leads to elimination of targeted Slc1a3+ cells by apoptosis, thereby preventing their malignant transformation. In contrast, pre-ciliated cells (Krt5+, Prom1+, Trp73+) remain cancer-prone and give rise to serous tubal intraepithelial carcinomas and overt HGSC. These findings identify transitional pre-ciliated cells as a cancer-prone cell state and point to pre-ciliation mechanisms as diagnostic and therapeutic targets.
    DOI:  https://doi.org/10.1038/s41467-024-52984-1
  9. J Natl Cancer Inst. 2024 Oct 01. pii: djae200. [Epub ahead of print]
    When is prostate cancer really cancer?
    CANCER-GG1 Writing Group
      Prostate cancer (PC) is a major cause of cancer-related deaths worldwide, with far more diagnoses than deaths annually. Recent discussions have challenged whether Grade Group 1 (GG1) PC should be labeled "cancer" due to its indolent nature. To address this question, an international symposium convened stakeholders from various fields. We summarize key discussion points: autopsy studies reveal GG1 is so common in aging males as to be perhaps a normal aspect of aging. Pure GG1 has no capacity to metastasize. Modern diagnostic pathways focus on detecting higher-grade disease, explicitly omitting biopsy if GG 2 or higher is not suspected, so GG1 has effectively become an "incidentaloma." Recent spatial transcriptomics of prostate sections identifies a continuum of genomic changes-including alterations characteristic of malignancy in histologically normal regions, so the designation of cancer based entirely on conventional pathology findings increasingly seems arbitrary at least to an extent. Pathologists discussed heterogeneity and diagnostic challenges, suggesting "acinar neoplasm" as one possible alternative label. GG1 should not be considered "normal," and absolutely requires ongoing active surveillance; whether patients would adhere to surveillance absent a cancer diagnosis is unknown. Patient perspectives highlighted the adverse effects of overtreatment and the burden of a cancer diagnosis. The anticipated impact on screening and treatment varies across health-care systems, but many believe public health would on balance greatly improve if GG1-along with lesions in other organs with no capacity to cause symptoms or threaten life-were labeled something other than "cancer." Ultimately, our goal is to reduce PC mortality while minimizing harms associated with both overdiagnosis and overtreatment.
    DOI:  https://doi.org/10.1093/jnci/djae200
  10. Nat Genet. 2024 Oct 02.
    Aneuploidy as a driver of human cancer.
    Eran Sdeor, Hajime Okada, Ron Saad, Tal Ben-Yishay, Uri Ben-David.
      Aneuploidy, an abnormal chromosome composition, is a major contributor to cancer development and progression and an important determinant of cancer therapeutic responses and clinical outcomes. Despite being recognized as a hallmark of human cancer, the exact role of aneuploidy as a 'driver' of cancer is still largely unknown. Identifying the specific genetic elements that underlie the recurrence of common aneuploidies remains a major challenge of cancer genetics. In this Review, we discuss recurrent aneuploidies and their function as drivers of tumor development. We then delve into the context-dependent identification and functional characterization of the driver genes underlying driver aneuploidies and examine emerging strategies to uncover these driver genes using cancer genomics data and cancer models. Lastly, we explore opportunities for targeting driver aneuploidies in cancer by leveraging the functional consequences of these common genetic alterations.
    DOI:  https://doi.org/10.1038/s41588-024-01916-2
  11. Cancer Discov. 2024 Oct 04. 14(10): 1783-1809
    The Epigenetic Hallmarks of Cancer.
    Manel Esteller, Mark A Dawson, Cigall Kadoch, Feyruz V Rassool, Peter A Jones, Stephen B Baylin.
      Cancer is a complex disease in which several molecular and cellular pathways converge to foster the tumoral phenotype. Notably, in the latest iteration of the cancer hallmarks, "nonmutational epigenetic reprogramming" was newly added. However, epigenetics, much like genetics, is a broad scientific area that deserves further attention due to its multiple roles in cancer initiation, progression, and adaptive nature. Herein, we present a detailed examination of the epigenetic hallmarks affected in human cancer, elucidating the pathways and genes involved, and dissecting the disrupted landscapes for DNA methylation, histone modifications, and chromatin architecture that define the disease. Significance: Cancer is a disease characterized by constant evolution, spanning from its initial premalignant stages to the advanced invasive and disseminated stages. It is a pathology that is able to adapt and survive amidst hostile cellular microenvironments and diverse treatments implemented by medical professionals. The more fixed setup of the genetic structure cannot fully provide transformed cells with the tools to survive but the rapid and plastic nature of epigenetic changes is ready for the task. This review summarizes the epigenetic hallmarks that define the ecological success of cancer cells in our bodies.
    DOI:  https://doi.org/10.1158/2159-8290.CD-24-0296
  12. Biomark Res. 2024 Sep 27. 12(1): 110
    Single-cell sequencing to multi-omics: technologies and applications.
    Xiangyu Wu, Xin Yang, Yunhan Dai, Zihan Zhao, Junmeng Zhu, Hongqian Guo, Rong Yang.
      Cells, as the fundamental units of life, contain multidimensional spatiotemporal information. Single-cell RNA sequencing (scRNA-seq) is revolutionizing biomedical science by analyzing cellular state and intercellular heterogeneity. Undoubtedly, single-cell transcriptomics has emerged as one of the most vibrant research fields today. With the optimization and innovation of single-cell sequencing technologies, the intricate multidimensional details concealed within cells are gradually unveiled. The combination of scRNA-seq and other multi-omics is at the forefront of the single-cell field. This involves simultaneously measuring various omics data within individual cells, expanding our understanding across a broader spectrum of dimensions. Single-cell multi-omics precisely captures the multidimensional aspects of single-cell transcriptomes, immune repertoire, spatial information, temporal information, epitopes, and other omics in diverse spatiotemporal contexts. In addition to depicting the cell atlas of normal or diseased tissues, it also provides a cornerstone for studying cell differentiation and development patterns, disease heterogeneity, drug resistance mechanisms, and treatment strategies. Herein, we review traditional single-cell sequencing technologies and outline the latest advancements in single-cell multi-omics. We summarize the current status and challenges of applying single-cell multi-omics technologies to biological research and clinical applications. Finally, we discuss the limitations and challenges of single-cell multi-omics and potential strategies to address them.
    Keywords:  Computational biology; Metabolome; Microbiome; Proteomics; Single-cell multi-omics; Spatial transcriptomics; scBCR-seq; scRNA-seq; scTCR-seq
    DOI:  https://doi.org/10.1186/s40364-024-00643-4
  13. Sci Rep. 2024 09 30. 14(1): 22591
    Reconstructing oral cavity tumor evolution through brush biopsy.
    Evit John, Tom Lesluyes, Toby M Baker, Maxime Tarabichi, Ann Gillenwater, Jennifer R Wang, Peter Van Loo, Xiao Zhao.
      Oral potentially malignant disorders (OPMDs) with genomic alterations have a heightened risk of evolving into oral squamous cell carcinoma (OSCC). Currently, genomic data are typically obtained through invasive tissue biopsy. However, brush biopsy is a non-invasive method that has been utilized for identifying dysplastic cells in OPMD but its effectiveness in reflecting the genomic landscape of OPMDs remains uncertain. This pilot study investigates the potential of brush biopsy samples in accurately reconstructing the genomic profile and tumor evolution in a patient with both OPMD and OSCC. We analyzed single nucleotide variants (SNVs), copy number aberrations (CNAs), and subclonal architectures in paired tissue and brush biopsy samples. The results showed that brush biopsy effectively captured 90% of SNVs and had similar CNA profiles as those seen in its paired tissue biopsies in all lesions. It was specific, as normal buccal mucosa did not share these genomic alterations. Interestingly, brush biopsy revealed shared SNVs and CNAs between the distinct OPMD and OSCC lesions from the same patient, indicating a common ancestral origin. Subclonal reconstruction confirmed this shared ancestry, followed by divergent evolution of the lesions. These findings highlight the potential of brush biopsies in accurately representing the genomic profile of OPL and OSCC, proving insight into reconstructing tumor evolution.
    DOI:  https://doi.org/10.1038/s41598-024-72946-3
  14. J Clin Med. 2024 Sep 13. pii: 5445. [Epub ahead of print]13(18):
    Screening Strategies to Improve Early Diagnosis in Endometrial Cancer.
    Silvia Cabrera, Irene de la Calle, Sonia Baulies, Antonio Gil-Moreno, Eva Colas.
      Endometrial cancer is the most common gynecological malignancy in high-income countries and the sixth most common cancer in women. Overall incidence has risen in the last few decades as a consequence of the increase in the prevalence of its risk factors, mainly obesity and the aging of the population, and although diagnoses have increased across all age groups, the incidence rates have doubled in women under the age of 40 years. The survival rates of endometrial cancer are highly dependent on its stage at diagnosis, bringing to the fore the importance of early diagnosis. The aim of a screening strategy in this type of tumor should be to detect the disease in the pre-invasive or early stage (before developing myometrial invasion), which would improve cure rates, reduce the morbidity associated with aggressive treatment and offer uterus-sparing management options for younger women. The ideal screening tool in this scenario would be a minimally invasive, inexpensive and easy-to-perform test or auto-test, which could be implemented in a routine gynecologic checkup of patients at-risk or in the general adult population. In this comprehensive review, we aim to define the populations at higher risk of developing endometrial cancer, to assess the performance of current diagnostic tools when used in a screening setting and to discuss the accuracy of new molecular screening strategies.
    Keywords:  diagnosis; endometrial cancer; high-risk population; screening
    DOI:  https://doi.org/10.3390/jcm13185445
  15. Cancers (Basel). 2024 Sep 11. pii: 3129. [Epub ahead of print]16(18):
    The Role of ctDNA and Liquid Biopsy in the Diagnosis and Monitoring of Head and Neck Cancer: Towards Precision Medicine.
    Sami I Nassar, Amber Suk, Shaun A Nguyen, Dauren Adilbay, John Pang, Cherie-Ann O Nathan.
      Recent data have shown a continued rise in the worldwide annual incidence and mortality rates of head and neck cancers. The present standard for diagnosis and monitoring for disease recurrence or progression involves clinical examination, imaging, and invasive biopsy techniques of lesions suspected of being malignant. In addition to limitations relating to cost, time, and patient discomfort, these methodologies have inherent inaccuracies for detecting recurrence. In view of these limitations, the analysis of patient bodily fluid samples via liquid biopsy proposes a cost-effective and convenient alternative, which provides insight on the biogenetic and biomolecular underpinnings of oncologic disease processes. The monitoring of biomarkers for head and neck cancer via liquid biopsy, including circulating tumor DNA, circulating tumor cells, and circulating cell-free RNA, has shown clinical utility in the screening, diagnosis, prognostication, and monitoring of patients with various forms of head and neck cancer. The present review will provide an update on the current literature examining the use of liquid biopsy in head and neck cancer care and the clinical applicability of potential biomarkers, with a focus on viral and non-viral circulating tumor DNA. Possible future avenues for research to address specific shortcomings of liquid biopsy will be discussed.
    Keywords:  cancer biomarkers; ctDNA; genetic mutations; genomic sequencing; head and neck cancer; liquid biopsy; nasopharyngeal carcinoma; oropharyngeal carcinoma; squamous cell carcinoma
    DOI:  https://doi.org/10.3390/cancers16183129
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