bims-tumhet Biomed News
on Tumor Heterogeneity
Issue of 2022–11–06
twelve papers selected by
Sergio Marchini, Humanitas Research
  1. Spatial transcriptomics technology in cancer research.
  2. Uterine lavage identifies cancer mutations and increased TP53 somatic mutation burden in individuals with ovarian cancer.
  3. Emerging strategies: PARP inhibitors in combination with immune checkpoint blockade in BRCA1 and BRCA2 mutation-associated and triple-negative breast cancer.
  4. MYC promotes immune-suppression in triple-negative breast cancer via inhibition of interferon signaling.
  5. Accidentals of the DNA Symphony.
  6. MethBank 4.0: an updated database of DNA methylation across a variety of species.
  7. Aberrantly hypermethylated ARID1B is a novel biomarker and potential therapeutic target of colon adenocarcinoma.
  8. Fundamental and practical approaches for single-cell ATAC-seq analysis.
  9. Pan-cancer single-cell analysis reveals the heterogeneity and plasticity of cancer-associated fibroblasts in the tumor microenvironment.
  10. The DNA damage induced immune response: Implications for cancer therapy.
  11. De novo analysis of bulk RNA-seq data at spatially resolved single-cell resolution.
  12. Microsatellite instability detection in breast cancer using drop-off droplet digital PCR.
  1. Front Oncol. 2022 ;12 1019111
    Spatial transcriptomics technology in cancer research.
    Qichao Yu, Miaomiao Jiang, Liang Wu.
      In recent years, spatial transcriptomics (ST) technologies have developed rapidly and have been widely used in constructing spatial tissue atlases and characterizing spatiotemporal heterogeneity of cancers. Currently, ST has been used to profile spatial heterogeneity in multiple cancer types. Besides, ST is a benefit for identifying and comprehensively understanding special spatial areas such as tumor interface and tertiary lymphoid structures (TLSs), which exhibit unique tumor microenvironments (TMEs). Therefore, ST has also shown great potential to improve pathological diagnosis and identify novel prognostic factors in cancer. This review presents recent advances and prospects of applications on cancer research based on ST technologies as well as the challenges.
    Keywords:  prognostic factor; spatial heterogeneity; spatial transcriptomics (ST); tertiary lymphoid structure (TLS); tumor interface; tumor microenvironment
    DOI:  https://doi.org/10.3389/fonc.2022.1019111
  2. Cancer Res Commun. 2022 Oct;2(10): 1282-1292
    Uterine lavage identifies cancer mutations and increased TP53 somatic mutation burden in individuals with ovarian cancer.
    Talayeh S Ghezelayagh, Brendan F Kohrn, Jeanne Fredrickson, Enna Manhardt, Marc R Radke, Ronit Katz, Heidi J Gray, Renata R Urban, Kathryn P Pennington, John B Liao, Kemi M Doll, Elise J Simons, Jennifer K Burzawa, Barbara A Goff, Paul Speiser, Elizabeth M Swisher, Barbara M Norquist, Rosa Ana Risques.
      Current screening methods for ovarian cancer (OC) have failed to demonstrate a significant reduction in mortality. Uterine lavage combined with TP53 ultra-deep sequencing for the detection of disseminated OC cells has emerged as a promising tool, but this approach has not been tested for early-stage disease or non-serous histologies. In addition, lavages carry multiple background mutations, the significance of which is poorly understood. Uterine lavage was collected preoperatively in 34 patients undergoing surgery for suspected ovarian malignancy including 14 patients with benign disease and 20 patients with OC (6 non-serous and 14 high grade serous-like (serous)). Ultra-deep duplex sequencing (~3000x) with a panel of common OC genes identified the tumor mutation in 33% of non-serous (all early stage) and in 79% of serous cancers (including four early stage). In addition, all lavages carried multiple somatic mutations (average of 25 mutations per lavage), more than half of which corresponded to common cancer driver mutations. Driver mutations in KRAS, PIK3CA, PTEN, PPP2R1A and ARID1A presented as larger clones than non-driver mutations and with similar frequency in lavages from patients with and without OC, indicating prevalent somatic evolution in all patients. Driver TP53 mutations, however, presented as significantly larger clones and with higher frequency in lavages from individuals with OC, suggesting that TP53-specific clonal expansions are linked to ovarian cancer development. Our results demonstrate that lavages capture cancer cells, even from early-stage cancers, as well as other clonal expansions and support further exploration of TP53 mutation burden as a potential OC risk factor.
    Keywords:  Uterine lavage; clonal expansions; ovarian cancer; somatic evolution
    DOI:  https://doi.org/10.1158/2767-9764.crc-22-0314
  3. Breast Cancer Res Treat. 2022 Nov 01.
    Emerging strategies: PARP inhibitors in combination with immune checkpoint blockade in BRCA1 and BRCA2 mutation-associated and triple-negative breast cancer.
    Tanya Gupta, Shaveta Vinayak, Melinda Telli.
      Poly (adenosine diphosphate-ribose) polymerase (PARP) inhibitor monotherapy in germline BRCA1 and BRCA2 mutation-associated metastatic breast cancer is a well-tolerated and an effective therapeutic strategy, however, the durability of response can be limited. Checkpoint inhibitors targeting the PD-1/PD-L1 axis as monotherapy in metastatic triple-negative breast cancer (mTNBC) have a limited role due to low response rates, but are capable of long, durable responses. Combination PARP inhibition with checkpoint blockade is an emerging area of investigation with potential synergy to produce robust responses with durability. Mechanistically, PARP inhibition activates the stimulator of interferon gene (STING) pathway to promote dendritic cell and T lymphocyte recruitment, increases tumor neoantigens, and upregulates PD-L1 expression to increase the immunogenicity of the tumor and thereby potentially enhance responses to immunotherapy. Several clinical trials have reported early results on PARP inhibitor and PD-1/PD-L1 checkpoint inhibitor combinations. All studies have shown safety and tolerability of this combination regimen. In advanced breast cancer associated with a germline BRCA1 or BRCA2 mutation, response rates have been high and similar to what is observed with PARP inhibitor monotherapy. Additional follow-up is needed to see if combination with a checkpoint inhibitor can lead to a clinically meaningful extension of durability of response in patients with germline mutations in BRCA1 and BRCA2. In unselected mTNBC in the 1st-3rd line setting, response rates of combined PARP inhibitor and PD-1/PD-L1 inhibitors have ranged from 18-21%, with higher rates of response among those with alterations in homologous recombination DNA repair pathway genes. Multiple ongoing studies will report additional data on combinations of PARP inhibitors and checkpoint blockade in the future and this combination strategy remains an active area of investigation.
    Keywords:  BRCA1; BRCA2; Checkpoint inhibitor; Homologous recombination deficiency; PARP inhibitor; PD-1; PD-L1; STING pathway
    DOI:  https://doi.org/10.1007/s10549-022-06780-4
  4. Nat Commun. 2022 Nov 02. 13(1): 6579
    MYC promotes immune-suppression in triple-negative breast cancer via inhibition of interferon signaling.
    Dario Zimmerli, Chiara S Brambillasca, Francien Talens, Jinhyuk Bhin, Renske Linstra, Lou Romanens, Arkajyoti Bhattacharya, Stacey E P Joosten, Ana Moises Da Silva, Nuno Padrao, Max D Wellenstein, Kelly Kersten, Mart de Boo, Maurits Roorda, Linda Henneman, Roebi de Bruijn, Stefano Annunziato, Eline van der Burg, Anne Paulien Drenth, Catrin Lutz, Theresa Endres, Marieke van de Ven, Martin Eilers, Lodewyk Wessels, Karin E de Visser, Wilbert Zwart, Rudolf S N Fehrmann, Marcel A T M van Vugt, Jos Jonkers.
      The limited efficacy of immune checkpoint inhibitor treatment in triple-negative breast cancer (TNBC) patients is attributed to sparse or unresponsive tumor-infiltrating lymphocytes, but the mechanisms that lead to a therapy resistant tumor immune microenvironment are incompletely known. Here we show a strong correlation between MYC expression and loss of immune signatures in human TNBC. In mouse models of TNBC proficient or deficient of breast cancer type 1 susceptibility gene (BRCA1), MYC overexpression dramatically decreases lymphocyte infiltration in tumors, along with immune signature remodelling. MYC-mediated suppression of inflammatory signalling induced by BRCA1/2 inactivation is confirmed in human TNBC cell lines. Moreover, MYC overexpression prevents the recruitment and activation of lymphocytes in both human and mouse TNBC co-culture models. Chromatin-immunoprecipitation-sequencing reveals that MYC, together with its co-repressor MIZ1, directly binds promoters of multiple interferon-signalling genes, resulting in their downregulation. MYC overexpression thus counters tumor growth inhibition by a Stimulator of Interferon Genes (STING) agonist via suppressing induction of interferon signalling. Together, our data reveal that MYC suppresses innate immunity and facilitates tumor immune escape, explaining the poor immunogenicity of MYC-overexpressing TNBCs.
    DOI:  https://doi.org/10.1038/s41467-022-34000-6
  5. Cancer Res. 2022 Nov 02. 82(21): 3880-3881
    Accidentals of the DNA Symphony.
    Anjui Wu, Gerhardt Attard.
      Cancer epigenome profiling such as DNA methylation (5mC) and DNA hydroxymethylation (5hmC) is emerging as a sensitive approach for cancer detection and risk stratification. 5mC modification has been widely described in many cancer types including prostate cancer; however, the 5hmC landscape is yet to be explored. In this issue of Cancer Research, Sjöström and colleagues have comprehensively incorporated genomic, transcriptomic, and epigenomic, including 5hmC, data to interrogate the molecular evolution of prostate cancer. See related article by Sjöström et al., p. 3888.
    DOI:  https://doi.org/10.1158/0008-5472.CAN-22-2750
  6. Nucleic Acids Res. 2022 Nov 01. pii: gkac969. [Epub ahead of print]
    MethBank 4.0: an updated database of DNA methylation across a variety of species.
    Mochen Zhang, Wenting Zong, Dong Zou, Guoliang Wang, Wei Zhao, Fei Yang, Song Wu, Xinran Zhang, Xutong Guo, Yingke Ma, Zhuang Xiong, Zhang Zhang, Yiming Bao, Rujiao Li.
      DNA methylation, as the most intensively studied epigenetic mark, regulates gene expression in numerous biological processes including development, aging, and disease. With the rapid accumulation of whole-genome bisulfite sequencing data, integrating, archiving, analyzing, and visualizing those data becomes critical. Since its first publication in 2015, MethBank has been continuously updated to include more DNA methylomes across more diverse species. Here, we present MethBank 4.0 (https://ngdc.cncb.ac.cn/methbank/), which reports an increase of 309% in data volume, with 1449 single-base resolution methylomes of 23 species, covering 236 tissues/cell lines and 15 biological contexts. Value-added information, such as more rigorous quality evaluation, more standardized metadata, and comprehensive downstream annotations have been integrated in the new version. Moreover, expert-curated knowledge modules of featured differentially methylated genes associated with biological contexts and methylation analysis tools have been incorporated as new components of MethBank. In addition, MethBank 4.0 is equipped with a series of new web interfaces to browse, search, and visualize DNA methylation profiles and related information. With all these improvements, we believe the updated MethBank 4.0 will serve as a fundamental resource to provide a wide range of data services for the global research community.
    DOI:  https://doi.org/10.1093/nar/gkac969
  7. Front Genet. 2022 ;13 914354
    Aberrantly hypermethylated ARID1B is a novel biomarker and potential therapeutic target of colon adenocarcinoma.
    Salem Baldi, Yun He, Igor Ivanov, Hassan Khamgan, Mohammed Safi, Mohammed Alradhi, Abdullah Shopit, Abdullah Al-Danakh, Murad Al-Nusaif, Yaping Gao, Hui Tian.
      Background and Objective: Understanding the tumor microenvironment (TME) and immune cell infiltration (ICI) may help guide immunotherapy efforts for colon cancer (COAD). However, whether ARID1B is truly regulated by hypermethylation or linked to immune infiltration remains unknown. The current work focused on the ARID1B gene expression and methylation in COAD, as well as its relation with ICI. Methods and Results: Multiple tools based on TCGA were used to analyze the differences in the expression of the ARID1B gene, DNA methylation, and its association with various clinicopathological features, somatic mutations, copy number variation, and the prognosis of patients with COAD. According to the analysis results, patients with high mRNA, low methylation levels showed better overall survival than patients with low mRNA, high methylation levels. The correlation analysis of immune cell infiltration and immune checkpoint gene expression showed that the infiltration rates of the main ICI subtypes, cancer-associated fibroblast, and myeloid cells were significantly enriched and correlated with ARID1B in COAD. An association between ARID1B expression and immune infiltration in COAD was found by correlating ICI indicators with ARID1B expression in the immune cell composition of the COAD microenvironment. Notably, M2 chemokines were related to ARID1B expression, while M1 chemokines were not. Conclusion: This study provided evidence that ARID1B may have a role in the pathogenesis of COAD. The specific underlying mechanisms that could be responsible for ARID1B's downregulation in COAD will need to be investigated in the future.
    Keywords:  ARID1B; Colon adenocarcinoma; DNA Methylation; Immune Cell Infiltration; RNA expression; TCGA
    DOI:  https://doi.org/10.3389/fgene.2022.914354
  8. Abiotech. 2022 Sep;3(3): 212-223
    Fundamental and practical approaches for single-cell ATAC-seq analysis.
    Peiyu Shi, Yage Nie, Jiawen Yang, Weixing Zhang, Zhongjie Tang, Jin Xu.
      Assays for transposase-accessible chromatin through high-throughput sequencing (ATAC-seq) are effective tools in the study of genome-wide chromatin accessibility landscapes. With the rapid development of single-cell technology, open chromatin regions that play essential roles in epigenetic regulation have been measured at the single-cell level using single-cell ATAC-seq approaches. The application of scATAC-seq has become as popular as that of scRNA-seq. However, owing to the nature of scATAC-seq data, which are sparse and noisy, processing the data requires different methodologies and empirical experience. This review presents a practical guide for processing scATAC-seq data, from quality evaluation to downstream analysis, for various applications. In addition to the epigenomic profiling from scATAC-seq, we also discuss recent studies in which the function of non-coding variants has been investigated based on cell type-specific cis-regulatory elements and how to use the by-product genetic information obtained from scATAC-seq to infer single-cell copy number variants and trace cell lineage. We anticipate that this review will assist researchers in designing and implementing scATAC-seq assays to facilitate research in diverse fields.
    Keywords:  Bioinformatic tools; Chromatin accessibility; Data analysis; scATAC-seq
    DOI:  https://doi.org/10.1007/s42994-022-00082-5
  9. Nat Commun. 2022 Nov 04. 13(1): 6619
    Pan-cancer single-cell analysis reveals the heterogeneity and plasticity of cancer-associated fibroblasts in the tumor microenvironment.
    Han Luo, Xuyang Xia, Li-Bin Huang, Hyunsu An, Minyuan Cao, Gyeong Dae Kim, Hai-Ning Chen, Wei-Han Zhang, Yang Shu, Xiangyu Kong, Zhixiang Ren, Pei-Heng Li, Yang Liu, Huairong Tang, Ronghao Sun, Chao Li, Bing Bai, Weiguo Jia, Yi Liu, Wei Zhang, Li Yang, Yong Peng, Lunzhi Dai, Hongbo Hu, Yong Jiang, Yiguo Hu, Jingqiang Zhu, Hong Jiang, Zhihui Li, Carlos Caulin, Jihwan Park, Heng Xu.
      Cancer-associated fibroblasts (CAFs) are the predominant components of the tumor microenvironment (TME) and influence cancer hallmarks, but without systematic investigation on their ubiquitous characteristics across different cancer types. Here, we perform pan-cancer analysis on 226 samples across 10 solid cancer types to profile the TME at single-cell resolution, illustrating the commonalities/plasticity of heterogenous CAFs. Activation trajectory of the major CAF types is divided into three states, exhibiting distinct interactions with other cell components, and relating to prognosis of immunotherapy. Moreover, minor CAF components represent the alternative origin from other TME components (e.g., endothelia and macrophages). Particularly, the ubiquitous presentation of endothelial-to-mesenchymal transition CAF, which may interact with proximal SPP1+ tumor-associated macrophages, is implicated in endothelial-to-mesenchymal transition and survival stratifications. Our study comprehensively profiles the shared characteristics and dynamics of CAFs, and highlight their heterogeneity and plasticity across different cancer types. Browser of integrated pan-cancer single-cell information is available at https://gist-fgl.github.io/sc-caf-atlas/ .
    DOI:  https://doi.org/10.1038/s41467-022-34395-2
  10. DNA Repair (Amst). 2022 Oct 03. pii: S1568-7864(22)00142-2. [Epub ahead of print]120 103409
    The DNA damage induced immune response: Implications for cancer therapy.
    Eliana M Barros, Stuart A McIntosh, Kienan I Savage.
      Genomic instability is a hallmark of tumourigenesis, influencing tumour development and progression. In particular, defects in the DNA damage response (DDR) have been extensively investigated and are known to shape therapeutic response. Since immune checkpoint blockade (ICB) therapy has been approved for treatment of tumours with defective mismatch repair the interplay between DDR pathway deficiency and the immune system has been of particular interest. The cGAS/STING signalling pathway has recently emerged as a key mediator of inflammation in response to DNA damage.This was identified through transcriptional profiling of BRCA1/2 deficient breast cancers and Fanconi Anaemia (FA) patient bone marrow, revealing a common transcriptional subgroup associated with BRCA1/2 and FA deficiency characterised by upregulation of innate immune signalling genes. Additionally, it is now apparent that the DNA damage arising from a multitude of DNA repair defects and DNA damage induced by some classical chemotherapies/radiation also has the ability to induce an innate immune response mediated by cGAS/STING activation. Here we review the role of intrinsic and extrinsic DNA damage in mediating immune activation and its context within tumourigenesis, as well as the potential therapeutic opportunities it represents for the treatment of cancer, such as combining DNA damaging agents with immunotherapies.
    Keywords:  DNA-damage cGAS STING innate immune
    DOI:  https://doi.org/10.1016/j.dnarep.2022.103409
  11. Nat Commun. 2022 Oct 30. 13(1): 6498
    De novo analysis of bulk RNA-seq data at spatially resolved single-cell resolution.
    Jie Liao, Jingyang Qian, Yin Fang, Zhuo Chen, Xiang Zhuang, Ningyu Zhang, Xin Shao, Yining Hu, Penghui Yang, Junyun Cheng, Yang Hu, Lingqi Yu, Haihong Yang, Jinlu Zhang, Xiaoyan Lu, Li Shao, Dan Wu, Yue Gao, Huajun Chen, Xiaohui Fan.
      Uncovering the tissue molecular architecture at single-cell resolution could help better understand organisms' biological and pathological processes. However, bulk RNA-seq can only measure gene expression in cell mixtures, without revealing the transcriptional heterogeneity and spatial patterns of single cells. Herein, we introduce Bulk2Space ( https://github.com/ZJUFanLab/bulk2space ), a deep learning framework-based spatial deconvolution algorithm that can simultaneously disclose the spatial and cellular heterogeneity of bulk RNA-seq data using existing single-cell and spatial transcriptomics references. The use of bulk transcriptomics to validate Bulk2Space unveils, in particular, the spatial variance of immune cells in different tumor regions, the molecular and spatial heterogeneity of tissues during inflammation-induced tumorigenesis, and spatial patterns of novel genes in different cell types. Moreover, Bulk2Space is utilized to perform spatial deconvolution analysis on bulk transcriptome data from two different mouse brain regions derived from our in-house developed sequencing approach termed Spatial-seq. We have not only reconstructed the hierarchical structure of the mouse isocortex but also further annotated cell types that were not identified by original methods in the mouse hypothalamus.
    DOI:  https://doi.org/10.1038/s41467-022-34271-z
  12. Oncogene. 2022 Nov 03.
    Microsatellite instability detection in breast cancer using drop-off droplet digital PCR.
    Khadidja Zeyneb Klouch, Marc-Henri Stern, Olfa Trabelsi-Grati, Nicolas Kiavue, Luc Cabel, Amanda Bortolini Silveira, Caroline Hego, Aurore Rampanou, Tatiana Popova, Guillaume Bataillon, Sarah Nasr, Charlotte Proudhon, Marc Michel, Victor Renault, Julien Masliah Planchon, Anne Vincent-Salomon, Jean-Yves Pierga, Ivan Bieche, Shufang Renault, François-Clément Bidard.
      The use of conventional methods (immunohistochemistry, pentaplex PCR) for detecting microsatellite instability (MSI), a predictive biomarker of immunotherapy efficacy, is debated for cancers with low MSI prevalence, such as breast cancer (BC). We developed two multiplex drop-off droplet digital PCR (ddPCR) assays targeting four microsatellites, initially identified from public BC whole-genome sequencing dataset. Performances of the assays were investigated and 352 tumor DNA and 28 circulating cell-free DNA from BC patients, with unknown MSI status were blindly screened. Cross-validation of ddPCR MSI status with other MSI detection methods was performed. We then monitored circulating tumor DNA (ctDNA) dynamics before and during pembrolizumab immunotherapy in one patient with MSI-high (MSI-H) metastatic BC. The assays showed high analytical specificity and sensitivity (limit of detection = 0.16%). Among N = 380 samples, seven (1.8%) were found as MSI-H by ddPCR with six of them confirmed by next-generation sequencing (NGS). Specificity was 100% in N = 133 microsatellite stable BC submitted to NGS. In the patient with MSI-H metastatic BC, ctDNA monitoring revealed an early decrease of microsatellite mutant allelic frequencies during immunotherapy. These results demonstrated MSI detection by ddPCR, a non-invasive, fast and cost-effective approach, allowing for large pre-screening of BC patients who may benefit from immunotherapy.
    DOI:  https://doi.org/10.1038/s41388-022-02504-6
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