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| Open AccessTrajectory of immune evasion and cancer progression in hepatocellular carcinoma
In order to design cancer immune therapies, it is important to understand how tumours evade the immune response that is mounted against them. Authors here analyse the distribution and properties of immune cells in hepatocellular carcinoma and describe a progressive tumour-immune co-evolution programme from early to late stage cancer.
- Phuong H. D. Nguyen
- , Martin Wasser
- & Valerie Chew
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Article
| Open AccessCancer stem cell regulated phenotypic plasticity protects metastasized cancer cells from ferroptosis
The contribution of breast cancer stem cells (BCSCs) to metastasis needs further elucidation. Here, the authors show that BCSCs secrete DKK1 to protect metastasizing cancer cells from ferroptosis via upregulation of SLC7A11, and further show that the combination of a ferroptosis inducer with a DKK1 inhibitor reduces metastasis.
- Mingming Wu
- , Xiao Zhang
- & Tao Zhu
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Article
| Open AccessTargeting SOX10-deficient cells to reduce the dormant-invasive phenotype state in melanoma
Mechanisms underlying tumor cell plasticity remain poorly understood. Here, the authors show the presence of a dormant-invasive SOX10- subpopulation in cutaneous melanoma that can be targeted by cIAP1/2 inhibitors.
- Claudia Capparelli
- , Timothy J. Purwin
- & Andrew E. Aplin
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Article
| Open AccessSingle-cell transcriptomics links malignant T cells to the tumor immune landscape in cutaneous T cell lymphoma
Cutaneous T cell lymphomas (CTCL) are still poorly characterised at the molecular and single-cell level. Here, the authors analyse CTCL patient samples using single-cell RNA-seq, TCR and whole-exome sequencing, revealing the molecular profiles of malignant T cells and their association with the microenvironment and clinical outcomes.
- Xiangjun Liu
- , Shanzhao Jin
- & Yang Wang
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Article
| Open AccessIntegrative molecular and clinical profiling of acral melanoma links focal amplification of 22q11.21 to metastasis
Despite acral melanoma being the most common melanoma subtype in non-White individuals, its molecular drivers remain unknown. Here, the authors integrate genomic and clinical data from 104 patients and identify late-arising focal amplifications of chr22q11.21 and LZTR1 as a key tumour promoter in this region.
- Farshad Farshidfar
- , Kahn Rhrissorrakrai
- & Ruth Halaban
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Article
| Open AccessProteomic analysis of archival breast cancer clinical specimens identifies biological subtypes with distinct survival outcomes
Protein level information enables the identification of potential biomarkers and therapeutic targets for breast cancer. Here, the authors perform proteomic analysis of 2 cohorts of breast cancer surgical specimens and identify distinct subtypes, immune features and survival outcomes.
- Karama Asleh
- , Gian Luca Negri
- & Gregg B. Morin
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Article
| Open AccessDeciphering spatial genomic heterogeneity at a single cell resolution in multiple myeloma
Osteolytic lesions (OL) are frequent in multiple myeloma (MM), but are poorly understood. Here, the authors characterise OLs in MM patient samples using single-cell RNA-seq, revealing genes that are specifically regulated in OL compared to random bone marrow aspirates and that reflect the response to induction therapy.
- Maximilian Merz
- , Almuth Maria Anni Merz
- & Jens Hillengass
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Article
| Open AccessSingle-cell chromatin accessibility landscape in kidney identifies additional cell-of-origin in heterogenous papillary renal cell carcinoma
The heterogeneity of cell-of-origin for papillary renal cell carcinoma (pRCC) remains unknown. Here, with single-cell ATAC-seq from normal human kidney cells and ATACseq profiles from pRCC samples, the authors show that pRCC can originate from kidney collecting duct principal cells and this subtype is associated with advanced pRCC.
- Qi Wang
- , Yang Zhang
- & Jingping Yang
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Article
| Open AccessSingle-cell analysis of human primary prostate cancer reveals the heterogeneity of tumor-associated epithelial cell states
The changes that prostate cancer (PCa) induces in its microenvironment are not fully understood. Here the authors use single-cell RNA-seq and organoids to characterise how the microenvironment responds to PCa, and also identify tumour-associated epithelial cell states and club cells.
- Hanbing Song
- , Hannah N. W. Weinstein
- & Franklin W. Huang
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Article
| Open AccessGenomic alterations and evolution of cell clusters in metastatic invasive micropapillary carcinoma of the breast
Invasive micropapillary carcinoma (IMPC) is a highly metastatic rare form of breast cancer but its genomic alterations are largely unknown. Here, the authors show that monoclonal metastatic ancestors share copy-number loss of PRDM16 and IGSF9 and gain of ALDH2 in primary samples from IMPC patients.
- Qianqian Shi
- , Kang Shao
- & Li Fu
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Article
| Open AccessTopographic mapping of the glioblastoma proteome reveals a triple-axis model of intra-tumoral heterogeneity
Gioblastoma tumours consist of different niches defined by histology. Here, the authors use proteomics and machine learning to assign protein expression programs to these niches, and reveal that KRAS and hypoxia are associated with drug resistance.
- K. H. Brian Lam
- , Alberto J. Leon
- & Phedias Diamandis
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Article
| Open AccessIntegrated single-cell transcriptome analysis reveals heterogeneity of esophageal squamous cell carcinoma microenvironment
The microenvironment of oesophageal squamous cell carcinomas (ESCC) is heterogeneous and can strongly impact response to treatment. Here, the authors characterize the ESCC tumour microenvironment with single-cell RNA-seq, finding CST1 + myofibroblasts with potential biological and prognostic significance as well as immunosuppression signatures.
- Huy Q. Dinh
- , Feng Pan
- & En-Min Li
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Article
| Open AccessEpigenetic loss of heterogeneity from low to high grade localized prostate tumours
High tumour heterogeneity hinders the identification of molecular subtypes in prostate cancer. Here, the authors integrate single-cell chromatin accessibility data with multiplex imaging and reveal distinct chromatin features and transcriptional factor binding signatures in high- and low-grade prostate tumours.
- Sebnem Ece Eksi
- , Alex Chitsazan
- & Andrew C. Adey
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Article
| Open AccessThe histologic phenotype of lung cancers is associated with transcriptomic features rather than genomic characteristics
The molecular determinants of lung cancer histologic subtypes are not well understood. Here the authors analyze lung cancers of mixed histology and find that histologic subtypes are associated with transcriptomic features rather than genomic profiles in most tumors.
- Ming Tang
- , Hussein A. Abbas
- & Jianjun Zhang
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Article
| Open AccessDynamic prostate cancer transcriptome analysis delineates the trajectory to disease progression
Transcriptional changes during prostate cancer progression are not yet fully understood. Here, the authors integrate a transcriptomics atlas of prostate cancer and validate it with preclinical models and single-cell RNA-seq, revealing the role of EZH2 and macrophage polarisation in tumour progression.
- Marco Bolis
- , Daniela Bossi
- & Jean-Philippe P. Theurillat
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Article
| Open AccessTumor evolution selectively inactivates the core microRNA machinery for immune evasion
Dysregulation of the microRNA machinery has crucial roles in cancer development. Here the authors show that inactivation of proteins involved in microRNA-mediated gene silencing, such as ANKRD52 or AGO2, confers resistance to T cell-mediated immune response in a preclinical cancer model.
- Tian-Yu Song
- , Min Long
- & Yong Cang
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Article
| Open AccessSpatial and temporal intratumour heterogeneity has potential consequences for single biopsy-based neuroblastoma treatment decisions
Neuroblastoma is a devastating tumour in children. Here, the authors analyse multi-region patient samples using genomics and transcriptomics, revealing temporal and spatial heterogeneity and questioning the reliability of single-biopsy based diagnostics.
- Karin Schmelz
- , Joern Toedling
- & Angelika Eggert
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Article
| Open AccessAccurate and scalable variant calling from single cell DNA sequencing data with ProSolo
Obtaining accurate variant calls from multiple displacement amplified single cell DNA sequencing data needs dedicated models that account for amplification bias and copy errors. Here, the authors describe ProSolo, a model for calling single nucleotide variants with control over the false discovery rate.
- David Lähnemann
- , Johannes Köster
- & Alexander Schönhuth
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Article
| Open AccessCold and heterogeneous T cell repertoire is associated with copy number aberrations and loss of immune genes in small-cell lung cancer
Small-cell lung cancer (SCLC) is an aggressive disease with limited therapeutic options. Here the authors perform an immunogenomic analysis of limited-stage SCLC, revealing a homogeneous mutational landscape, but limited T-cell infiltration and a cold and heterogeneous T cell repertoire.
- Ming Chen
- , Runzhe Chen
- & Jianjun Zhang
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Article
| Open AccessDeciphering intratumoral heterogeneity using integrated clonal tracking and single-cell transcriptome analyses
DNA barcoding is a promising technology for the simultaneous analysis of genetic and phenotypic heterogeneity. Here, the authors combine DNA barcoding and single-cell RNA-seq to study heterogeneity, progression and response to therapy in B-cell acute lymphoblastic leukaemia patient-derived xenografts.
- Humberto Contreras-Trujillo
- , Jiya Eerdeng
- & Rong Lu
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Article
| Open AccessDeciphering cell lineage specification of human lung adenocarcinoma with single-cell RNA sequencing
The origin and progression of lung adenocarcinoma (LUAD) are still poorly understood. Here, the authors analyse LUAD composition and progression in patient samples using single-cell RNA-seq and multiplex imaging, revealing a potential transcriptional divergence from alveolar type 2 cells.
- Zhoufeng Wang
- , Zhe Li
- & Weimin Li
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Article
| Open AccessIndependent somatic evolution underlies clustered neuroendocrine tumors in the human small intestine
Small intestine neuroendocrine tumors (SI-NETs) are frequently multifocal and metastatic, but their tumourigenesis is still poorly understood. Here, the authors analyse multifocal SI-NET tumours with whole-genome sequencing, revealing the landscape of genomic alterations and frequent polyclonal origins.
- Erik Elias
- , Arman Ardalan
- & Erik Larsson
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Article
| Open AccessLongitudinal single-cell analysis of a myeloma mouse model identifies subclonal molecular programs associated with progression
The molecular programs that underlie progression in multiple myeloma (MM) are incompletely understood. Here the authors use a mouse model of MM and single-cell RNA-seq to define subclonal expression programs that arise during progression and that inform targeted therapeutic strategies.
- Danielle C. Croucher
- , Laura M. Richards
- & Suzanne Trudel
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Article
| Open AccessConvergence of oncogenic cooperation at single-cell and single-gene levels drives leukemic transformation
Identifying how genetic alterations cooperate in cancer is challenging. Here the authors analyze leukemia mouse models with both oncogenic NRAS and EZH2 mutations using single-cell RNA-sequencing, evaluate oncogenic cooperation, and identify GEM as a regulator of leukemia-initiating cells.
- Yuxuan Liu
- , Zhimin Gu
- & Jian Xu
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Article
| Open AccessPparg signaling controls bladder cancer subtype and immune exclusion
PPARg is differentially expressed in bladder cancer subtypes. Here, the authors show in mice that when an activated form of PPARg is expressed in basal bladder cells tumours do not form, however in the presence of injury the basal cells differentiate into luminal cells.
- Tiffany Tate
- , Tina Xiang
- & Cathy Lee Mendelsohn
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Article
| Open AccessSingle-cell transcriptomic analysis of the tumor ecosystems underlying initiation and progression of papillary thyroid carcinoma
The characterisation of the papillary thyroid carcinoma (PTC) tumour microenvironment remains crucial. Here, the authors perform single-cell RNA sequencing in 11 patients and identify potential opportunities for the use of immunotherapy and its combination with anti-angiogenic therapy in PTC.
- Weilin Pu
- , Xiao Shi
- & Yu-Long Wang
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Article
| Open AccessSingle-cell analysis of patient-derived PDAC organoids reveals cell state heterogeneity and a conserved developmental hierarchy
Pancreatic tumors are frequently divided into basal and classical subtypes. Here, the authors use single cell sequencing to investigate organoids derived from pancreatic cancer tissue and find a hierarchy of distinct cell states, and classical and basal cells existing within the same tumor.
- Teresa G. Krieger
- , Solange Le Blanc
- & Christian Conrad
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Article
| Open AccessLoss of polycomb repressive complex 1 activity and chromosomal instability drive uveal melanoma progression
The molecular underpinnings driving uveal melanoma (UM) progression are unknown. Here the authors show that loss of Polycomb Repressive Complex 1 triggers chromosomal instability, which promotes inflammatory signaling and migration in UM.
- Mathieu F. Bakhoum
- , Jasmine H. Francis
- & Ashley M. Laughney
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Article
| Open AccessCloneSig can jointly infer intra-tumor heterogeneity and mutational signature activity in bulk tumor sequencing data
Intratumour heterogeneity (ITH) and mutational signatures are typically analysed separately, even though they are not necessarily independent. Here, the authors present CloneSig, a tool for the joint estimation of ITH and mutational signatures, with which they analyse the TCGA and PCAWG datasets.
- Judith Abécassis
- , Fabien Reyal
- & Jean-Philippe Vert
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Article
| Open AccessDissecting esophageal squamous-cell carcinoma ecosystem by single-cell transcriptomic analysis
Esophageal squamous-cell carcinomas (ESCC) have poor prognosis, and detailed molecular profiles are necessary to identify prognostic markers. Here the authors analyse 60 ESCC patient samples using scRNA-seq, TCR-seq and genomics; they find mucosal immunity markers associated with survival and immunosuppressive microenvironments.
- Xiannian Zhang
- , Linna Peng
- & Dongxin Lin
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Article
| Open AccessLong non-coding RNA NR2F1-AS1 induces breast cancer lung metastatic dormancy by regulating NR2F1 and ΔNp63
Disseminated tumor cells often become dormant before awakening for metastatic growth. Here, the authors report that the lncRNA, NR2F1-AS1, is upregulated in dormant mesenchymal-like breast cancer stem-like cells and promotes dissemination but inhibits proliferation, leading to metastatic dormancy.
- Yingjie Liu
- , Peiyuan Zhang
- & Guohong Hu
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Article
| Open AccessSingle-cell evaluation reveals shifts in the tumor-immune niches that shape and maintain aggressive lesions in the breast
The classification of breast lesions as indolent or aggressive to tailor treatment is crucial. Here, the authors use single-cell transcriptomics and multiparametric imaging of a breast cancer mouse model, report distinct tumor-immune features for the two types of lesions, and suggest the role of IL-17 signaling in disease progression.
- Vidya C. Sinha
- , Amanda L. Rinkenbaugh
- & Helen Piwnica-Worms
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Article
| Open AccessThe evolution of hematopoietic cells under cancer therapy
The mutational effects of chemotherapies on healthy cells are unclear. Here, the authors show that the mutational signature of platinum-based drugs -but not 5-fluorouracil- is detectable in secondary acute myeloid leukemia, implying that the clonal expansion begins after the start of therapy.
- Oriol Pich
- , Albert Cortes-Bullich
- & Nuria Lopez-Bigas
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Article
| Open AccessChronological genome and single-cell transcriptome integration characterizes the evolutionary process of adult T cell leukemia-lymphoma
Characterising the clonal architecture of Adult T-cell leukemia-lymphoma (ATL) remains crucial. Here, the authors develop a capture-based sequencing panel and use deep DNA and single cell RNA sequencing and report distinct genomic and transcriptomic features associated with subclonal evolution.
- Makoto Yamagishi
- , Miyuki Kubokawa
- & Kaoru Uchimaru
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Article
| Open AccessLineage-defined leiomyosarcoma subtypes emerge years before diagnosis and determine patient survival
Heterogeneity in leiomyosarcomas (LMS) makes treatment of the disease challenging. Here the authors analyze LMS heterogeneity and molecular LMS subtypes using genomics and transcriptomics, finding origins in distinct lineages and associations with survival, in addition to the early emergence of metastatic clones.
- Nathaniel D. Anderson
- , Yael Babichev
- & Adam Shlien
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Article
| Open AccessDissecting spatial heterogeneity and the immune-evasion mechanism of CTCs by single-cell RNA-seq in hepatocellular carcinoma
Circulating tumour cells can be useful for monitoring disease progression but how they survive in the circulatory system is unclear. Here, the authors use single-cell sequencing of circulating tumour cells from multiple vascular sites in liver cancer patients and identify genes that may help the cells survive.
- Yun-Fan Sun
- , Liang Wu
- & Xin-Rong Yang
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Article
| Open AccessAntibody-drug conjugates with dual payloads for combating breast tumor heterogeneity and drug resistance
Intratumor heterogeneity in breast cancer can limit the clinical success of antibody-drug conjugates (ADCs). In this study, the authors develop dual payload Her2-ADCs that show potent anti-tumor activity against heterogeneous breast tumors in vivo.
- Chisato M. Yamazaki
- , Aiko Yamaguchi
- & Kyoji Tsuchikama
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Article
| Open AccessChromosomal copy number heterogeneity predicts survival rates across cancers
Intratumour heterogeneity (ITH) is associated with worse prognosis in cancer, and efficient frameworks to measure it are needed. Here the authors develop a method to estimate copy number heterogeneity, and propose that it is driven by chromosomal instability and can predict pan-cancer survival.
- Erik van Dijk
- , Tom van den Bosch
- & Daniël M. Miedema
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Article
| Open AccessCell-free DNA captures tumor heterogeneity and driver alterations in rapid autopsies with pre-treated metastatic cancer
It is currently unclear if cell-free DNA samples from metastatic cancers are as informative as tissue ones for cancer profiling. Here the authors show that cell-free DNA samples from rapid autopsies capture clonal and subclonal alterations of metastatic tumours and reveal more driver alterations than single tissue samples.
- Bernard Pereira
- , Christopher T. Chen
- & Dejan Juric
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Article
| Open AccessEvolution of core archetypal phenotypes in progressive high grade serous ovarian cancer
High-grade serous ovarian cancer (HGSOC) is prone to developing resistance to treatment. Here, the authors use single-cell RNA-seq and an analysis of archetypes, and find that shifts in metabolism and proliferation are associated with the response to treatment and clonal heterogeneity in HGSOC.
- Aritro Nath
- , Patrick A. Cosgrove
- & Andrea H. Bild
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Article
| Open AccessCo-evolution of tumor and immune cells during progression of multiple myeloma
Clonal evolution in multiple myeloma (MM) needs to be understood in both the tumor and its microenvironment. Here the authors perform single-cell multi-omics profiling of samples from MM patients at different stages, finding transitions in the immune cell composition throughout progression.
- Ruiyang Liu
- , Qingsong Gao
- & Li Ding
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Article
| Open AccessSingle-cell profiling of tumor heterogeneity and the microenvironment in advanced non-small cell lung cancer
Comprehensive profiles of tumour and microenvironment are critical to understand heterogeneity in non-small cell lung cancer (NSCLC). Here, the authors profile 42 late-stage NSCLC patients with single-cell RNA-seq, revealing immune landscapes that are associated with cancer subtype or heterogeneity.
- Fengying Wu
- , Jue Fan
- & Caicun Zhou
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Article
| Open AccessEpigenomic landscape of human colorectal cancer unveils an aberrant core of pan-cancer enhancers orchestrated by YAP/TAZ
The role of epigenetic deregulation in colorectal cancer (CRC) is not fully understood yet. Here the authors use patient-derived organoids, epigenomics and single-cell RNA-seq to reveal that YAP/TAZ are key regulators that bind to active enhancers in CRC and promote tumour survival.
- Giulia Della Chiara
- , Federica Gervasoni
- & Massimiliano Pagani
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Article
| Open AccessNormal tissue architecture determines the evolutionary course of cancer
Some cancers occur in spatially constrained tissues such as the mammary gland, and how the morphological features influence the evolution of the cancer is unclear. Here, the authors use mathematical modeling to study the question of competition for space and provide inferences on the mode of evolution of cancers in such tissues.
- Jeffrey West
- , Ryan O. Schenck
- & Alexander R. A. Anderson
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Article
| Open AccessLandscapes of cellular phenotypic diversity in breast cancer xenografts and their impact on drug response
The heterogeneity of breast cancer has a major role in drug response and resistance. In this study, the authors use patient-derived tumour xenografts as a platform for drug testing and correlation with single-cell proteomic phenotypes characterized by mass cytometry.
- Dimitra Georgopoulou
- , Maurizio Callari
- & Carlos Caldas
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Article
| Open AccessClonal architecture in mesothelioma is prognostic and shapes the tumour microenvironment
The impact of intratumour heterogeneity on immune surveillance and clinical outcomes has not been adequately explored in malignant pleural mesothelioma (MPM). Here the authors analyse the influence of evolution on the survival and immune landscape of MPM patients using multi-region sequencing data.
- Min Zhang
- , Jin-Li Luo
- & Dean A. Fennell
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Article
| Open AccessInter- and intra-tumor heterogeneity of metastatic prostate cancer determined by digital spatial gene expression profiling
The inter- and intra-tumor heterogeneity of metastatic prostate cancer (mPC) is underexplored. Here the authors use Digital Spatial Profiling to study gene and protein expression heterogeneity in 27 mPC patients, finding variation in associated pathways and potential immunotherapy targets.
- Lauren Brady
- , Michelle Kriner
- & Peter S. Nelson
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Article
| Open AccessIdentification of leukemic and pre-leukemic stem cells by clonal tracking from single-cell transcriptomics
Leukaemic stem cells drive acute myeloid leukaemia (AML) progression and relapse but they are incompletely characterized. Here, the authors combine single-cell transcriptomics and clonal tracking using nuclear and mitochondrial somatic variants to distinguish healthy, pre-leukaemic and leukaemic stem cells in AML.
- Lars Velten
- , Benjamin A. Story
- & Lars M. Steinmetz
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Article
| Open AccessInnate immune evasion revealed in a colorectal zebrafish xenograft model
Zebrafish has emerged as an important vertebrate model to study tumor biology and immune response. Here, using a zebrafish xenograft model, the authors show that the engraftment capacity of human colorectal cancer cell lines is influenced by innate immune response and immunoediting.
- Vanda Póvoa
- , Cátia Rebelo de Almeida
- & Rita Fior