Focus 26 January 2021

Cancer

Cancer is a group of heterogeneous diseases that accounts for 1 in 6 deaths globally. Current research efforts focus on screening, early detection and discovering improved treatment options with the aim of decreasing patient mortality. This editorial selection highlights some of our recent most exciting papers that significantly move forward the rapid evolving field of cancer research.

Featured articles

Genomic and immune landscape Of metastatic pheochromocytoma and paraganglioma

The molecular mechanisms underlying metastasis in pheochromocytoma/paraganglioma (mPPGL) remain to be explored. Here, the authors perform genomic and immunogenomic profiling of mPPGL tumors and suggest potential biomarkers for risk of metastasis and immunotherapy response.
- Bruna Calsina
- Elena Piñeiro-Yáñez
- Mercedes Robledo
Article Open Access 28 Feb 2023 Nature Communications
CD26-negative and CD26-positive tissue-resident fibroblasts contribute to functionally distinct CAF subpopulations in breast cancer

The origin of cancer-associated fibroblasts (CAFs) in cancer remains to be identified. Here, single-cell transcriptomics, in vivo and in vitro studies suggest that CD26+ and CD26- normal fibroblasts transform into distinct CAF subpopulations in mouse models of breast cancer.
- Julia M. Houthuijzen
- Roebi de Bruijn
- Jos Jonkers
Article Open Access 12 Jan 2023 Nature Communications
Molecular characterization of Richter syndrome identifies de novo diffuse large B-cell lymphomas with poor prognosis

Richter syndrome (RS) is the transformation of chronic lymphocytic leukaemia (CLL) into aggressive lymphoma, in most cases diffuse large B-cell lymphoma (DLBCL). Here, the authors characterize the DNA methylation and transcriptomic profiles of RS samples, find a clonally-related CLL epigenetic imprint, and develop classifiers for “RS-type” de novo DLBCLs.
- Julien Broséus
- Sébastien Hergalant
- Stephan Stilgenbauer
Article Open Access 19 Jan 2023 Nature Communications
Dynamic partitioning of branched-chain amino acids-derived nitrogen supports renal cancer progression

Primary and metastatic tumours have different metabolic phenotypes due to changes in nutrient availability. Here the authors perform multi-omic analyses of primary and metastatic renal cancer cells grown in a physiological medium and show that the reprogramming of the branched-chain amino acid catabolism and urea cycle through re-expression of ASS1 allows metabolic flexibility during renal cancer progression.
- Marco Sciacovelli
- Aurelien Dugourd
- Christian Frezza
Article Open Access 20 Dec 2022 Nature Communications
Breast cancer plasticity is restricted by a LATS1-NCOR1 repressive axis

LATS1 is reported to regulate the transition of luminal-basal-like cell plasticity in breast cancer. Here the authors report that LATS1 limits the progression of luminal breast cancer by associating with NCOR1 nuclear corepressor to repress ERα-downregulated genes in luminal cells.
- Yael Aylon
- Noa Furth
- Moshe Oren
Article Open Access 28 Nov 2022 Nature Communications
Inactivation of LATS1/2 drives luminal-basal plasticity to initiate basal-like mammary carcinomas

LATS1/2 kinases are reported to be tumour suppressors in many cancers. Here the authors show that conditional deletion of LATS1/2 in the mature mouse luminal mammary epithelium leads to luminal-basal plasticity and development of basal-like carcinomas.
- Joseph G. Kern
- Andrew M. Tilston-Lunel
- Xaralabos Varelas
Article Open Access 28 Nov 2022 Nature Communications
A comprehensive single-cell map of T cell exhaustion-associated immune environments in human breast cancer

T cell exhaustion in breast tumours remains to be fully characterised. Here, single cell transcriptomics and imaging mass cytometry analysis of luminal breast tumours with or without exhausted T cells suggests distinct patterns of PD-1 and CXCL13 expression in T cells, and of MHC-I, but not PD-L1, expression in tumour cells.
- Sandra Tietscher
- Johanna Wagner
- Bernd Bodenmiller
Article Open Access 6 Jan 2023 Nature Communications
The splanchnic mesenchyme is the tissue of origin for pancreatic fibroblasts during homeostasis and tumorigenesis

Cancer-associated fibroblasts (CAFs) are the main component of the stroma in pancreatic cancer, but their tissue of origin remains to be defined. Here the authors perform lineage tracing and single cell RNA sequencing in mice and suggest the splanchnic mesenchyme as the tissue of origin for CAFs.
- Lu Han
- Yongxia Wu
- Gustavo Leone
Article Open Access 3 Jan 2023 Nature Communications
LY6D marks pre-existing resistant basosquamous tumor subpopulations

The identification of distinct cell populations with cellular plasticity in skin basal cell carcinoma is important for understanding treatment resistance mechanisms. Here, the authors identify the resistant LY6D⁺ basosquamous population that correlates with poor clinical outcomes.
- Daniel Haensel
- Sadhana Gaddam
- Anthony E. Oro
Article Open Access 6 Dec 2022 Nature Communications
Genomic disparities between cancers in adolescent and young adults and in older adults

The biological underpinnings underlying the increased mortality and morbidity in adolescents and young adults (AYA) remains poorly understood. Here, the authors investigate the clinical and genomic disparities in AYA and older adults in a cohort of more than 100,000 cancer patients.
- Xiaojing Wang
- Anne-Marie Langevin
- Siyuan Zheng
Article Open Access 24 Nov 2022 Nature Communications
Collaborative study from the Bladder Cancer Advocacy Network for the genomic analysis of metastatic urothelial cancer

The Bladder Cancer Advocacy Network established the UC-GENOME study in order to create a biobank and data repository for metastatic urothelial carcinoma. Here, the authors present the first characterization and analysis of DNA and RNA sequencing data from the 218 patients included in the UC-GENOME.
- Jeffrey S. Damrauer
- Wolfgang Beckabir
- Matthew I. Milowsky
Article Open Access 4 Nov 2022 Nature Communications
Epithelial TGFβ engages growth-factor signalling to circumvent apoptosis and drive intestinal tumourigenesis with aggressive features

It remains critical to identify colorectal cancers (CRC) that will disseminate as early as possible. Here, the authors identify CRC tumours that are aggressive and prone to early dissemination, characterised by epithelial TGFβ and growth-factor signalling - which could be targeted with MEK/EGFR inhibitors.
- Dustin J. Flanagan
- Raheleh Amirkhah
- Owen J. Sansom
Article Open Access 7 Dec 2022 Nature Communications
A framework for clinical cancer subtyping from nucleosome profiling of cell-free DNA

Nucleosome profiling from cell-free DNA (cfDNA) represents a potential approach for cancer detection and classification. Here, the authors develop Griffin, a computational framework for tumour subtype classification based on cfDNA nucleosome profiling that can work with ultra-low pass sequencing data.
- Anna-Lisa Doebley
- Minjeong Ko
- Gavin Ha
Article Open Access 3 Dec 2022 Nature Communications
Multiregional single-cell dissection of tumor and immune cells reveals stable lock-and-key features in liver cancer

Multiregion sequencing is needed to better capture the heterogeneity of hepatocellular carcinoma (HCC) and intrahepatic cholangiocarcinoma (iCCA). Here, the authors analyse HCC and iCCA tumours with multiregion single-cell RNA-seq, revealing cellular dynamics and communication networks with immune cells.
- Lichun Ma
- Sophia Heinrich
- Xin Wei Wang
Article Open Access 7 Dec 2022 Nature Communications
Regulome analysis in B-acute lymphoblastic leukemia exposes Core Binding Factor addiction as a therapeutic vulnerability

The ETV6-RUNX1 chimeric- and native RUNX1-responsive regulomes in paediatric B-acute lymphoblastic leukemia (B-ALL) remain to be characterized. Here, the authors reveal functional antagonism between the two transcription factors predominantly for the regulation of cell cycle-associated pathways and dependency on native RUNX1 for tumorigenesis which can be targeted pharmacologically.
- Jason P. Wray
- Elitza M. Deltcheva
- Tariq Enver
Article Open Access 21 Nov 2022 Nature Communications
Reversible Myc hypomorphism identifies a key Myc-dependency in early cancer evolution

Happloinsufficiency of Myc delays onset of cancers in mice. Here, the authors generated a mouse model of reversible cMyc hypomorphism and show that metronomic reduction of c-Myc in adult mice confers protection against cancers without side effects and that the bottleneck in early cancer evolution is dependent upon Myc.
- Nicole M. Sodir
- Luca Pellegrinet
- Gerard I. Evan
Article Open Access 9 Nov 2022 Nature Communications
Enhancer decommissioning by MLL4 ablation elicits dsRNA-interferon signaling and GSDMD-mediated pyroptosis to potentiate anti-tumor immunity

The role of enhancer de-regulation in anti-tumor immunity remains to be explored. Here, the authors suggest that ablation of MLL3 and MLL4, two enhancer-associated H3K4 monomethyltransferases, increases tumor immunogenicity and promotes anti-tumor T cell response.
- Hanhan Ning
- Shan Huang
- Deqing Hu
Article Open Access 2 Nov 2022 Nature Communications
MIR retrotransposons link the epigenome and the transcriptome of coding genes in acute myeloid leukemia

The links between DNA methylation and gene expression are poorly understood on large-scale. Here the authors show that MIR retrotransposons within introns can play this role in acute myeloid leukemia harbouring mutations in epigenetic modifiers.
- Aristeidis G. Telonis
- Qin Yang
- Maria E. Figueroa
Article Open Access 31 Oct 2022 Nature Communications
Connecting multiple microenvironment proteomes uncovers the biology in head and neck cancer

The biological understanding of poor prognosis associated with lymph node metastasis in head and neck cancer (HNC) remains crucial. Here, a proteomic characterisation of 140 multisite samples from a 59-HNC patient cohort and machine learning reveals potential biomarkers and metastasis related signatures.
- Ariane F. Busso-Lopes
- Leandro X. Neves
- Adriana F. Paes Leme
Article Open Access 7 Nov 2022 Nature Communications
A local tumor microenvironment acquired super-enhancer induces an oncogenic driver in colorectal carcinoma

The changes in super-enhancer (SE) landscape of cancers are mainly attributed to cell-intrinsic genomic alterations. Here, the authors perform epigenomic profiling on primary colorectal cancers (CRCs) and their matched normal tissues and show that local tumour microenvironment induces a SE activation and that its target, PDZK1IP1 promotes CRC growth.
- Royce W. Zhou
- Jia Xu
- Ramon E. Parsons
Article Open Access 17 Oct 2022 Nature Communications
Polarized NHE1 and SWELL1 regulate migration direction, efficiency and metastasis

Cell migration regulates diverse (patho)physiological processes, including cancer metastasis. Here the authors show that the chloride ion channel SWELL1 and the ion exchanger NHE1 are preferentially enriched at the trailing and leading edges, respectively, of migrating cells and regulate cell volume to propel confined cells, favouring breast cancer cell extravasation and metastasis.
- Yuqi Zhang
- Yizeng Li
- Konstantinos Konstantopoulos
Article Open Access 17 Oct 2022 Nature Communications
Single cell analysis of cribriform prostate cancer reveals cell intrinsic and tumor microenvironmental pathways of aggressive disease

The molecular and cellular underpinnings of cribriform prostate cancer aggressiveness remain to be explored. Here, the authors perform single-cell RNA-sequencing, TCR sequencing and histology and reveal cancer cell intrinsic pathways and an immunosuppressive tumour microenvironment.
- Hong Yuen Wong
- Quanhu Sheng
- Paula J. Hurley
Article Open Access 13 Oct 2022 Nature Communications
Single-nuclei and bulk-tissue gene-expression analysis of pheochromocytoma and paraganglioma links disease subtypes with tumor microenvironment

Pheochromocytomas and paragangliomas (PCPG) are rare neuroendocrine tumours. Here, the authors use single-nuclei and bulk-tissue RNA-seq to characterise PCPG tumours and their microenvironments and reveal molecular subtypes as well as expression patterns associated with metastasis.
- Magnus Zethoven
- Luciano Martelotto
- Richard W. Tothill
Article Open Access 21 Oct 2022 Nature Communications
Enhancing Gasdermin-induced tumor pyroptosis through preventing ESCRT-dependent cell membrane repair augments antitumor immune response

Activation of ESCRT-mediated cell membrane repair can reduce the extent of tumor cell pyroptosis. Here the authors develop two formulations (an injectable hydrogel and a cell patch) for the sustained release of a Gasdermin-D bacteria-based delivery system and of biodegradable nanoparticles loaded with an ESCRT inhibitor, triggering pyroptosis and antitumor immune responses in preclinical cancer models.
- Zhaoting Li
- Fanyi Mo
- Quanyin Hu
Article Open Access 24 Oct 2022 Nature Communications
P300 promotes tumor recurrence by regulating radiation-induced conversion of glioma stem cells to vascular-like cells

Therapeutic stress induces phenotypic plasticity in glioma stem cells although the mechanisms underlying this remain poorly understood. Here, the authors show that P300 mediates the radiation-induced vascular-like conversion of glioma stem cells to promote tumor recurrence.
- Sree Deepthi Muthukrishnan
- Riki Kawaguchi
- Harley I. Kornblum
Article Open Access 19 Oct 2022 Nature Communications
HSF1 is a driver of leukemia stem cell self-renewal in acute myeloid leukemia

Acute myeloid leukaemia (AML) is maintained by self-renewing leukemic stem cells. Here the authors show that Heat Shock Transcription Factor 1 (HSF1) is specifically required for the maintenance of AML stem cells, while sparing steady-state and stressed haematopoiesis and that pharmacologically targeting HSF1 may have broad anti-leukemic effects.
- Qianze Dong
- Yan Xiu
- Chen Zhao
Article Open Access 16 Oct 2022 Nature Communications
Common anti-cancer therapies induce somatic mutations in stem cells of healthy tissue

Specific anti-cancer therapies are highly mutagenic to cancer cells but the mutational impact on healthy tissues remains elusive. Here, the authors use organoids and whole-genome sequencing to characterise somatic mutations in healthy colon and liver adult stem cells after chemo- or radiotherapy.
- Ewart Kuijk
- Onno Kranenburg
- Arne Van Hoeck
Article Open Access 7 Oct 2022 Nature Communications
Molecular characterization of renal cell carcinoma tumors from a phase III anti-angiogenic adjuvant therapy trial

Based on the S-TRAC results, sunitinib is approved as adjuvant treatment for adult patients at high risk of recurrent RCC following nephrectomy. Here, the authors report the results of an integrated multi-omics tumor analysis of 171 patients from the trial and identify specific molecular subtypes as well as potential new targets.
- Robert J. Motzer
- Jean-François Martini
- Alain Ravaud
Article Open Access 10 Oct 2022 Nature Communications
Sirtuin5 protects colorectal cancer from DNA damage by keeping nucleotide availability

Sirtuin 5 (SIRT5) has been associated to colorectal cancer and metabolic regulation. Here, the authors show that SIRT5 silencing reduces nucleotide availability leading to DNA damage and tumor suppression in colorectal cancer models.
- Hao-Lian Wang
- Yan Chen
- Jing-Yuan Fang
Article Open Access 17 Oct 2022 Nature Communications
Temporal profiling of the breast tumour microenvironment reveals collagen XII as a driver of metastasis

The distribution and organisation of matrix molecules in the tumour stroma help shape solid tumour progression. Here they perform temporal proteomic profiling of the matrisome during breast cancer progression and show that collagen XII secreted from CAFs provides a pro-invasive microenvironment.
- Michael Papanicolaou
- Amelia L. Parker
- Thomas R. Cox
Article Open Access 6 Aug 2022 Nature Communications
High-throughput mutagenesis identifies mutations and RNA-binding proteins controlling CD19 splicing and CART-19 therapy resistance

Multiple alternative splicing events in CD19 mRNA have been associated with resistance/relapse to CD19 CAR-T therapy in patients with B cell malignancies. Here, by combining patient data and a high-throughput mutagenesis screen, the authors identify single point mutations and RNA-binding proteins that can control CD19 splicing and be associated with CD19 CAR-T therapy resistance.
- Mariela Cortés-López
- Laura Schulz
- Julian König
Article Open Access 22 Sep 2022 Nature Communications
Fatty acids homeostasis during fasting predicts protection from chemotherapy toxicity

Fasting has been reported to protect from chemotherapy-associated toxicity. Here, the authors show that fatty acid profiles in erythrocyte membranes and gene expression from peripheral blood mononuclear cells are associated to the fasting-mediated benefits during cancer treatment in mice and patients.
- Marta Barradas
- Adrián Plaza
- Pablo J. Fernandez-Marcos
Article Open Access 27 Sep 2022 Nature Communications
Epigenetic activation of the FLT3 gene by ZNF384 fusion confers a therapeutic susceptibility in acute lymphoblastic leukemia

Different molecular subtypes defined by specific gene rearrangements have been described for acute lymphoblastic leukaemia (ALL). Here, the authors show that ZNF384 fusion activates FLT3 expression conferring a therapeutic vulnerability for ZNF384- rearranged ALL subtype.
- Xujie Zhao
- Ping Wang
- Jun J. Yang
Article Open Access 14 Sep 2022 Nature Communications
Oncogenic RAS commandeers amino acid sensing machinery to aberrantly activate mTORC1 in multiple myeloma

RAS mutations are commonly found in multiple myeloma (MM). Here, the authors show that oncogenic RAS mutations activate mTORC1 signalling in MM and combining mTORC1 and MEK/ERK inhibitors synergize to improve survival in preclinical models.
- Yandan Yang
- Arnold Bolomsky
- Ryan M. Young
Article Open Access 17 Sep 2022 Nature Communications
Conserved features of TERT promoter duplications reveal an activation mechanism that mimics hotspot mutations in cancer

TERT promoter mutations are the most common noncoding alterations in cancers, although some remain to be characterised. Here, the authors identify TERT promoter duplications across seven cancer types that are functionally equivalent to well-known hotspot TERT mutations and are clonal in a multifocal glioblastoma patient.
- Carter J. Barger
- Abigail K. Suwala
- Joseph F. Costello
Article Open Access 16 Sep 2022 Nature Communications
Spatio-temporal analysis of prostate tumors in situ suggests pre-existence of treatment-resistant clones

Spatial heterogeneity in prostate cancer can contribute to its resistance to androgen deprivation therapy (ADT). Here, the authors analyse prostate cancer samples before and after ADT using Spatial Transcriptomics, and find heterogeneous pre-treatment tumour cell populations and stromal cells that are associated with resistance.
- Maja Marklund
- Niklas Schultz
- Joakim Lundeberg
Article Open Access 17 Sep 2022 Nature Communications
Clonal diversification and histogenesis of malignant germ cell tumours

The molecular characterisation of germ cell tumours (GCT) is necessary to understand their development and histological diversification. Here, the authors use whole-genome and transcriptome sequencing of GCTs across distinct histologies to reveal their somatic evolution and clonal diversification, as well as identify several putative biomarkers for treatment stratification.
- Thomas R. W. Oliver
- Lia Chappell
- Sam Behjati
Article Open Access 11 Aug 2022 Nature Communications
The impact of rare germline variants on human somatic mutation processes

The impact of germline variants on somatic alterations in cancer remains to be explored in large-scale datasets. Here, the authors study the association of rare germline variants with somatic mutational processes in more than 15,000 tumors, and reveal that damaging variants in newly-identifed genes are prevalent in the population.
- Mischan Vali-Pour
- Ben Lehner
- Fran Supek
Article Open Access 28 Jun 2022 Nature Communications
A multi-omic dissection of super-enhancer driven oncogenic gene expression programs in ovarian cancer

Super-enhancers and their associated transcription factor networks have been shown to influence ovarian cancer biology. Here, based on an integrated set of genomic and epigenomic datasets, the authors identify clinically relevant super-enhancers amplified in ovarian cancer patients and functionally validate their activity.
- Michael R. Kelly
- Kamila Wisniewska
- Hector L. Franco
Article Open Access 22 Jul 2022 Nature Communications
Lymphatic-preserving treatment sequencing with immune checkpoint inhibition unleashes cDC1-dependent antitumor immunity in HNSCC

Response rates to immune checkpoint inhibitors (ICI) in patients with head and neck squamous cell carcinoma (HNSCC) remain low. Here the authors show that ablative treatment of tumor-draining regional lymphatics, a standard of care approach in patients, impairs the tumor response to ICI in preclinical HNSCC models.
- Robert Saddawi-Konefka
- Aoife O’Farrell
- J. Silvio Gutkind
Article Open Access 25 Jul 2022 Nature Communications
Unified classification and risk-stratification in Acute Myeloid Leukemia

Classification and risk-stratification for Acute Myeloid Leukemia (AML) at diagnosis are primarily based on cytogenetics and only a few gene mutations. Here, the authors study the genomic landscape of 3653 AML patients and characterize 16 non-overlapping molecular subgroups of clinical relevance for disease classification and risk prognostication.
- Yanis Tazi
- Juan E. Arango-Ossa
- Elli Papaemmanuil
Article Open Access 8 Aug 2022 Nature Communications
Targeting de novo lipogenesis and the Lands cycle induces ferroptosis in KRAS-mutant lung cancer

Mutant KRAS (KM) is associated with poor prognosis in lung cancer and reported to promote lipid metabolism. Here, the authors show that fatty acid synthesis, which provides lipids to repair oxidized phospholipids through the FASN-Lands cycle axis, is a specific vulnerability for KM lung cancer.
- Caterina Bartolacci
- Cristina Andreani
- Pier Paolo Scaglioni
Article Open Access 26 Jul 2022 Nature Communications
Discovering the drivers of clonal hematopoiesis

Identifying the genetic drivers of clonal haematopoiesis (CH) has been challenging due to their low frequencies and a lack of adequate tools. Here, the authors use a reverse calling to detect blood somatic mutations and the IntOGen pipeline to identify CH drivers in large cancer genomics data sets based on signals of positive selection.
- Oriol Pich
- Iker Reyes-Salazar
- Nuria Lopez-Bigas
Article Open Access 23 Jul 2022 Nature Communications
Accurate determination of CRISPR-mediated gene fitness in transplantable tumours

Gene fitness and essentiality analyses using in vivo cancer models are challenging due to multiple confounders. Here, the authors develop a quantitative approach to study CRISPR-transduced patient-derived xenografts, which they use to analyse in vivo gene fitness in breast cancers and the biological features that influence uncertainty in fitness estimation.
- Peter Eirew
- Ciara O’Flanagan
- Samuel Aparicio
Article Open Access 4 Aug 2022 Nature Communications
Inherited MUTYH mutations cause elevated somatic mutation rates and distinctive mutational signatures in normal human cells

Inherited mutations in MUTYH have been shown to predispose patients to colorectal cancers. Here, the authors show that MUTYH mutations lead to an increased somatic base substitution mutation rate in normal intestinal epithelial cells, which is the likely cause for the increased cancer risk.
- Philip S. Robinson
- Laura E. Thomas
- Michael R. Stratton
Article Open Access 8 Jul 2022 Nature Communications
The drug-induced phenotypic landscape of colorectal cancer organoids

The heterogeneity underlying cancer organoid phenotypes is not yet well understood. Here, the authors develop an imaging analysis assay for high throughput phenotypic screening of colorectal organoids that allows to define specific morphological changes that occur following different drug treatments.
- Johannes Betge
- Niklas Rindtorff
- Michael Boutros
Article Open Access 6 Jun 2022 Nature Communications
Identifying colorectal cancer caused by biallelic MUTYH pathogenic variants using tumor mutational signatures

Germline biallelic pathogenic MUTYH variants predispose patients to colorectal cancer (CRC); however, approaches to identify MUTYH variant carriers are lacking. Here, the authors evaluated mutational signatures that could distinguish MUTYH carriers in large CRC cohorts, and found MUTYH-associated somatic mutations.
- Peter Georgeson
- Tabitha A. Harrison
- Daniel D. Buchanan
Article Open Access 6 Jun 2022 Nature Communications
Comparison of methods and resources for cell-cell communication inference from single-cell RNA-Seq data

Multiple methods to infer cell-cell communication (CCC) from single cell data are currently available. Here, the authors systematically compare 16 CCC inference resources and 7 methods, and develop the LIANA framework as an interface to use and compare all these approaches.
- Daniel Dimitrov
- Dénes Türei
- Julio Saez-Rodriguez
Article Open Access 9 Jun 2022 Nature Communications

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