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

Aberrant non-canonical NF-κB signalling reprograms the epigenome landscape to drive oncogenic transcriptomes in multiple myeloma

The downstream molecular mechanisms following the activation of the NF-κB pathway in multiple myeloma (MM) remain to be characterised. Here, it is shown that aberrant non-canonical NF-κB signalling causes epigenomic reprogramming leading to transcriptional changes that favour MM progression.
- Daniel A. Ang
- Jean-Michel Carter
- Yinghui Li
ArticleOpen Access21 Mar 2024 Nature Communications
FinaleMe: Predicting DNA methylation by the fragmentation patterns of plasma cell-free DNA

DNA methylation from cell-free DNA (cfDNA) can be profiled using whole genome bisulfite sequencing (WGBS). Here, the authors develop a computational method, FinaleMe, that predicts DNA methylation and tissues of-origin in cfDNA and validate its performance using paired deep and shallow-coverage whole-genome sequencing (WGS) and WGBS data.
- Yaping Liu
- Sarah C. Reed
- Manolis Kellis
ArticleOpen Access30 Mar 2024 Nature Communications
Hematopoietic stem cells with granulo-monocytic differentiation state overcome venetoclax sensitivity in patients with myelodysplastic syndromes

Secondary resistance to venetoclax in patients with myelodysplastic syndromes (MDS) is not completely elucidated. Here, the authors show that haematopoietic stem cells with a granulo-monocytic differentiation transcriptional state drive secondary resistance to venetoclax in MDS patients who previously failed hypomethylating agent therapy.
- Juan Jose Rodriguez-Sevilla
- Irene Ganan-Gomez
- Simona Colla
ArticleOpen Access18 Mar 2024 Nature Communications
Loss of CREBBP and KMT2D cooperate to accelerate lymphomagenesis and shape the lymphoma immune microenvironment

CREBBP and KMT2D mutations frequently co-occur in B cell lymphomas with unclear significance. Here the authors show that they cooperate to skew B cell fate decisions and induce a CD8-depleted immune-evasive microenvironment to facilitate lymphomagenesis.
- Jie Li
- Christopher R. Chin
- Ari M. Melnick
ArticleOpen Access3 Apr 2024 Nature Communications
Combination of acalabrutinib with lenalidomide and rituximab in relapsed/refractory aggressive B-cell non-Hodgkin lymphoma: a single-arm phase II trial

Potential synergism between BTK inhibitor and lenalidomide in treating aggressive B-cell lymphoma has been suggested. Here, the authors report a single-arm phase II clinical trial of combination of acalabrutinib, lenalidomide and rituximab in patients with aggressive Relapsed/Refractory aggressive B-cell non-Hodgkin lymphoma.
- Changhee Park
- Ho Sup Lee
- Youngil Koh
ArticleOpen Access30 Mar 2024 Nature Communications
Evolving copy number gains promote tumor expansion and bolster mutational diversification

Understanding the timing and fitness of somatic copy number alterations (SCNAs) in cancer would shed light on cancer progression and evolution. Here, the authors develop Butte, a computational framework to estimate the timing of clonal SCNAs that encompass multiple gains, and apply it on whole-genome sequencing data from 184 samples.
- Zicheng Wang
- Yunong Xia
- Ruping Sun
ArticleOpen Access6 Mar 2024 Nature Communications
Converging and evolving immuno-genomic routes toward immune escape in breast cancer

Immune response during breast cancer progression remains to be explored. Here, the characterisation of sequential and parallel multiregion samples of an index patient and a cohort of metastatic triple-negative breast cancers reveals convergent immune evasion mechanisms and an increase in tumor genomic heterogeneity.
- Juan Blanco-Heredia
- Carla Anjos Souza
- Leticia De Mattos-Arruda
ArticleOpen Access21 Feb 2024 Nature Communications
KDM3B inhibitors disrupt the oncogenic activity of PAX3-FOXO1 in fusion-positive rhabdomyosarcoma

There is lack of therapies targeting the PAX3-FOXO1 fusion oncogene in fusion-positive rhabdomyosarcoma (FP-RMS). Here, the authors identify and characterise an inhibitor with highest inhibition of histone lysine demethylase 3B that suppresses PAX3-FOXO1 activity in FP-RMS.
- Yong Yean Kim
- Berkley E. Gryder
- Javed Khan
ArticleOpen Access24 Feb 2024 Nature Communications
Experimental evidence for cancer resistance in a bat species

Bats have been suggested to be resistant to cancer due to mechanisms related to their evolved longevity, but the associated molecular drivers are still understudied. Here, the authors examine cancer resistance mechanisms across seven bat species using in vitro and in vivo models, and identify HIF1A, COPS5, and RPS3 as related genes.
- Rong Hua
- Yuan-Shuo Ma
- Zhen Liu
ArticleOpen Access15 Feb 2024 Nature Communications
Regression-based Deep-Learning predicts molecular biomarkers from pathology slides

Cancer biomarkers are often continuous measurements, which poses challenges for their prediction using classification-based deep learning. Here, the authors develop a regression-based deep learning method to predict continuous biomarkers - such as the homologous repair deficiency score - from cancer histopathology images.
- Omar S. M. El Nahhas
- Chiara M. L. Loeffler
- Jakob Nikolas Kather
ArticleOpen Access10 Feb 2024 Nature Communications
Molecular and clinical analyses of PHF6 mutant myeloid neoplasia provide their pathogenesis and therapeutic targeting

PHD finger protein 6 (PHF6) somatic mutations have been identified in blood malignancies. Here, the authors perform genetic analyses of PHF6-mutant myeloid neoplasms which show specific sex-associated genetic correlations and functional collaboration between PHF6 and RUNX1 associated with prognostic value.
- Yasuo Kubota
- Xiaorong Gu
- Jaroslaw P. Maciejewski
ArticleOpen Access28 Feb 2024 Nature Communications
Macro CD5L⁺ deteriorates CD8⁺T cells exhaustion and impairs combination of Gemcitabine-Oxaliplatin-Lenvatinib-anti-PD1 therapy in intrahepatic cholangiocarcinoma

The role of the tumor microenvironment in immunotherapy response in intrahepatic cholangiocarcinoma remains unclear. Here, single cell RNA and TCR sequencing of samples before and after immunotherapy highlights the role of CD8 T-cell status conversion and exhaustion induced by Macro CD5L+ in treatment response.
- Jia-Cheng Lu
- Lei-Lei Wu
- Jia Fan
ArticleOpen Access20 Jan 2024 Nature Communications
UPP1 promotes lung adenocarcinoma progression through the induction of an immunosuppressive microenvironment

Characterising the tumour microenvironment features of lung adenocarcinoma (LUAD) remains crucial. Here, the authors perform single cell RNA sequencing data analysis of 117 LUAD samples and functional assays and highlight the immunosuppressive role of UPP1high tumour cells.
- Yin Li
- Manling Jiang
- Chunlai Lu
ArticleOpen Access8 Feb 2024 Nature Communications
Epigenetic reprogramming shapes the cellular landscape of schwannoma

Schwannomas are regularly treated with radiotherapy, but the molecular effects on these tumours and their microenvironment remain unclear. Here, the authors show that radiotherapy can induce epigenetic reprogramming and immune infiltration in schwannomas, and develop the snARC-seq approach to analyse the epigenomic evolution at the single-cell level.
- S. John Liu
- Tim Casey-Clyde
- David R. Raleigh
ArticleOpen Access12 Jan 2024 Nature Communications
Deep learning-based phenotyping reclassifies combined hepatocellular-cholangiocarcinoma

Combined hepatocellular-cholangiocarcinomas (cHCC-CCA) are challenging to diagnose, as they exhibit features of hepatocellular carcinoma (HCC) and intrahepatic cholangiocarcinoma (ICCA). Here, the authors use deep learning to re-classify cHCC-CCA tumours into HCC or ICCA based on histopathology images.
- Julien Calderaro
- Narmin Ghaffari Laleh
- Jakob Nikolas Kather
ArticleOpen Access14 Dec 2023 Nature Communications
Genomic and epigenomic integrative subtypes of renal cell carcinoma in a Japanese cohort

Renal cell carcinoma (RCC) subtypes are associated with different molecular alterations and clinical outcomes, but they need to be characterised in diverse cohorts. Here, the authors perform genomic, transcriptomic, and epigenomic profiling in a large cohort of Japanese RCC cases, and identify epi-subtypes associated with a particular immune environment.
- Akihiko Fukagawa
- Natsuko Hama
- Tatsuhiro Shibata
ArticleOpen Access16 Dec 2023 Nature Communications
Mosaic chromosomal alterations in peripheral blood leukocytes of children in sub-Saharan Africa

Mosaic chromosomal alterations (mCAs) in peripheral blood leukocytes are associated with an increased risk of malignancy. Here, the authors use genome-wide genotyping array data to investigate the prevalence of mCAs in sub-Saharan African children with versus those without Burkitt lymphoma.
- Weiyin Zhou
- Anja Fischer
- Sam M. Mbulaiteye
ArticleOpen Access6 Dec 2023 Nature Communications
Whole-genome sequencing reveals the molecular implications of the stepwise progression of lung adenocarcinoma

Current sequencing technologies can shed light on the stepwise progression of lung adenocarcinoma. Here, the authors characterize tumor progression in lung adenocarcinomas from an early stage using short and long read whole-genome sequencing, bulk and spatial transcriptomics, and epigenomics.
- Yasuhiko Haga
- Yoshitaka Sakamoto
- Ayako Suzuki
ArticleOpen Access15 Dec 2023 Nature Communications
Distinct mesenchymal cell states mediate prostate cancer progression

The components of the tumour microenvironment contribute to prostate cancer initiation and progression. Here the authors perform single-cell RNA sequencing and spatial transcriptomics analysis of prostate cancer stroma from mouse models at different stages of the disease and develop a gene signature to predict distant metastasis in patients.
- Hubert Pakula
- Mohamed Omar
- Massimo Loda
ArticleOpen Access8 Jan 2024 Nature Communications
KRAS allelic imbalance drives tumour initiation yet suppresses metastasis in colorectal cancer in vivo

The function of wild-type KRAS in KRAS mutant cancers remains to be explored. Here, the authors show that deletion of the tumour-suppressive wild-type Kras in a KRASG12D driven colon cancer model exacerbates tumour initiation in a MAPK dependent manner, while acting to suppress metastasis through impaired immune suppression.
- Arafath K. Najumudeen
- Sigrid K. Fey
- Owen J. Sansom
ArticleOpen Access2 Jan 2024 Nature Communications
Genetic and epigenetic features of bilateral Wilms tumor predisposition in patients from the Children’s Oncology Group AREN18B5-Q

The genetic and epigenetic predisposition of bilateral Wilms tumour remains to be investigated. Here, the authors perform multiomics analysis and identify the predominant genetic and epigenetic events associated with bilateral Wilms tumour predisposition.
- Andrew J. Murphy
- Changde Cheng
- Xiang Chen
ArticleOpen Access18 Dec 2023 Nature Communications
Niacin restriction with NAMPT-inhibition is synthetic lethal to neuroendocrine carcinoma

Nicotinamide phosphoribosyltransferase (NAMPT), a key enzyme for NAD synthesis, has been proposed as a potential target for cancer therapy. Here, the authors show synthetic lethality when combining NAMPT inhibition with Niacin restriction in neuroendocrine-type cancer.
- Miyuki Nomura
- Mai Ohuchi
- Nobuhiro Tanuma
ArticleOpen Access13 Dec 2023 Nature Communications
TMIGD2 is an orchestrator and therapeutic target on human acute myeloid leukemia stem cells

The immune receptor Transmembrane and immunoglobulin domain containing 2 (TMIGD2) mediates T-cell and nature killer cells co-stimulation upon B7-family HHLA2 engagement. Here, the authors show that TMIGD2 is expressed in Acute Myeloid Leukaemia stem cells regulating self-renewal and differentiation to facilitate leukemogenesis.
- Hao Wang
- R. Alejandro Sica
- Xingxing Zang
ArticleOpen Access2 Jan 2024 Nature Communications
Enhanced SREBP2-driven cholesterol biosynthesis by PKCλ/ι deficiency in intestinal epithelial cells promotes aggressive serrated tumorigenesis

The underlying mechanisms driving colorectal cancer (CRC) through the serrated route are largely unknown. Here, the authors show that reduced aPKC levels increase cholesterol biosynthesis to promote aggressiveness in serrated tumours and targeting this pathway reduces tumourigenesis in preclinical models of serrated CRC.
- Yu Muta
- Juan F. Linares
- Jorge Moscat
ArticleOpen Access13 Dec 2023 Nature Communications
Itaconate promotes hepatocellular carcinoma progression by epigenetic induction of CD8⁺ T-cell exhaustion

Itaconate is an immunomodulatory metabolite that has been reported to regulate tumorigenesis. Here, the authors show that macrophage-derived itaconate induces epigenetic-mediated CD8⁺ T cell exhaustion, promoting hepatocellular carcinoma development.
- Xuemei Gu
- Haoran Wei
- Ping Gao
ArticleOpen Access9 Dec 2023 Nature Communications
Mapping and modeling human colorectal carcinoma interactions with the tumor microenvironment

Tumour-microenvironment interactions, pivotal in cancer progression, are challenging to replicate in vitro. Here, the authors use single-cell RNA-seq to analyse these interactions in colorectal cancer within organoid models, and aim to emulate and understand these crucial interactions by introducing specific microenvironmental components.
- Ning Li
- Qin Zhu
- Christopher J. Lengner
ArticleOpen Access30 Nov 2023 Nature Communications
Mirabegron displays anticancer effects by globally browning adipose tissues

Targeting metabolism is currently a promising approach for cancer treatment. Here, the authors show that the beta3 agonist mirabegron inhibits tumor progression by browning adipose tissues in preclinical murine models.
- Xiaoting Sun
- Wenhai Sui
- Yihai Cao
ArticleOpen Access22 Nov 2023 Nature Communications
Mouse models of pediatric high-grade gliomas with MYCN amplification reveal intratumoral heterogeneity and lineage signatures

Paediatric high-grade gliomas with MYCN amplification (HGG-MYCN) are rare and highly aggressive. Here, the authors generate a mouse model for HGG-MYCN that can recapitulate the histological and molecular profiles of the human tumours, and perform high-throughput drug screening to identify potential treatment options.
- Melanie Schoof
- Shweta Godbole
- Ulrich Schüller
ArticleOpen Access24 Nov 2023 Nature Communications
The promise of data science for health research in Africa

In this Review article, the authors discuss emerging efforts to build ethical governance frameworks for data science health research in Africa and the opportunities to advance these through investments by African governments and institutions, international funding organizations and collaborations for research and capacity development.
- Clement A. Adebamowo
- Shawneequa Callier
- BridgELSI Project as part of the DS-I Africa Consortium
Review ArticleOpen Access29 Sep 2023 Nature Communications
Genomic signatures of past and present chromosomal instability in Barrett’s esophagus and early esophageal adenocarcinoma

Genome complexity is a distinguishing feature of advanced cancers in contrast to precancerous conditions. Here, by analysing chromosomal copy-number evolution in early cancers and precancerous lesions of the oesophagus, the authors reveal signatures of ongoing chromosomal instability and its role in promoting tumour progression.
- Chunyang Bao
- Richard W. Tourdot
- Cheng-Zhong Zhang
ArticleOpen Access4 Oct 2023 Nature Communications
Enhanced clinical assessment of hematologic malignancies through routine paired tumor and normal sequencing

Targeted sequencing panels such as MSK-IMPACT have been successfully used to profile solid tumours in clinical settings. Here, the authors develop and implement the MSK-IMPACT Heme sequencing panel and platform to profile haematologic malignancies using paired tumor and normal tissues.
- Ryan N. Ptashkin
- Mark D. Ewalt
- Maria E. Arcila
ArticleOpen Access28 Oct 2023 Nature Communications
Imaging and multi-omics datasets converge to define different neural progenitor origins for ATRT-SHH subgroups

Atypical teratoid rhabdoid tumors (ATRT) are divided into three molecular subgroups, which could have different lineages of origin. Here, the authors use tumour imaging, multi-omics and genetically engineered mouse models to determine the anatomical region and cell lineage of origin of ATRT subtypes.
- María-Jesús Lobón-Iglesias
- Mamy Andrianteranagna
- Franck Bourdeaut
ArticleOpen Access20 Oct 2023 Nature Communications
Molecular landscape and functional characterization of centrosome amplification in ovarian cancer

The prevalence of centrosome amplification (CA) and the genomic landscape of chromosomal instability in high-grade serous ovarian carcinoma (HGSOC) remain to be explored. Here the authors suggest CA as a potential driver of tumour evolution and a biomarker for treatment response in HGSOC.
- Carolin M. Sauer
- James A. Hall
- James D. Brenton
ArticleOpen Access16 Oct 2023 Nature Communications
Chromatin accessibility landscape of relapsed pediatric B-lineage acute lymphoblastic leukemia

The molecular mechanisms underlying relapse in pediatric B-lineage acute lymphoblastic leukemia (B-ALL) patients remain to be explored. Here, the authors characterise the chromatin accessibility landscape of B-ALL and identify subtype and drug response specific patterns.
- Han Wang
- Huiying Sun
- Yu Liu
ArticleOpen Access25 Oct 2023 Nature Communications
Critical requirement of SOS1 for tumor development and microenvironment modulation in KRAS^G12D-driven lung adenocarcinoma

Critical regulators of RAS signaling pathways in oncogenic RAS-driven tumors remain to be explored. Here, the authors show the development of KRAS(G12D)-driven lung adenocarcinoma is dependent on SOS1, with dual roles in both tumor and stroma.
- Fernando C. Baltanás
- Rósula García-Navas
- Eugenio Santos
ArticleOpen Access20 Sep 2023 Nature Communications
CSTF2 mediated mRNA N⁶-methyladenosine modification drives pancreatic ductal adenocarcinoma m⁶A subtypes

N6-methyladenosine (m6A) modification has important implications in different cancer subtypes. Here, the authors perform transcriptomic m6A profiling to identify two subtypes of pancreatic ductal adenocarcinoma with differential m6A modifications and different clinical outcomes, which is driven by m6A regulator CSTF2.
- Yanfen Zheng
- Xingyang Li
- Zhixiang Zuo
ArticleOpen Access10 Oct 2023 Nature Communications
Distinct and targetable role of calcium-sensing receptor in leukaemia

Several parameters in the bone marrow (BM) niche regulate leukaemic stem cell status and disease progression. Here, the authors show that calcium-sensing receptor affects the location of acute myeloid leukaemia (AML) cells in the BM niche which influences self-renewal of leukaemic stem cells and AML development
- Raquel S. Pereira
- Rahul Kumar
- Daniela S. Krause
ArticleOpen Access6 Oct 2023 Nature Communications
TET2 lesions enhance the aggressiveness of CEBPA-mutant acute myeloid leukemia by rebalancing GATA2 expression

TET2 and GATA2 are two frequently co-mutated genes in CEBPA double mutated acute myeloid leukemia (AML). Here the authors show that the underlying mechanism for this cooccurrence is for TET2 loss-of-function mutation to counteract the increase in GATA2 expression, which is disadvantageous to these type of AML cells.
- Elizabeth Heyes
- Anna S. Wilhelmson
- Bo T. Porse
ArticleOpen Access4 Oct 2023 Nature Communications
MYC Deregulation and PTEN Loss Model Tumor and Stromal Heterogeneity of Aggressive Triple-Negative Breast Cancer

Few mouse models recapitulate the complexity of triple negative breast cancer (TNBC). Here, the authors develop and characterise a TNBC mouse model harbouring two common TNBC mutations: amplification of the oncogene MYC and deletion of the tumour suppressor PTEN.
- Zinab O. Doha
- Xiaoyan Wang
- Rosalie C. Sears
ArticleOpen Access13 Sep 2023 Nature Communications
Proteogenomics of different urothelial bladder cancer stages reveals distinct molecular features for papillary cancer and carcinoma in situ

Urothelial bladder cancer (UC) progression occurs as a multi-step process that leads to different kinds of lesions and subtypes. Here, the authors characterise benign and invasive lesions that occur during UC progression using proteogenomics in patient samples and show critical molecular pathways and prognostic associations.
- Zhenmei Yao
- Ning Xu
- Chen Ding
ArticleOpen Access13 Sep 2023 Nature Communications
Intermittent dietary methionine deprivation facilitates tumoral ferroptosis and synergizes with checkpoint blockade

The application of dietary methionine intervention is of particular interest in the field of cancer therapy. Here the authors show that intermittent but not sustained deprivation of methionine promotes tumor ferroptosis and improves response to checkpoint inhibitors.
- Ying Xue
- Fujia Lu
- Weimin Wang
ArticleOpen Access8 Aug 2023 Nature Communications
Combining gut microbiota modulation and chemotherapy by capecitabine-loaded prebiotic nanoparticle improves colorectal cancer therapy

Gut microbiota regulates colorectal cancer (CRC) progression and respond to therapy. Here the authors generate nanoparticles using prebiotic micelles and loaded with the chemo drug capecitabine that boost gastrointestinal probiotic response, increase anti-tumour immunity and improve survival when provided orally in CRC preclinical murine models.
- Tianqun Lang
- Runqi Zhu
- Yaping Li
ArticleOpen Access7 Aug 2023 Nature Communications
Circulating trans fatty acids are associated with prostate cancer in Ghanaian and American men

Analyses of the association between fatty acids and prostate cancer have often neglected African patients. Here, the authors analyse 24 circulating fatty acids in Ghanaian, African American, and European American men, and explore the associations with socio-demographic factors, diet, FADS1/2 locus, and prostate cancer.
- Tsion Zewdu Minas
- Brittany D. Lord
- Stefan Ambs
ArticleOpen Access19 Jul 2023 Nature Communications

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