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The IL6/JAK/STAT3 signaling axis is a therapeutic vulnerability in SMARCB1-deficient bladder cancer
SMARCB1 is frequently lost in solid cancer and reported to support tumourigenesis through STAT3 activation. Here, the authors show in several preclinical models that targeting IL6/JAK/STAT3 molecular pathway is a potential therapeutic approach for SMARCB1-deficient bladder cancer.
- Chandra Sekhar Amara
- , Karthik Reddy Kami Reddy
- & Nagireddy Putluri
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Article
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Mutant p53 gains oncogenic functions through a chromosomal instability-induced cytosolic DNA response
Here the authors show that gain-of-function mutant p53s predispose cells to chromosomal instability by targeting MCMs, leading to activation of a cGAS-STING-non-canonical NF-κB signaling that promotes tumor metastasis and immunosuppression.
- Mei Zhao
- , Tianxiao Wang
- & Ge Zhou
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p53 suppresses MHC class II presentation by intestinal epithelium to protect against radiation-induced gastrointestinal syndrome
Radiation induced gastrointestinal syndrome is a complication of radiotherapy and the tumor suppressor p53 is implicated in protection from gastrointestinal toxicity. Here Wang and colleagues show that p53 protection against radiation-induced gastrointestinal syndrome involves intestinal stem cell function and inhibition of inflammation triggered by radiation via the IL12- p40/MHC-II axis.
- Jianming Wang
- , Chun-Yuan Chang
- & Wenwei Hu
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Article
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SETD2 deficiency accelerates sphingomyelin accumulation and promotes the development of renal cancer
SET domain–containing 2 (SETD2) is reported as an immunosuppressor in clear cell renal cell carcinoma (ccRCC). Here the authors show that SETD2 loss enhances de novo sphingomyelin biosynthesis during the transition from polycystic kidney disease to ccRCC.
- Hanyu Rao
- , Changwei Liu
- & Xianting Ding
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Dual targeted extracellular vesicles regulate oncogenic genes in advanced pancreatic cancer
KRASG12D mutations frequently co-occur with mutated TP53 tumour suppressor in patients with pancreatic ductal adenocarcinoma (PDAC). Here the authors report the design of dual targeted therapeutic extracellular vesicles containing high copy numbers of TP53 mRNA and siKRASG12D, showing anti-tumor activity in PDAC preclinical models.
- Chi-Ling Chiang
- , Yifan Ma
- & L. James Lee
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Article
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Oncogenic context shapes the fitness landscape of tumor suppression
Alterations in oncogenes and tumor suppressor genes are a hallmark of cancer, yet how they interact remains poorly understood. Here, the authors describe a quantitative functional cancer genomics platform in genetically engineered mice, and uncover complex interactions between tumor suppressors and KRAS, BRAF, and EGFR oncogenes across more than 100 different lung tumor genotypes.
- Lily M. Blair
- , Joseph M. Juan
- & Ian P. Winters
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Loss of LCMT1 and biased protein phosphatase 2A heterotrimerization drive prostate cancer progression and therapy resistance
Loss of PP2A activity is often associated with cancer but the underlying mechanism remains unclear. Here, the authors show that decreased methylation of PP2A catalytic C subunit caused by loss of LCMT-1 in prostate cancer abrogates the tumor suppressor activity of PP2A on AR/MED1-dependent gene expression, proposing decreased methyl-PP2A-C as a prognostic marker for prostate cancer progression.
- Reyaz ur Rasool
- , Caitlin M. O’Connor
- & Irfan A. Asangani
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RAD51C-XRCC3 structure and cancer patient mutations define DNA replication roles
In this study, the authors present structures and functional analyses for the RAD51C-XRCC3 tumor suppressor complex, providing insights into recurrent mutations in cancer and Fanconi Anemia patients that uncover distinct DNA replication fork protection, restart and reversal regions.
- Michael A. Longo
- , Sunetra Roy
- & Katharina Schlacher
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Article
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p53 restoration in small cell lung cancer identifies a latent cyclophilin-dependent necrosis mechanism
p53 inactivation is nearly universal in small-cell lung cancer (SCLC), but its tumor suppressive role in this cancer type is poorly understood. Here the authors show that intertumoral heterogeneity in SCLC influences the biological mechanisms of p53-mediated tumor suppression and identify a role for cyclophilins in p53-dependent necrotic cell death.
- Jonuelle Acosta
- , Qinglan Li
- & David M. Feldser
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Structures of p53/BCL-2 complex suggest a mechanism for p53 to antagonize BCL-2 activity
The human tumor suppressor p53 interacts with the BCL-2 family proteins to regulate apoptosis. Here, the authors solve the structures of p53 in complex with the antiapoptotic protein BCL-2 and suggest a mechanism by which p53 promotes apoptosis by competitively antagonizing the interaction of BCL-2 with pro-apoptotic BCL-2 family proteins.
- Hudie Wei
- , Haolan Wang
- & Yongheng Chen
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Article
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Hyperphosphorylated PTEN exerts oncogenic properties
PTEN has tumor suppressive functions. Here the authors report that PTEN C-tail hyperphosphorylation promotes neoplastic growth through oncogenic activation of WNT signalling.
- Janine H. van Ree
- , Karthik B. Jeganathan
- & Jan M. van Deursen
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Article
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Protein stabilization of ITF2 by NF-κB prevents colitis-associated cancer development
NF-κB activation contributes to colitis-associated colorectal cancer (CAC). Here the authors show that NF-κB subunit, p65 stabilizes ITF2, which then suppresses NF-κB downstream genes and inhibits CAC progression.
- Mingyu Lee
- , Yi-Sook Kim
- & Hyun-Woo Shin
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Article
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Rewired m6A epitranscriptomic networks link mutant p53 to neoplastic transformation
The dysregulation of the m6A epitranscriptomic networks have been reported to contribute to the development of gliomas. Here, the authors utilize induced pluripotent stem cell-derived astrocytes with a p53 mutation and demonstrate that mutant p53 upregulates the m6A reader YTHDF2, resulting in the initiation of gliomas.
- An Xu
- , Mo Liu
- & Dung-Fang Lee
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The TINCR ubiquitin-like microprotein is a tumor suppressor in squamous cell carcinoma
TINCR encodes a p53-regulated ubiquitin-like microprotein expressed in stratified epithelia. Tincr loss promotes UVB-induced skin carcinogenesis in mice and deletions and mutations in human squamous cell carcinoma support a tumor suppressor role.
- Lucia Morgado-Palacin
- , Jessie A. Brown
- & Adolfo A. Ferrando
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Structural mechanism for inhibition of PP2A-B56α and oncogenicity by CIP2A
Tumour suppressors are inhibited in cancers and their reactivation could provide novel therapy opportunities. Here, the authors study the structural mechanism by which human tumour suppressor Protein Phosphatase 2A is inhibited in breast cancer cells by the oncoprotein CIP2A.
- Karolina Pavic
- , Nikhil Gupta
- & Jukka Westermarck
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Long non-coding RNA-derived peptides are immunogenic and drive a potent anti-tumour response
Long noncoding RNA molecules are RNA transcripts long thought to remain untranslated. In this study, the authors demonstrate that certain lncRNA can be translated into peptides that are immunogenic to CD8+ T cells and promote anti-tumour responses when delivered as vaccine vectors in mice.
- Wojciech Barczak
- , Simon M. Carr
- & Nicholas B. La Thangue
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Loss of phosphatase CTDNEP1 potentiates aggressive medulloblastoma by triggering MYC amplification and genomic instability
Group 3 medulloblastomas (MBs) have the worst prognosis amongst the subtypes of MBs and are associated with MYC amplifications. Here the authors identify that mutations in CTDNEP1 cause MYC activation, amplification, and genomic instability in this subtype of MBs.
- Zaili Luo
- , Dazhuan Xin
- & Q. Richard Lu
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USP5-Beclin 1 axis overrides p53-dependent senescence and drives Kras-induced tumorigenicity
Oncogene-induced senescence (OIS) occurs in premalignant lung adenomas, but infrequently in malignant adenocarcinomas. Here the authors show that USP5-Beclin 1 axis overcomes OIS in Kras-driven lung cancer by enhancing MDM2-mediated p53 degradation.
- Juan Li
- , Yang Wang
- & Zhi-Xiong Jim Xiao
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PPM1D suppresses p53-dependent transactivation and cell death by inhibiting the Integrated Stress Response
The authors describe a functional crosstalk between the p53 network and the integrated stress response through the p53 repressor PPM1D. Inhibition of PPM1D potentiates p53-dependent transactivation and apoptosis via induction of the HRI-eIF2α-ATF4 pathway.
- Zdenek Andrysik
- , Kelly D. Sullivan
- & Joaquin M. Espinosa
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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
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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
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DAXX-ATRX regulation of p53 chromatin binding and DNA damage response
The tumor suppressor proteins DAXX and ATRX are frequently mutated in cancers with alternative lengthening of telomeres (ALT). This study shows that DAXX-ATRX regulates p53 chromatin accessibility and DNA damage response and that disruption of this pathway is critical for ALT cell survival.
- Nitish Gulve
- , Chenhe Su
- & Paul. M. Lieberman
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PTEN inhibits AMPK to control collective migration
Pten is a tumour suppressor gene that is associated with highly invasive cancers such as glioblastoma. Here the authors show that PTEN loss results in increased migratory behaviour, which can be countered by targeting AMPK activity.
- Florent Peglion
- , Lavinia Capuana
- & Sandrine Etienne-Manneville
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Different hotspot p53 mutants exert distinct phenotypes and predict outcome of colorectal cancer patients
The differential effects of TP53 missense mutations in colorectal cancer (CRC) remain to be explored. Here the authors compare the gain of function impact of two frequent TP53 mutations in CRC and show that p53R273 mutants control a transcriptional program, which drives oncogenic signaling pathways, leading to a more aggressive phenotype and worse patient outcome.
- Ori Hassin
- , Nishanth Belugali Nataraj
- & Moshe Oren
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Article
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Comprehensive characterization of PTEN mutational profile in a series of 34,129 colorectal cancers
Loss of the tumour suppressor gene PTEN leads to the activation of pro-tumourigenic signalling pathways. Here, the authors analyse sequencing data from a large cohort of colorectal cancer patients harbouring PTEN mutations and identify distinct patterns of associations with genomic and clinical features.
- Ilya G. Serebriiskii
- , Valery Pavlov
- & Erica A. Golemis
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LKB1 drives stasis and C/EBP-mediated reprogramming to an alveolar type II fate in lung cancer
LKB1 tumour suppressor gene is frequently mutated in lung adenocarcinoma. Here the authors show that in genetically engineered mouse models of lung cancer Lkb1 restoration induces growth arrest and drives neoplastic cells toward a more differentiated and less proliferative alveolar type II cell-like state via C/EBP-mediated reprogramming.
- Christopher W. Murray
- , Jennifer J. Brady
- & Monte M. Winslow
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Article
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Gαi2-induced conductin/axin2 condensates inhibit Wnt/β-catenin signaling and suppress cancer growth
Wnt/β-catenin signalling is frequently hyperactivated in colorectal carcinoma (CRC). Here the authors show that Gαi2 inhibits this signalling pathway by promoting the condensation of conductin/axin2 and β-catenin degradation, and consequently suppresses CRC growth.
- Cezanne Miete
- , Gonzalo P. Solis
- & Dominic B. Bernkopf
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USP44 regulates irradiation-induced DNA double-strand break repair and suppresses tumorigenesis in nasopharyngeal carcinoma
Radiotherapy is the mainstay treatment for nasopharyngeal carcinoma (NPC). Here the authors show that the deubiquitinase, USP44, increases radiosensitivity of NPC cells by promoting the degradation of Ku80, and thus enhancing the levels of DNA damage.
- Yang Chen
- , Yin Zhao
- & Na Liu
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Article
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SPOP mutation induces replication over-firing by impairing Geminin ubiquitination and triggers replication catastrophe upon ATR inhibition
Geminin-Cdt1 plays essential roles in the regulation of DNA replication. Here the authors reveal that the CULLIN3 E3 ubiquitin ligase adaptor protein SPOP prevents DNA replication over-firing and genome instability by affecting Geminin ubiquitination.
- Jian Ma
- , Qing Shi
- & Haojie Huang
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Synthetic essentiality between PTEN and core dependency factor PAX7 dictates rhabdomyosarcoma identity
PTEN copy number loss is found in 25% of fusion-negative rhabdomyosarcomas (FN-RMS). Here, the authors use a Hedgehog-driven FN-RMS mouse model to show that PTEN loss drives the expression of core transcription factor PAX7 and its transcriptional axis, which determines FN-RMS tumour identity.
- Casey G. Langdon
- , Katherine E. Gadek
- & Mark E. Hatley
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Article
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SMARCA4/2 loss inhibits chemotherapy-induced apoptosis by restricting IP3R3-mediated Ca2+ flux to mitochondria
SMARCA4/2 loss in ovarian and lung cancers is associated with chemotherapy resistance. Here, the authors show that SMARCA4/2 deficiency in cancer cells reduces the expression of the ER-Ca2+ channel IP3R3 and subsequently calcium transfer to the mitochondria, which inhibits apoptotic cell death.
- Yibo Xue
- , Jordan L. Morris
- & Sidong Huang
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Article
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Inhibition of CK1ε potentiates the therapeutic efficacy of CDK4/6 inhibitor in breast cancer
Acquisition of CDK4/6i resistance represents a major clinical challenge. Here, the authors report that inhibition of CK1ε can prevent acquisition of CDK4/6i resistance, potentiating the therapeutic efficacy of CDK4/6i in human breast cancer.
- Fabin Dang
- , Li Nie
- & Wenyi Wei
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Article
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Acquisition of aneuploidy drives mutant p53-associated gain-of-function phenotypes
Previous studies report that mutant p53 proteins have gain-of-function activities and cause oncogenic phenotypes. Herein, the authors engineered two isogenic epithelial cell lines to express wild-type or missense mutant p53 or be deficient for p53 protein and show that aneuploidy drives several of the GOF phenotypes previously ascribed to mutant p53.
- Lindsay N. Redman-Rivera
- , Timothy M. Shaver
- & Jennifer A. Pietenpol
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USP12 downregulation orchestrates a protumourigenic microenvironment and enhances lung tumour resistance to PD-1 blockade
The cancer cell-extrinsic roles of deubiquitinases are unclear. Here the authors show that deubiquitinase USP12 downregulation contributes to development of an immune-suppressive tumour microenvironment in KRAS-driven lung cancers and mechanistically this is through the insufficient deubiquitination of the NF-κB inhibitor, PPM1B.
- Zhaojuan Yang
- , Guiqin Xu
- & Yongzhong Liu
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BRCA2 binding through a cryptic repeated motif to HSF2BP oligomers does not impact meiotic recombination
BRCA2 and its interactor HSF2BP are required for meiotic recombination. Here, the authors define the interaction structurally, revealing that a repeat in BRCA2 binds two HSF2BP units, increasing the affinity. This region is, however, not essential for mouse meiosis.
- Rania Ghouil
- , Simona Miron
- & Alex N. Zelensky
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Article
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Loss of fragile site-associated tumor suppressor promotes antitumor immunity via macrophage polarization
The role of common fragile site associated genes such as FATS in the immune system is unclear. Here the authors show that deletion of Fats in a mouse tumour model leads to reduced tumour growth and change of macrophage phenotype from an M2-like to M1-like function.
- Lijuan Zhang
- , Kai Zhang
- & Rongxin Zhang
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Article
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Whole-genome profiling of nasopharyngeal carcinoma reveals viral-host co-operation in inflammatory NF-κB activation and immune escape
The genomic characterisation of nasopharyngeal carcinoma (NPC) remains crucial. Here, the authors perform whole-genome sequencing for 70 NPCs with EBV gene expression, report the somatic alterations and EBV-mediated effects converging on NF-κB activation and immune escape and identify targetable homozygous MTAP deletions.
- Jeff P. Bruce
- , Ka-Fai To
- & Kwok-Wai Lo
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Article
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Multi-omics profiling of primary small cell carcinoma of the esophagus reveals RB1 disruption and additional molecular subtypes
Primary small cell carcinoma of the oesophagus has a poor prognosis, and has not been fully characterised molecularly. Here, the authors study the disease using multi-omics technology and find frequent RB1 disruptions and similarities to small cell lung cancer, opening potential therapeutic avenues.
- Renda Li
- , Zhenlin Yang
- & Jie He
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Article
| Open Access
Tumor suppressor p53 regulates intestinal type 2 immunity
P53 is a well-known tumour suppressor, however its role in intestinal type 2 immunity is currently unclear. Here authors report that during parasitic infections, p53 triggers tuft cell Ca2+ influx and IL-25 release, and shows a regulatory role for p53 in intestinal type 2 immunity via transcriptional regulation of the Lrmp gene.
- Chun-Yuan Chang
- , Jianming Wang
- & Wenwei Hu
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Article
| Open Access
Cut-like homeobox 1 (CUX1) tumor suppressor gene haploinsufficiency induces apoptosis evasion to sustain myeloid leukemia
Cut-like homeobox 1 (CUX1) is a haploinsufficient tumor suppressor commonly inactivated in acute myeloid leukemia and high-risk myelodysplasia. Here, in a genetically modified murine model, the authors show that CUX1 deficiency impairs apoptosis leading to leukemia when combined with mutant Flt3-ITD.
- Emmanuelle Supper
- , Saskia Rudat
- & Chi C. Wong
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Article
| Open Access
Structural insight into the molecular mechanism of p53-mediated mitochondrial apoptosis
The structure of human tumor suppressor p53 in complex with the antiapoptotic protein BCL-xL reveals the basis of the p53–BCL-xL interaction and provides insight into the mechanisms of p53-mediated mitochondrial apoptosis.
- Hudie Wei
- , Lingzhi Qu
- & Yongheng Chen
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Article
| Open Access
Dominant role of CDKN2B/p15INK4B of 9p21.3 tumor suppressor hub in inhibition of cell-cycle and glycolysis
The human chromosome locus 9p21.3 is a tumour suppressor hub which encodes three CDK inhibitors, p15INK4B, p14ARF and p16INK4A. Here, the authors show that p15INK4B inhibits the cell cycle and glycolysis in a murine model of HRas + ‐mediated urothelial carcinoma and has a more relevant role as a tumour suppressor than its neighbouring p16INK4A.
- Yong Xia
- , Yan Liu
- & Xue-Ru Wu
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Article
| Open Access
EGCG binds intrinsically disordered N-terminal domain of p53 and disrupts p53-MDM2 interaction
Epigallocatechin gallate (EGCG) is a catechin flavonoid which induces apoptosis in cancerous cells, but the underlying molecular mechanisms remain poorly understood. Here authors use an interdisciplinary approach to show a direct interaction between EGCG and the tumor suppressor p53 and demonstrate that EGCG inhibits ubiquitination of p53 by MDM2.
- Jing Zhao
- , Alan Blayney
- & Chunyu Wang
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Article
| Open Access
The oncogenicity of tumor-derived mutant p53 is enhanced by the recruitment of PLK3
The mechanisms of how gain-of-function (GOF) mutant p53 drives carcinogenesis are unclear. Here, the authors show that a GOF mutant p53 requires its transactivation capability to induce mouse lung tumors and this is dependent on PLK3 phosphorylation of GOF mutant p53.
- Catherine A. Vaughan
- , Shilpa Singh
- & Sumitra Deb
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Article
| Open Access
Distinct mechanisms control genome recognition by p53 at its target genes linked to different cell fates
The tumor suppressor p53 is a master regulator of cellular stress response pathways, including cell cycle arrest and apoptosis. Here, the authors identify molecular mechanisms of p53 binding to high- and low-affinity p53 response elements in the genome, linked to cell cycle arrest and pro-apoptotic genes, respectively.
- Marina Farkas
- , Hideharu Hashimoto
- & Steven B. McMahon
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Article
| Open Access
Structural insights into TSC complex assembly and GAP activity on Rheb
Tuberous sclerosis complex (TSC) regulates cell growth by controlling the activity of mTORC1. The structure of human TSC complex reveals an arch-shaped, asymmetric architecture and a 2:2:1 stoichiometry of TSC1, TSC2, and TBC1D7 subunits and suggests a mechanism by which TSC2 accelerates GTP hydrolysis against a small GTPase Rheb.
- Huirong Yang
- , Zishuo Yu
- & Yanhui Xu
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Article
| Open Access
A phospho-switch controls RNF43-mediated degradation of Wnt receptors to suppress tumorigenesis
RNF43 is frequently mutated in cancers and negatively regulates Wnt signalling. Here, the authors report that RNF43 phosphorylation at a serine triplet is required for the negative regulation of Wnt signalling and that the phosphorylation of RNF43 suppresses cancer-associated oncogenic RNF43 mutants.
- Tadasuke Tsukiyama
- , Juqi Zou
- & Shigetsugu Hatakeyama
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Article
| Open Access
The REGγ inhibitor NIP30 increases sensitivity to chemotherapy in p53-deficient tumor cells
How the REGγ-proteasome pathway is regulated during the cell cycle or genotoxic insults remains unclear. Here, the authors show that NIP30 acts as a molecular switch to regulate the REGγ-proteasome activity and may provide an approach to combat drug-resistant tumours lacking functional p53.
- Xiao Gao
- , Qingwei Wang
- & Jianru Xiao
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Article
| Open Access
Landscape of somatic single nucleotide variants and indels in colorectal cancer and impact on survival
Large scale sequencing study is of paramount importance to unravel the heterogeneity of colorectal cancer. Here, the authors sequenced 205 cancer genes in more than 2000 tumours and identified additional mutated driver genes, determined that mutational burden and specific mutations in TP53 are associated with survival odds.
- Syed H. Zaidi
- , Tabitha A. Harrison
- & Ulrike Peters
p53 rapidly restructures 3D chromatin organization to trigger a transcriptional response