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p53 is an important tumour suppressor gene. Two papers now show in a Kras-driven lung cancer model that p53-mediated tumour suppression is only engaged late during tumour progression, when the Kras oncogenic signal reaches a threshold sufficient to activate the ARF–p53 pathway. Therefore, p53 re-expression in p53-deficient lung tumours does not restrict early stages of tumorigenesis, but induces tumour regression of more aggressive tumours.

Little is known about how mutations in genes encoding tumor suppressors influence metastatic site selection and whether sustained inactivation of such genes influences tumor maintenance at these sites. A new study shows that restoration of Smad4 expression in extant pancreatic metastases has anti-tumor effects in the liver but pro-tumor effects in the lungs.

Using mouse pancreatic cancer models, Tsanov et al. show that reactivation of SMAD4 at metastatic sites promotes tumor growth in the lung through RUNX1 but restrains metastatic growth through KLF4 in the liver, influenced by organ-specific epigenetic states.

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.

Cui et al. identify an important role for MLL3 in regulating the hybrid epithelial–mesenchymal transition state in breast cancer and show that deletion of MLL3 enhances metastatic capacity through increased IFNγ signalling.

Subretinal viral delivery, in mice, of an adenine base editor and a single-guide RNA targeting a nonsense mutation in the Rpe65 gene restores near-normal levels of retinal and visual functions.

Synthetic biology can be used to regulate target genes and uncover gene function in physiologically relevant settings. Here Robles-Oteiza et al. describe a new recombinase-based system for conditional inactivation and inducible restoration of gene function and develop new mouse models to study p53 and Rb.

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.

NF-κB transcription factors have been implicated in cellular transformation and tumorigenesis, but despite extensive biochemical characterization of NF-κB signalling, its requirement in tumour development is not completely understood. Here, the NF-κB pathway is shown to be required for the development of tumours in a mouse model of lung adenocarcinoma in a p53-status-dependent manner, providing support for the development of NF-κB inhibitory drugs as targeted therapies.

Studies using mouse models of lung adenocarcinoma identify an association between age, iron homeostasis and tumour initiation potential that involves NUPR1 and lipocalin-2.

Loss of RB promotes both malignant progression and the development of metastatic disease; however, whereas reactivation of the RB pathway can revert metastatic tumour cell states to non-metastatic cell states, malignant cell proliferation is supported by MAPK–CDK2-dependent suppression of RB.

Tsang et al. show that copper modulates the activity of autophagic kinases ULK1/2 to control autophagy, and is required for KRAS^G12D-driven tumour growth and cancer survival in response to starvation.

Pierce et al perform genome-wide CRISPR screening and identify LKB1 as a regulator of chromatin accessibility and metastatic progression in lung cancer through a mechanism of SOX17-mediated epigenetic changes.

This study uses chromatin marks in four mouse cell types to identify ∼1,600 large multi-exonic transcriptional units that do not overlap known protein-coding loci and are highly conserved. Putative functions are assigned to each of these large intervening non-coding RNAs, which range from ES pluripotency to cell proliferation.

SETD2 inactivation leads to heightened mTORC1 signaling, oxidative metabolism and protein synthesis in KRAS-driven mouse models of lung adenocarcinoma, contributing to the understanding of how SETD2 deficiency drives early and widespread tumor growth.