Pan-cancer analysis reveals TAp63-regulated oncogenic lncRNAs that promote cancer progression through AKT activation

The most frequent genetic alterations across multiple human cancers are mutations in TP53 and the activation of the PI3K/AKT pathway, two events crucial for cancer progression. Mutations in TP53 lead to the inhibition of the tumour and metastasis suppressor TAp63, a p53 family member. By performing a mouse-human cross species analysis between the TAp63 metastatic mammary adenocarcinoma mouse model and models of human breast cancer progression, we identified two TAp63-regulated oncogenic lncRNAs, TROLL-2 and TROLL-3. Further, using a pan-cancer analysis of human cancers and multiple mouse models of tumour progression, we revealed that these two lncRNAs induce the activation of AKT to promote cancer progression by regulating the nuclear to cytoplasmic translocation of their effector, WDR26, via the shuttling protein NOLC1. Our data provide preclinical rationale for the implementation of these lncRNAs and WDR26 as therapeutic targets for the treatment of human tumours dependent upon mutant TP53 and/or the PI3K/AKT pathway.


Statistics
For all statistical analyses, confirm that the following items are present in the figure legend, table legend, main text, or Methods section.
n/a Confirmed The exact sample size (n) for each experimental group/condition, given as a discrete number and unit of measurement A statement on whether measurements were taken from distinct samples or whether the same sample was measured repeatedly The statistical test(s) used AND whether they are one-or two-sided Only common tests should be described solely by name; describe more complex techniques in the Methods section.
A description of all covariates tested A description of any assumptions or corrections, such as tests of normality and adjustment for multiple comparisons A full description of the statistical parameters including central tendency (e.g. means) or other basic estimates (e.g. regression coefficient) AND variation (e.g. standard deviation) or associated estimates of uncertainty (e.g. confidence intervals) For null hypothesis testing, the test statistic (e.g. F, t, r) with confidence intervals, effect sizes, degrees of freedom and P value noted For manuscripts utilizing custom algorithms or software that are central to the research but not yet described in published literature, software must be made available to editors and reviewers. We strongly encourage code deposition in a community repository (e.g. GitHub). See the Nature Research guidelines for submitting code & software for further information.

Data
Policy information about availability of data All manuscripts must include a data availability statement. This statement should provide the following information, where applicable: -Accession codes, unique identifiers, or web links for publicly available datasets -A list of figures that have associated raw data -A description of any restrictions on data availability Public available data used in this paper were obtained from UCSC (http://genome.ucsc.edu/cgibin/hgGateway) and The Cancer Genome Atlas (TCGA) breast cancer and melanoma datasets (http://www.cancer.gov/about-nci/organization/ccg/research/structural-genomics/tcga). The source data underlying Figs. 1a-h, 2a-d, 2f, 2h, 3b-e, 4b-f, 5a, 5c, 5e, 6a-e and Supplementary Figs. 1a-i, 2a-m, 2o, 2q, 3a-k, 4a-h, 5a-m', 5o', 5q', 5s', 5u', 5x'-a", 5c", 5e", 6a-6l" are provided as Source Data File. All the other data (imaging) supporting the findings of this study are available from the corresponding author upon reasonable request.

nature research | reporting summary
April 2020 Field-specific reporting Please select the one below that is the best fit for your research. If you are not sure, read the appropriate sections before making your selection.

Life sciences Behavioural & social sciences Ecological, evolutionary & environmental sciences
For a reference copy of the document with all sections, see nature.com/documents/nr-reporting-summary-flat.pdf

Life sciences study design
All studies must disclose on these points even when the disclosure is negative.

Sample size
For all the in vitro experiments, a minimum of three biological replicates were used per sample. For all the in vivo experiment, a minimum of five mice were used per each group. No statistical method was used to determine the sample/group size.
Data exclusions None of the replicates was excluded from any of the presented data.

Replication
Experiments were successfully performed at least three times. All replication attempts were successful.
Randomization Mice were randomly allocated into different experimental groups before being injected with the cell lines of interest. For experiments involving cellular and biological studies, three independent experiments have been performed, allocating randomly cells in experimental groups.

Blinding
Tumour volume assessment and the quantification of lung nodules were blinded. The IHC and ISH signals and the proportion of positive tissue were measured blindly. For most of the other experiments, the results were quantified and appropriate statistical tests were performed to evaluate difference and statistical significance.

Reporting for specific materials, systems and methods
We require information from authors about some types of materials, experimental systems and methods used in many studies. Here, indicate whether each material, system or method listed is relevant to your study. If you are not sure if a list item applies to your research, read the appropriate section before selecting a response.