{"entity": "journal", "iuid": "5a75a1f80afc420190972c67e7d60f26", "timestamp": "2026-08-23T09:24:49.283Z", "links": {"self": {"href": "https://publications-affiliated.scilifelab.se/journal/Mol%20Cancer.json"}, "display": {"href": "https://publications-affiliated.scilifelab.se/journal/Mol%20Cancer"}}, "title": "Mol Cancer", "issn": "1476-4598", "issn-l": null, "publications_count": 3, "publications": [{"entity": "publication", "iuid": "8eef0e19ea284ff5a9f93021e3b33f6b", "links": {"self": {"href": "https://publications-affiliated.scilifelab.se/publication/8eef0e19ea284ff5a9f93021e3b33f6b.json"}, "display": {"href": "https://publications-affiliated.scilifelab.se/publication/8eef0e19ea284ff5a9f93021e3b33f6b"}}, "title": "Co-occurring mutations identify prognostic subgroups of microsatellite stable colorectal cancer.", "authors": [{"family": "Nunes", "given": "Lu\u00eds", "initials": "L"}, {"family": "Stenersen", "given": "Jakob M\u00f8rkved", "initials": "JM"}, {"family": "Kryeziu", "given": "Kushtrim", "initials": "K"}, {"family": "Sj\u00f6blom", "given": "Tobias", "initials": "T"}, {"family": "Glimelius", "given": "Bengt", "initials": "B"}, {"family": "Lothe", "given": "Ragnhild A", "initials": "RA"}, {"family": "Sveen", "given": "Anita", "initials": "A"}], "type": "journal article", "published": "2024-11-25", "journal": {"title": "Mol Cancer", "issn": "1476-4598", "volume": "23", "issue": "1", "pages": "264", "issn-l": null}, "abstract": "Co-occurring mutations in pairs of genes can pinpoint clinically relevant subgroups of cancer. Most colorectal cancers (CRCs) are microsatellite stable (MSS) and have few frequent mutations. Large patient cohorts and broad genomic coverage are needed for comprehensive co-mutation profiling.\n\nCo-mutations were identified in a population-based Swedish cohort analyzed by whole-genome sequencing (n=819 stage I-IV MSS CRCs). Prognostic value was further evaluated in a publicly available dataset of clinically sequenced metastatic CRCs (MSK-IMPACT; n=934 MSS). Multivariable Cox proportional hazards analyses with clinicopathological parameters were performed for locoregional (stage I-III) and metastatic (stage IV and recurrent) cancers separately.\n\nPrevalent co-mutations were detected in 23 unique gene pairs, 20 of which included APC, TP53, KRAS and/or PIK3CA. Several co-mutations involving APC were associated with good overall survival in locoregional CRC, including APC-TCF7L2 (multivariable HR: 0.49, 95% CI 0.27-0.89). This co-mutation was prognostic also in metastatic cancers (multivariable HR: 0.49 and 0.37, 95% CI: 0.24-0.98 and 0.17-0.82 in the Swedish and MSK cohorts, respectively). APC-SOX9 co-mutations were mutually exclusive with APC-TCF7L2, and the co-mutations combined had stronger prognostic associations than APC alone in both metastatic cohorts. BRAF p.V600E-RNF43 co-mutations were associated with poor overall and recurrence-free survival in locoregional CRC (multivariable HR: 4.13 and 3.2, 95% CI: 1.78-9.54 and 1.53-8.04, respectively).\n\nWe report a genome-wide evaluation of co-occurring mutations in MSS CRCs, and suggest that co-mutations can improve the prognostic stratification compared to single mutations alone.", "doi": "10.1186/s12943-024-02173-x", "pmid": "39587554", "labels": [], "xrefs": [{"db": "pmc", "key": "PMC11587607"}, {"db": "pii", "key": "10.1186/s12943-024-02173-x"}], "notes": [], "created": "2026-08-20T12:20:43.325Z", "modified": "2026-08-20T12:20:43.392Z"}, {"entity": "publication", "iuid": "77436d743f664db9b6ff9c08415bad88", "links": {"self": {"href": "https://publications-affiliated.scilifelab.se/publication/77436d743f664db9b6ff9c08415bad88.json"}, "display": {"href": "https://publications-affiliated.scilifelab.se/publication/77436d743f664db9b6ff9c08415bad88"}}, "title": "Loss of the tumour suppressor LKB1/STK11 uncovers a leptin-mediated sensitivity mechanism to mitochondrial uncouplers for targeted cancer therapy.", "authors": [{"family": "Angelopoulou", "given": "Andriani", "initials": "A"}, {"family": "Theocharous", "given": "Giorgos", "initials": "G"}, {"family": "Valakos", "given": "Dimitrios", "initials": "D"}, {"family": "Polyzou", "given": "Aikaterini", "initials": "A"}, {"family": "Magkouta", "given": "Sophia", "initials": "S"}, {"family": "Myrianthopoulos", "given": "Vassilios", "initials": "V"}, {"family": "Havaki", "given": "Sophia", "initials": "S"}, {"family": "Fiorillo", "given": "Marco", "initials": "M"}, {"family": "Tremi", "given": "Ioanna", "initials": "I"}, {"family": "Vachlas", "given": "Konstantinos", "initials": "K"}, {"family": "Nisotakis", "given": "Theodoros", "initials": "T"}, {"family": "Thanos", "given": "Dimitris-Foivos", "initials": "DF"}, {"family": "Pantazaki", "given": "Anastasia", "initials": "A"}, {"family": "Kletsas", "given": "Dimitris", "initials": "D"}, {"family": "Bartek", "given": "Jiri", "initials": "J"}, {"family": "Petty", "given": "Russell", "initials": "R"}, {"family": "Thanos", "given": "Dimitris", "initials": "D"}, {"family": "McCrimmon", "given": "Rory J", "initials": "RJ"}, {"family": "Papaspyropoulos", "given": "Angelos", "initials": "A"}, {"family": "Gorgoulis", "given": "Vassilis G", "initials": "VG"}], "type": "letter", "published": "2024-07-25", "journal": {"title": "Mol Cancer", "issn": "1476-4598", "volume": "23", "issue": "1", "pages": "147", "issn-l": null}, "abstract": "Non-small cell lung cancer (NSCLC) constitutes one of the deadliest and most common malignancies. The LKB1/STK11 tumour suppressor is mutated in \u223c 30% of NSCLCs, typically lung adenocarcinomas (LUAD). We implemented zebrafish and human lung organoids as synergistic platforms to pre-clinically screen for metabolic compounds selectively targeting LKB1-deficient tumours. Interestingly, two kinase inhibitors, Piceatannol and Tyrphostin 23, appeared to exert synthetic lethality with LKB1 mutations. Although LKB1 loss alone accelerates energy expenditure, unexpectedly we find that it additionally alters regulation of the key energy homeostasis maintenance player leptin (LEP), further increasing the energetic burden and exposing a vulnerable point; acquired sensitivity to the identified compounds. We show that compound treatment stabilises Hypoxia-inducible factor 1-alpha (HIF1A) by antagonising Von Hippel-Lindau (VHL)-mediated HIF1A ubiquitination, driving LEP hyperactivation. Importantly, we demonstrate that sensitivity to piceatannol/tyrphostin 23 epistatically relies on a HIF1A-LEP-Uncoupling Protein 2 (UCP2) signaling axis lowering cellular energy beyond survival, in already challenged LKB1-deficient cells. Thus, we uncover a pivotal metabolic vulnerability of LKB1-deficient tumours, which may be therapeutically exploited using our identified compounds as mitochondrial uncouplers.", "doi": "10.1186/s12943-024-02061-4", "pmid": "39048991", "labels": [], "xrefs": [{"db": "pmc", "key": "PMC11270803"}, {"db": "pii", "key": "10.1186/s12943-024-02061-4"}], "notes": [], "created": "2026-08-21T12:39:26.356Z", "modified": "2026-08-21T12:39:26.385Z"}, {"entity": "publication", "iuid": "eb1effe28abd4309ba85a82ff5a22943", "links": {"self": {"href": "https://publications-affiliated.scilifelab.se/publication/eb1effe28abd4309ba85a82ff5a22943.json"}, "display": {"href": "https://publications-affiliated.scilifelab.se/publication/eb1effe28abd4309ba85a82ff5a22943"}}, "title": "Chromatin insulation orchestrates matrix metalloproteinase gene cluster expression reprogramming in aggressive breast cancer tumors.", "authors": [{"family": "Llin\u00e0s-Arias", "given": "Pere", "initials": "P"}, {"family": "Ensenyat-Mendez", "given": "Miquel", "initials": "M"}, {"family": "\u00cd\u00f1iguez-Mu\u00f1oz", "given": "Sandra", "initials": "S"}, {"family": "Orozco", "given": "Javier I J", "initials": "JIJ"}, {"family": "Valdez", "given": "Betsy", "initials": "B"}, {"family": "Salomon", "given": "Matthew P", "initials": "MP"}, {"family": "Matsuba", "given": "Chikako", "initials": "C"}, {"family": "Solivellas-Pieras", "given": "Maria", "initials": "M"}, {"family": "Bedoya-L\u00f3pez", "given": "Andr\u00e9s F", "initials": "AF"}, {"family": "Ses\u00e9", "given": "Borja", "initials": "B"}, {"family": "Mezger", "given": "Anja", "initials": "A"}, {"family": "Ormestad", "given": "Mattias", "initials": "M"}, {"family": "Unzueta", "given": "Fernando", "initials": "F"}, {"family": "Strand", "given": "Siri H", "initials": "SH"}, {"family": "Boiko", "given": "Alexander D", "initials": "AD"}, {"family": "Hwang", "given": "E Shelley", "initials": "ES"}, {"family": "Cort\u00e9s", "given": "Javier", "initials": "J"}, {"family": "DiNome", "given": "Maggie L", "initials": "ML"}, {"family": "Esteller", "given": "Manel", "initials": "M"}, {"family": "Lupien", "given": "Mathieu", "initials": "M"}, {"family": "Marzese", "given": "Diego M", "initials": "DM"}], "type": "journal article", "published": "2023-11-28", "journal": {"title": "Mol Cancer", "issn": "1476-4598", "volume": "22", "issue": "1", "pages": "190", "issn-l": null}, "abstract": "Triple-negative breast cancer (TNBC) is an aggressive subtype that exhibits a high incidence of distant metastases and lacks targeted therapeutic options. Here we explored how the epigenome contributes to matrix metalloprotease (MMP) dysregulation impacting tumor invasion, which is the first step of the metastatic process.\n\nWe combined RNA expression and chromatin interaction data to identify insulator elements potentially associated with MMP gene expression and invasion. We employed CRISPR/Cas9 to disrupt the CCCTC-Binding Factor (CTCF) binding site on an insulator element downstream of the MMP8 gene (IE8) in two TNBC cellular models. We characterized these models by combining Hi-C, ATAC-seq, and RNA-seq with functional experiments to determine invasive ability. The potential of our findings to predict the progression of ductal carcinoma in situ (DCIS), was tested in data from clinical specimens.\n\nWe explored the clinical relevance of an insulator element located within the Chr11q22.2 locus, downstream of the MMP8 gene (IE8). This regulatory element resulted in a topologically associating domain (TAD) boundary that isolated nine MMP genes into two anti-correlated expression clusters. This expression pattern was associated with worse relapse-free (HR = 1.57 [1.06 - 2.33]; p = 0.023) and overall (HR = 2.65 [1.31 - 5.37], p = 0.005) survival of TNBC patients. After CRISPR/Cas9-mediated disruption of IE8, cancer cells showed a switch in the MMP expression signature, specifically downregulating the pro-invasive MMP1 gene and upregulating the antitumorigenic MMP8 gene, resulting in reduced invasive ability and collagen degradation. We observed that the MMP expression pattern predicts DCIS that eventually progresses into invasive ductal carcinomas (AUC = 0.77, p < 0.01).\n\nOur study demonstrates how the activation of an IE near the MMP8 gene determines the regional transcriptional regulation of MMP genes with opposing functional activity, ultimately influencing the invasive properties of aggressive forms of breast cancer.", "doi": "10.1186/s12943-023-01906-8", "pmid": "38017545", "labels": [], "xrefs": [{"db": "pmc", "key": "PMC10683115"}, {"db": "pii", "key": "10.1186/s12943-023-01906-8"}], "notes": [], "created": "2026-08-21T12:39:24.542Z", "modified": "2026-08-21T12:39:24.558Z"}], "created": "2026-08-20T12:20:43.356Z", "modified": "2026-08-20T12:20:43.356Z"}