Genetic editing of colonic organoids provides a molecularly distinct and orthotopic preclinical model of serrated carcinogenesis

Lannagan, Tamsin R.M.; Lee, Young Kyung; Wang, Tongtong; Roper, Jatin; Bettington, Mark; Fennell, Lochlan; Vrbanac, Laura; Jonavicius, Lisa; Somashekar, Roshini; Gieniec, Krystyna A.; Yang, Miao; Ng, Joseph Kim Fai; Suzuki, Nobumi; Ichinose, Mari; Wright, Josephine; Kobayashi, Hiroki; Putoczki, Tracey L; Hayakawa, Yoku; Leedham, Simon J.; Abud, Helen E.; Yılmaz, Ömer H.; Marker, Julie; Klebe, Sonja; Wirapati, Pratyaksha; Mukherjee, Siddhartha; Tejpar, Sabine; Leggett, Barbara A.; Whitehall, Vicki; Worthley, Daniel L.; Woods, Susan L.

doi:10.1136/gutjnl-2017-315920

Cited by 100 publications

(87 citation statements)

References 56 publications

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“…Furthermore, testing for V600E BRAF in primary CRCs and matched metastases, suggests a good mutational status concordance between primary and secondary lesions and tumors lacking V600E BRAF do not acquire this mutation in their metastases [64]. However, BRAF mutation alone is not sufficient for malignant transformation [65] as demonstrated by recent studies that point out the pivotal role of WNT signaling hyperactivation in the "serrated pathway" [66] and suggest how mutant BRAF, phosphorylating the transcriptional co-repressor MAFG, via the BRAF-MEK-ERK axis, induces CpG-islands hypermethylation [5,67]; this could be the molecular confirmation of the link between BRAF mutation and CIMP-H/MSI status in CRC [68]. These new insights could explain the apparent change of the BRAF mutation clinical value during the natural history of CRC.…”

Section: Braf Mutations and Crc Carcinogenesismentioning

confidence: 99%

The heterogeneous clinical and pathological landscapes of metastatic Braf-mutated colorectal cancer

et al. 2020

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Colorectal cancer (CRC) is a complex and molecularly heterogeneous disease representing one of the most frequent causes of cancer-related death worldwide. About 8-15% of CRCs harbor a mutation in BRAF gene, a proto-oncogene involved in cell proliferation, differentiation and survival through the MAPK signaling cascade. The acquisition of BRAF mutation is an early event in the "serrated" CRC carcinogenetic pathway and is associated with specific and aggressive clinico-pathological and molecular features. Despite that the presence of BRAF mutation is a well-recognized negative prognostic biomarker in metastatic CRC (mCRC), a great heterogeneity in survival outcome characterizes these patients, due to the complex, and still not completely fully elucidated, interactions between the clinical, genetic and epigenetic landscape of BRAF mutations. Because of the great aggressiveness of BRAF-mutated mCRCs, only 60% of patients can receive a second-line chemotherapy; so intensive combined and tailored first-line approach could be a potentially effective strategy, but to minimize the selective pressure of resistant clones and to reduce side effects, a better stratification of patients bearing BRAF mutations is needed.

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Section: Braf Mutations and Crc Carcinogenesismentioning

confidence: 99%

The heterogeneous clinical and pathological landscapes of metastatic Braf-mutated colorectal cancer

et al. 2020

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“…These normal and cancer organoids can be used to determine the therapeutic response of drugs on healthy tissue versus tumour from the same patient to alleviate toxicity issues and facilitate the design of best treatment outcomes [190][191][192][193][194][195][196][197][198][199][200]. Moreover, organoids can be used for gene editing using CRISPR/Cas9 knock out techniques to identify key driver mutations requisite for cancer development and progression [204][205][206]. A most recent study has succeed in generating tumour reactive T cell population by co-culturing peripheral blood lymphocytes with tumour organoids from mismatch repair-deficient colorectal cancer and non-small cell lung cancer [195].…”

Section: Patient-derived Tumour Organoid Modellingmentioning

confidence: 99%

Ovarian Cancer, Cancer Stem Cells and Current Treatment Strategies: A Potential Role of Magmas in the Current Treatment Methods

Ahmed

Kadife²,

Raza

et al. 2020

Cells

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Epithelial ovarian cancer (EOC) constitutes 90% of ovarian cancers (OC) and is the eighth most common cause of cancer-related death in women. The cancer histologically and genetically is very complex having a high degree of tumour heterogeneity. The pathogenic variability in OC causes significant impediments in effectively treating patients, resulting in a dismal prognosis. Disease progression is predominantly influenced by the peritoneal tumour microenvironment rather than properties of the tumor and is the major contributor to prognosis. Standard treatment of OC patients consists of debulking surgery, followed by chemotherapy, which in most cases end in recurrent chemoresistant disease. This review discusses the different origins of high-grade serous ovarian cancer (HGSOC), the major sub-type of EOC. Tumour heterogeneity, genetic/epigenetic changes, and cancer stem cells (CSC) in facilitating HGSOC progression and their contribution in the circumvention of therapy treatments are included. Several new treatment strategies are discussed including our preliminary proof of concept study describing the role of mitochondria-associated granulocyte macrophage colony-stimulating factor signaling protein (Magmas) in HGSOC and its unique potential role in chemotherapy-resistant disease. of 35have been observed in OC patients but not in patients with benign and borderline tumours, and this hypomethylation correlates with advanced-stage disease and poor prognosis [48,49]. A genome-wide methylation profiling of blood cells from healthy controls and age-matched untreated OC patients identified CpG methylation of 2714 cancer-related genes, of which 56% were hypomethylated [50]. Ovarian Cancer Stem CellsCellular heterogeneity associated with genetic and epigenetic changes in tumours are linked with the initiation and expansion of CSCs, a population of cells within the tumour, which initiate tumour growth through self-renewal and differentiation processes [51,52]. These cells are more adaptive to the changing tumour microenvironment and tend to be more resistant to treatment. CSCs are highly plastic and a few numbers of isolated CSCs have been shown to be responsible for tumorgenesis and are more chemotherapy and radiation resistant due to their dormant state and a high expression of drug efflux pumps [53,54]. As a result, CSCs are able to adapt to different tumour microenvironments and survive due to their efficient DNA repair mechanisms and their capacity to evade host immune surveillance [55][56][57]. These inherent properties of CSCs suggest an active role in tumour relapse and emphasize the need to develop effective targeted therapies to improve clinical outcomes in patients [51][52][53][54][55][56][57].Stem cells have been identified in ovaries and fallopian tubes [58,59]. These cells express proteins including aldehyde dehydrogenase family 1 A2 (ALDH1A2), homeobox protein NANOG, LIM homeobox protein 9 (LHX9) and frizzled-related protein 1 (SRFP1) and have been observed in OSE, CIC and fimbria [2,[58][59][60][61][62]. In a...

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“…Inactivation of RNF43/ZNRF3-mediated feedback leads to an increased abundance of Wnt receptors at the cell surface, which renders cells hypersensitive to Wnt ligands in their environment (Koo et al, 2012). The resulting Wnt-dependent growth state drives tumorigenesis and generates a druggable addiction to Wnt ligands in these cancer subsets (Wu et al, 2011;Koo et al, 2012;Jiang et al, 2013;Ryland et al, 2013;Zhou et al, 2013;Lannagan et al, 2019). Indeed, blocking Wnt ligand biogenesis by smallmolecule inhibitors of the O-acyltransferase Porcupine (PORCN) suppresses the growth of RNF43-deleted pancreatic and small intestinal tumors in preclinical models (Chen et al, 2009;Jiang et al, 2013;Koo et al, 2015).…”

Section: Introductionmentioning

confidence: 99%

RNF 43 truncations trap CK 1 to drive niche‐independent self‐renewal in cancer

et al. 2020

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Wnt/β‐catenin signaling is a primary pathway for stem cell maintenance during tissue renewal and a frequent target for mutations in cancer. Impaired Wnt receptor endocytosis due to loss of the ubiquitin ligase RNF43 gives rise to Wnt‐hypersensitive tumors that are susceptible to anti‐Wnt‐based therapy. Contrary to this paradigm, we identify a class of RNF43 truncating cancer mutations that induce β‐catenin‐mediated transcription, despite exhibiting retained Wnt receptor downregulation. These mutations interfere with a ubiquitin‐independent suppressor role of the RNF43 cytosolic tail that involves Casein kinase 1 (CK1) binding and phosphorylation. Mechanistically, truncated RNF43 variants trap CK1 at the plasma membrane, thereby preventing β‐catenin turnover and propelling ligand‐independent target gene transcription. Gene editing of human colon stem cells shows that RNF43 truncations cooperate with p53 loss to drive a niche‐independent program for self‐renewal and proliferation. Moreover, these RNF43 variants confer decreased sensitivity to anti‐Wnt‐based therapy. Our data demonstrate the relevance of studying patient‐derived mutations for understanding disease mechanisms and improved applications of precision medicine.

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Genetic editing of colonic organoids provides a molecularly distinct and orthotopic preclinical model of serrated carcinogenesis

Abstract: We generate rapid, complex models of serrated CRC to determine the contribution of specific genetic alterations to carcinogenesis. Analysis of our models alongside patient data has led to the identification of a potential susceptibility for this tumour type.

Cited by 100 publications

References 56 publications

The heterogeneous clinical and pathological landscapes of metastatic Braf-mutated colorectal cancer

The heterogeneous clinical and pathological landscapes of metastatic Braf-mutated colorectal cancer

Ovarian Cancer, Cancer Stem Cells and Current Treatment Strategies: A Potential Role of Magmas in the Current Treatment Methods

RNF 43 truncations trap CK 1 to drive niche‐independent self‐renewal in cancer

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