Differentiation of high‐risk stage I and II colon tumors based on evaluation of <i>CAV1</i> gene expression

Kitowska, Agnieszka; Wesserling, Martyna; Seroczyńska, Barbara; Szutowicz, Andrzej; Ronowska, Anna; Pęksa, Rafał; Pawełczyk, Tadeusz

doi:10.1002/jso.23995

Cited by 8 publications

(6 citation statements)

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“…Although its role in metastasis formation is controversially discussed [ 55 ], there is evidence that CAV1 is decreased in early stages of carcinogenesis [ 56 , 57 ], but is found to be elevated at later stages [ 58 ], including in CRC [ 59 ]. Moreover, increased CAV1 expression in T4-stage CRCs was associated with increased invasiveness [ 60 ], and depletion of CAV1 reduced the invasive properties of human CRC cell lines [ 61 ].…”

Section: Resultsmentioning

confidence: 99%

BRAFV600E drives dedifferentiation in small intestinal and colonic organoids and cooperates with mutant p53 and Apc loss in transformation

et al. 2020

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BRAFV600E confers poor prognosis and is associated with a distinct subtype of colorectal cancer (CRC). Little is known, however, about the genetic events driving the initiation and progression of BRAFV600E mutant CRCs. Recent genetic analyses of CRCs indicate that BRAFV600E often coexists with alterations in the WNT- and p53 pathways, but their cooperation remains ill-defined. Therefore, we systematically compared small and large intestinal organoids from mice harboring conditional BraffloxV600E, Trp53LSL-R172H, and/or Apcflox/flox alleles. Using these isogenic models, we observe tissue-specific differences toward sudden BRAFV600E expression, which can be attributed to different ERK-pathway ground states in small and large intestinal crypts. BRAFV600E alone causes transient proliferation and suppresses epithelial organization, followed by organoid disintegration. Moreover, BRAFV600E induces a fetal-like dedifferentiation transcriptional program in colonic organoids, which resembles human BRAFV600E-driven CRC. Co-expression of p53R172H delays organoid disintegration, confers anchorage-independent growth, and induces invasive properties. Interestingly, p53R172H cooperates with BRAFV600E to modulate the abundance of transcripts linked to carcinogenesis, in particular within colonic organoids. Remarkably, WNT-pathway activation by Apc deletion fully protects organoids against BRAFV600E-induced disintegration and confers growth/niche factor independence. Still, Apc-deficient BRAFV600E-mutant organoids remain sensitive toward the MEK inhibitor trametinib, albeit p53R172H confers partial resistance against this clinically relevant compound. In summary, our systematic comparison of the response of small and large intestinal organoids to oncogenic alterations suggests colonic organoids to be better suited to model the human situation. In addition, our work on BRAF-, p53-, and WNT-pathway mutations provides new insights into their cooperation and for the design of targeted therapies.

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Section: Resultsmentioning

confidence: 99%

BRAFV600E drives dedifferentiation in small intestinal and colonic organoids and cooperates with mutant p53 and Apc loss in transformation

et al. 2020

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“…Interestingly, Caveolin-1 can both activate and inhibit the activity of the receptors (47,48). Accordingly, in some types of cancer Caveolin-1 was characterized as an oncosuppressor (breast cancer (49)), and in others as an oncogene (colorectal and prostate cancer (50,51)). Controversial data were also obtained for GBM, where in some experimental models…”

Section: Discussionmentioning

confidence: 99%

Investigation of Inter- and Intratumoral Heterogeneity of Glioblastoma Using TOF-SIMS

Gularyan

Гулин

Anufrieva

et al. 2020

Molecular & Cellular Proteomics

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Glioblastoma (GBM) is one of the most aggressive human cancers with a median survival of less than two years. A distinguishing pathological feature of GBM is a high degree of inter- and intratumoral heterogeneity. Intertumoral heterogeneity of GBM has been extensively investigated on genomic, methylomic, transcriptomic, proteomic and metabolomics levels, however only a few studies describe intratumoral heterogeneity because of the lack of methods allowing to analyze GBM samples with high spatial resolution. Here, we applied TOF-SIMS (Time-of-flight secondary ion mass spectrometry) for the analysis of single cells and clinical samples such as paraffin and frozen tumor sections obtained from 57 patients. We developed a technique that allows us to simultaneously detect the distribution of proteins and metabolites in glioma tissue with 800 nm spatial resolution. Our results demonstrate that according to TOF-SIMS data glioma samples can be subdivided into clinically relevant groups and distinguished from the normal brain tissue. In addition, TOF-SIMS was able to elucidate differences between morphologically distinct regions of GBM within the same tumor. By staining GBM sections with gold-conjugated antibodies against Caveolin-1 we could visualize border between zones of necrotic and cellular tumor and subdivide glioma samples into groups characterized by different survival of the patients. Finally, we demonstrated that GBM contains cells that are characterized by high levels of Caveolin-1 protein and cholesterol. This population may partly represent a glioma stem cells. Collectively, our results show that the technique described here allows to analyze glioma tissues with a spatial resolution beyond reach of most of other omics approaches and the obtained data may be used to predict clinical behavior of the tumor.

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“…In fact, this hypothesis is supported by the reported role of CAV‐1 promoting cell invasion and metastasis of CRC cells [14, 15]. Moreover, it has been recently reported that CAV‐1 determines unfavorable outcome in stage I–II CRC and was found associated with tumor with greater depths of invasiveness [16]. Thus, the precise status of CAV‐1 in CRC must be fully clarified due to discrepancies in the existing literature.…”

Section: Introductionmentioning

confidence: 93%

Caveolin‐1 is Markedly Downregulated in Patients with Early‐Stage Colorectal Cancer

et al. 2017

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Differentiation of high‐risk stage I and II colon tumors based on evaluation of CAV1 gene expression

Abstract: Evaluation of CAV1 expression offers valuable prognostic information for patients with colorectal cancer, and could be used to select patients with stage I or II disease, who are at increased risk of unfavorable outcomes.

Cited by 8 publications

References 50 publications

BRAFV600E drives dedifferentiation in small intestinal and colonic organoids and cooperates with mutant p53 and Apc loss in transformation

BRAFV600E drives dedifferentiation in small intestinal and colonic organoids and cooperates with mutant p53 and Apc loss in transformation

Investigation of Inter- and Intratumoral Heterogeneity of Glioblastoma Using TOF-SIMS

Caveolin‐1 is Markedly Downregulated in Patients with Early‐Stage Colorectal Cancer

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