Genetic Screens Identify a Context-Specific PI3K/p27Kip1 Node Driving Extrahepatic Biliary Cancer

Falcomatà, Chiara; Bärthel, Stefanie; Ulrich, Angelika; Diersch, Sandra; Veltkamp, Christian; Rad, Lena; Boniolo, Fabio; Solar, Myriam; Steiger, Katja; Seidler, Barbara; Żukowska, Magdalena; Madej, Joanna; Wang, Mingsong; Öllinger, Rupert; Maresch, Roman; Barenboim, Maxim; Eser, Stefan; Tschurtschenthaler, Markus; Mehrabi, Arianeb; Roessler, Stephanie; Goeppert, Benjamin; Kind, Alexander; Schnieke, Angelika; Robles, María S.; Bradley, Allan; Schmid, Roland M.; Schmidt-Supprian, Marc; Reichert, Maximilian; Weichert, Wilko; Sansom, Owen J.; Morton, Jennifer P.; Rad, Roland; Schneider, Günter; Saur, Dieter

doi:10.1158/2159-8290.cd-21-0209

Cited by 14 publications

(14 citation statements)

References 69 publications

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“…Future research investigating these molecular interactions may lead to better understanding of cancer pathogenesis and direct the design of new targeted therapies. 22,23 Regarding environmental influences on the development of BRAF-mutated cancers, we found 1 populationbased study that identified an association between high iodine content of drinking water and the prevalence of T1799A BRAF papillary thyroid carcinoma in 5 regions in China. 24 Another study identified an increased risk for colorectal cancer and nonmelanoma skin cancer in the first-degree relatives of index patients with BRAF V600E colorectal cancer.…”

Section: Association Of Braf V600e Expression With Second Primarymentioning

confidence: 97%

Association of BRAF V600E Status of Incident Melanoma and Risk for a Second Primary Malignancy: A Population-Based Study

Laila¹

2022

Cutis

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Section: Association Of Braf V600e Expression With Second Primarymentioning

confidence: 97%

Association of BRAF V600E Status of Incident Melanoma and Risk for a Second Primary Malignancy: A Population-Based Study

Laila¹

2022

Cutis

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“…To obtain cryosections, tissue was fixed in 4% buffered formalin for 2 h, dehydrated in a sucrose series (15% sucrose for 4 h and 30% sucrose overnight), embedded in Tissue-Tek (Sakura Finetek), snap-frozen and sectioned (6 µm). Sections were dried overnight, and staining performed using the Senescence β-Galactosidase Staining Kit (Cell Signaling Technology) 66 . ADMs and PanINs from three different slides per pancreas were assessed for SA-β-gal quantification.…”

Section: Senescence-associated β-Galactosidase (Sa-β-gal) Analysismentioning

confidence: 99%

Non-canonical functions of SNAIL drive context-specific cancer progression

et al. 2023

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SNAIL is a key transcriptional regulator in embryonic development and cancer. Its effects in physiology and disease are believed to be linked to its role as a master regulator of epithelial-to-mesenchymal transition (EMT). Here, we report EMT-independent oncogenic SNAIL functions in cancer. Using genetic models, we systematically interrogated SNAIL effects in various oncogenic backgrounds and tissue types. SNAIL-related phenotypes displayed remarkable tissue- and genetic context-dependencies, ranging from protective effects as observed in KRAS- or WNT-driven intestinal cancers, to dramatic acceleration of tumorigenesis, as shown in KRAS-induced pancreatic cancer. Unexpectedly, SNAIL-driven oncogenesis was not associated with E-cadherin downregulation or induction of an overt EMT program. Instead, we show that SNAIL induces bypass of senescence and cell cycle progression through p16INK4A-independent inactivation of the Retinoblastoma (RB)-restriction checkpoint. Collectively, our work identifies non-canonical EMT-independent functions of SNAIL and unravel its complex context-dependent role in cancer.

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“…118 In a recent study by Falcomatà et al in mice, an activating Kras (G12D) mutation was not able to induce neoplastic transformation of the extrahepatic bile duct but required the repression of tumour suppressor cyclindependent kinase inhibitor 1B (P27kiP1) or the Pik3ca mutation to induce the development of high-grade BilIN. 132 Ras-Raf-MEK-ERK pathway can be activated also by alterations in FGFR pathway. 133 Fusion or rearrangements in FGFR2 have been described in approximately 15%-30% of iCCA.…”

Section: Kras Mutationmentioning

confidence: 99%

“…They are more frequent in BilIN‐3, BilIN associated with invasive carcinoma, and LG‐IPNB, suggesting a role in malignant transformation 118 . In a recent study by Falcomatà et al in mice, an activating Kras (G12D) mutation was not able to induce neoplastic transformation of the extrahepatic bile duct but required the repression of tumour suppressor cyclin‐dependent kinase inhibitor 1B (P27kiP1) or the Pik3ca mutation to induce the development of high‐grade BilIN 132 …”

Section: Preneoplastic Lesions Of Cholangiocarcinomamentioning

confidence: 99%

Preneoplastic lesions in the liver: Molecular insights and relevance for clinical practice

Desjonqueres

Campani

Marra

et al. 2022

Liver International

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Hepatocellular carcinoma (HCC) and cholangiocarcinoma (CCA) are the most frequent primary liver cancers, accounting for approximately 80% and 15%, respectively. HCC carcinogenesis occurs mostly in cirrhosis and is a complex multi-step process, from precancerous lesions (low-grade and high-grade dysplastic nodules) to progressed HCC.During the different stages of liver carcinogenesis, there is an accumulation of pathological, genetic and epigenetic changes leading to initiation, malignant transformation and finally tumour progression. In contrast, a small subset of HCC occurs in normal liver from the transformation of hepatocellular adenoma (HCA), a benign hepatocellular tumour. The recent molecular classification enables to stratify HCAs according to their risk of complication, in particular malignant transformation, associated with mutations in exon 3 of the catenin beta 1 (CTNNB1) gene. Cholangiocarcinoma (CCA) derives from the multistep malignant transformation of preneoplastic lesions, like biliary intraepithelial neoplasia (BilIN) and intraductal papillary neoplasm of the bile duct (IPNB), for which a pre-operative diagnosis remains difficult. Different genetic alterations are involved in BilIN and IPNB progression, leading to the development of tubular or intestinal adenocarcinoma. The aims of this review are to describe the main clinical and molecular features of preneoplastic lesions leading to the development of HCC and CCA, their implications in clinical practice and the perspectives for future research.

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Genetic Screens Identify a Context-Specific PI3K/p27Kip1 Node Driving Extrahepatic Biliary Cancer

Abstract: Research Council (ERC CoG No. 648521 to D.S.), Cancer Research UK core funding to the CRUK Beatson Institute (A17196) and Cancer Research UK core funding to O.S. (A21139).Research.

Cited by 14 publications

References 69 publications

Association of BRAF V600E Status of Incident Melanoma and Risk for a Second Primary Malignancy: A Population-Based Study

Association of BRAF V600E Status of Incident Melanoma and Risk for a Second Primary Malignancy: A Population-Based Study

Non-canonical functions of SNAIL drive context-specific cancer progression

Preneoplastic lesions in the liver: Molecular insights and relevance for clinical practice

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