Context-Dependent Transformation of Adult Pancreatic Cells by Oncogenic K-Ras

Friedlander, Sharon; Chu, Gerald C.; Snyder, Eric L.; Girnius, Nomeda; Dibelius, Gregory; Crowley, Denise; Vasile, Eliza; DePinho, Ronald A.; Jacks, Tyler

doi:10.1016/j.ccr.2009.09.027

Cited by 312 publications

(278 citation statements)

References 54 publications

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“…Additionally, a recent study highlighted this tumorigenic mechanism in a model of pancreatic cancer. In that model, certain cell populations were refractory to transformation until exposed to an inflammatory environment generated by wounding (55). This raises the question of whether a tumorigenic load exists that can drive cancer formation in the Shh-expressing hair follicle TA population and represents a direction for future experiments.…”

Section: Discussionmentioning

confidence: 99%

Defining the origins of Ras/p53-mediated squamous cell carcinoma

White

Tran

Khuu

et al. 2011

Proc. Natl. Acad. Sci. U.S.A.

168

158

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The precise identity of cancer cells of origin and the molecular events of tumor initiation in epidermal squamous cell carcinoma (SCC) are unknown. Here we show that malignancy potential is related to the developmental capacity of the initiating cancer cell in a genetically defined, intact, and inducible in vivo model. Specifically, these data demonstrate that SCCs can originate from inside the hair follicle stem cell (SC) niche or from immediate progenitors, whereas more developmentally restricted progeny, the transit amplifying (TA) cells, are unable to generate even benign tumors in the same genetic context. Using a temporal model of tumorigenesis in situ, we highlight the phenotypes of cancer progression from the hair follicle SC niche, including hyperplasia, epithelial to mesenchymal transition, and SCC formation. Furthermore, we provide insights into the inability of hair follicle TA cells to respond to tumorigenic stimuli. mouse models of cancer | tumor initiating cells | epidermal stem cells S quamous cell carcinoma (SCC), a common type of nonmelanoma skin cancer, harbors significant risk of metastasis that can eventually lead to death (1). Permanent treatment and prevention of SCC requires an improved understanding of the unique cell types capable of initiating these malignancies and the mechanisms that underlie their transformation. Mutations in the Ras gene family are found in 30% of all human cancers and are often found in human cases of SCC (2-4). Numerous animal studies have extended the understanding of SCC by demonstrating a causative role for the Ras family in the development of SCC. In these mouse models, Ras signaling has been shown to be sufficient to drive epidermal tumorigenesis through either overexpression or targeted expression of an oncogenic form of Hras or Kras. These studies have targeted broad epidermal cell populations that include stem cells (SCs), as well as cells of the outer root sheath (ORS) and interfollicular epidermis (IFE) (4-9). Among these, a landmark article indicated that the SCC cells of origin reside in the hair follicle rather than the IFE (5). However, the keratin promoter used to drive oncogenic Ras expression did not allow for a direct determination of the cancer cell of origin amongst the different cell types in the hair follicle. The candidates for an SCC cell of origin therefore remained follicular SCs, ORS cells, transit amplifying (TA) cells in the matrix, and the differentiated cells of the inner root sheath (IRS) and hair shaft. In addition, other studies have shown that lineagerestricted or differentiated cells of the IFE are sufficient to serve as cancer cells of origin when subjected to supraphysiological levels of Ras activity at sites of mechanical stress (10). These high levels of Ras expression, however, are not normally found in human cases of SCC (10, 11). Between follicular SCs and TA cells, it is not clear whether one or both are capable of initiating tumorigenesis. Thus, we sought to directly compare the malignancy potential between follicular ...

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Section: Discussionmentioning

confidence: 99%

Defining the origins of Ras/p53-mediated squamous cell carcinoma

White

Tran

Khuu

et al. 2011

Proc. Natl. Acad. Sci. U.S.A.

168

158

View full text Add to dashboard Cite

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“…5) suggest that aberrant expression of LRH-1 might be linked to proliferation of dedifferentiated pancreatic cancer cells, which are associated with aggressive pancreatic tumors (37). Recent studies demonstrated the inherent plasticity of pancreatic cells that can be reprogrammed to the transient dedifferentiated progenitor-like states, which can give rise to PDAC (38)(39)(40). Because of the established roles of LRH-1 in pancreatic and stem cell differentiation (7-9, 20), we hypothesize that this receptor might contribute to the reprogramming events in the adult pancreas that lead to its transformation.…”

Section: Discussionmentioning

confidence: 99%

Nuclear receptor liver receptor homologue 1 (LRH-1) regulates pancreatic cancer cell growth and proliferation

Benod

Vinogradova

Jouravel

et al. 2011

Proc. Natl. Acad. Sci. U.S.A.

116

125

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An essential regulator of gene transcription, nuclear receptor liver receptor homologue 1 (LRH-1) controls cell differentiation in the developing pancreas and maintains cholesterol homeostasis in adults. Recent genome-wide association studies linked mutations in the LRH-1 gene and its up-stream regulatory regions to development of pancreatic cancer. In this work, we show that LRH-1 transcription is activated up to 30-fold in human pancreatic cancer cells compared to normal pancreatic ductal epithelium. This activation correlates with markedly increased LRH-1 protein expression in human pancreatic ductal adenocarcinomas in vivo. Selective blocking of LRH-1 by receptor specific siRNA significantly inhibits pancreatic cancer cell proliferation in vitro. The inhibition is tracked in part to the attenuation of the receptor's transcriptional targets controlling cell growth, proliferation, and differentiation. Previously, LRH-1 was shown to contribute to formation of intestinal tumors. This study demonstrates the critical involvement of LRH-1 in development and progression of pancreatic cancer, suggesting the LRH-1 receptor as a plausible therapeutic target for treatment of pancreatic ductal adenocarcinomas.protein target | gene regulation W ith mortality rate nearing its incidence, pancreatic ductal adenocarcinoma (PDAC) presents a challenge for modern oncology. Current chemotherapy drugs approved for pancreatic cancer are not organ specific and are modestly effective. Thus, there is a need for improved therapeutic options and effective pancreatic cancer drugs. Recent studies reveal that signaling pathways are similar in pancreatic development and malignant growth in the adult pancreas (1, 2). One of the common driving factors in pancreatic embryo-and oncogenesis is the nuclear receptor liver receptor homologue 1 (LRH-1,

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“…Deletion or homozygous inactive mutations in PDX1 is lethal in mice due to whole pancreatic agenesis (2,3). Conditional knockout of PDX1 gene in β cells leads to overt diabetes, whereas knockingdown of PDX1 expression results in decreased insulin secretion in mice (4). PDX1 mutant zebrafish also exhibit several key diabetic features including reduced β cell mass, decreased insulin and elevated glucose levels.…”

Section: Pdx1 and Pdx1 Involved Diseasesmentioning

confidence: 99%

PDX1 associated therapy in translational medicine

Yu¹,

Liu²,

Sanchez³

et al. 2016

Ann. Transl. Med.

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Pancreatic ductal adenocarcinoma (PDAC) is characterized by an extremely poor prognosis and a low median survival due to lack of the early and reliable detection and effective therapeutic options, despite improvements observed for many other cancers in last decade. Pancreatic and duodenal homeobox 1 (PDX1), which is a homeodomain-containing transcription factor and a key regulator for insulin gene expression, β cell maturation and proper β cell function maintenance in the pancreas. Our previous studies revealed that PDX1 promotes tumorigenesis and it is a promising therapeutic target for PDAC. For translational purposes, we developed three therapeutic platforms utilizing RNA interference (RNAi), gene therapy and small inhibitory drug targeting PDX1, and further validated them in PDAC preclinical models both in vitro and in vivo. These PDX1 targeted therapies significantly inhibited PDX1 expression in PDAC cells, ablated PDX1-expressing human PDAC xenograft tumor growth, and prolonged survival in the PDAC mouse models. The data from these preclinical studies proved the translational potentials of PDX1 targeted therapies in PDAC and suggest that the strategy of developing PDX1 targeted therapies would permit a rapid bench-to-bedside translation of other relevant gene therapies, which would eventually benefit the patients suffering from this deadly disease.

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Context-Dependent Transformation of Adult Pancreatic Cells by Oncogenic K-Ras

Cited by 312 publications

References 54 publications

Defining the origins of Ras/p53-mediated squamous cell carcinoma

Defining the origins of Ras/p53-mediated squamous cell carcinoma

Nuclear receptor liver receptor homologue 1 (LRH-1) regulates pancreatic cancer cell growth and proliferation

PDX1 associated therapy in translational medicine

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