Metastatic Pancreatic Cancer Is Dependent on Oncogenic Kras in Mice (original) (raw)
Related papers
KRAS: The Critical Driver and Therapeutic Target for Pancreatic Cancer
Cold Spring Harbor perspectives in medicine, 2017
RAS genes (HRAS, KRAS, and NRAS) comprise the most frequently mutated oncogene family in human cancer. With the highest RAS mutation frequencies seen with the top three causes of cancer deaths in the United States (lung, colorectal, and pancreatic cancer), the development of anti-RAS therapies is a major priority for cancer research. Despite more than three decades of intense effort, no effective RAS inhibitors have yet to reach the cancer patient. With bitter lessons learned from past failures and with new ideas and strategies, there is renewed hope that undruggable RAS may finally be conquered. With the KRAS isoform mutated in 84% of all RAS-mutant cancers, we focus on KRAS. With a near 100% KRAS mutation frequency, pancreatic ductal adenocarcinoma (PDAC) is considered the most RAS-addicted of all cancers. We review the role of KRAS as a driver and therapeutic target in PDAC.
Oncogenic Kras is required for both the initiation and maintenance of pancreatic cancer in mice
Journal of Clinical Investigation, 2012
Pancreatic cancer is almost invariably associated with mutations in the KRAS gene, most commonly KRAS G12D , that result in a dominant-active form of the KRAS GTPase. However, how KRAS mutations promote pancreatic carcinogenesis is not fully understood, and whether oncogenic KRAS is required for the maintenance of pancreatic cancer has not been established. To address these questions, we generated two mouse models of pancreatic tumorigenesis: mice transgenic for inducible Kras G12D , which allows for inducible, pancreas-specific, and reversible expression of the oncogenic Kras G12D , with or without inactivation of one allele of the tumor suppressor gene p53. Here, we report that, early in tumorigenesis, induction of oncogenic Kras G12D reversibly altered normal epithelial differentiation following tissue damage, leading to precancerous lesions. Inactivation of Kras G12D in established precursor lesions and during progression to cancer led to regression of the lesions, indicating that Kras G12D was required for tumor cell survival. Strikingly, during all stages of carcinogenesis, Kras G12D upregulated Hedgehog signaling, inflammatory pathways, and several pathways known to mediate paracrine interactions between epithelial cells and their surrounding microenvironment, thus promoting formation and maintenance of the fibroinflammatory stroma that plays a pivotal role in pancreatic cancer. Our data establish that epithelial Kras G12D influences multiple cell types to drive pancreatic tumorigenesis and is essential for tumor maintenance. They also strongly support the notion that inhibiting Kras G12D , or its downstream […]
Cancer Discovery, 2021
Pancreatic ductal adenocarcinoma (PDAC) is almost uniformly fatal and characterized by early metastasis. Oncogenic KRAS mutations prevail in 95% of PDAC tumors and co-occur with genetic alterations in the TP53 tumor suppressor in nearly 70% of patients. Most TP53 alterations are missense mutations that exhibit gain-of-function phenotypes that include increased invasiveness and metastasis, yet the extent of direct cooperation between KRAS effectors and mutant p53 remains largely undefined. We show that oncogenic KRAS effectors activate CREB1 to allow physical interactions with mutant p53 that hyperactivate multiple prometastatic transcriptional networks. Specifically, mutant p53 and CREB1 upregulate the prometastatic, pioneer transcription factor FOXA1, activating its transcriptional network while promoting WNT/β-catenin signaling, together driving PDAC metastasis. Pharmacologic CREB1 inhibition dramatically reduced FOXA1 and β-catenin expression and dampened PDAC metastasis, identif...
International Journal of Molecular Sciences
Pancreatic ductal adenocarcinoma (PDAC) is still one of the deadliest cancers in oncology because of its increasing incidence and poor survival rate. More than 90% of PDAC patients are KRAS mutated (KRASmu), with KRASG12D and KRASG12V being the most common mutations. Despite this critical role, its characteristics have made direct targeting of the RAS protein extremely difficult. KRAS regulates development, cell growth, epigenetically dysregulated differentiation, and survival in PDAC through activation of key downstream pathways, such as MAPK-ERK and PI3K-AKT-mammalian target of rapamycin (mTOR) signaling, in a KRAS-dependent manner. KRASmu induces the occurrence of acinar-to-ductal metaplasia (ADM) and pancreatic intraepithelial neoplasia (PanIN) and leads to an immunosuppressive tumor microenvironment (TME). In this context, the oncogenic mutation of KRAS induces an epigenetic program that leads to the initiation of PDAC. Several studies have identified multiple direct and indire...
Mutant p53R270H drives altered metabolism and increased invasion in pancreatic ductal adenocarcinoma
JCI insight, 2018
Pancreatic cancer is characterized by nearly universal activating mutations in KRAS. Among other somatic mutations, TP53 is mutated in more than 75% of human pancreatic tumors. Genetically engineered mice have proven instrumental in studies of the contribution of individual genes to carcinogenesis. Oncogenic Kras mutations occur early during pancreatic carcinogenesis and are considered an initiating event. In contrast, mutations in p53 occur later during tumor progression. In our model, we recapitulated the order of mutations of the human disease, with p53 mutation following expression of oncogenic Kras. Further, using an inducible and reversible expression allele for mutant p53, we inactivated its expression at different stages of carcinogenesis. Notably, the function of mutant p53 changes at different stages of carcinogenesis. Our work establishes a requirement for mutant p53 for the formation and maintenance of pancreatic cancer precursor lesions. In tumors, mutant p53 becomes di...
Mutant p53 drives metastasis and overcomes growth arrest/senescence in pancreatic cancer
Proceedings of the National Academy of Sciences, 2010
TP53 mutation occurs in 50-75% of human pancreatic ductal adenocarcinomas (PDAC) following an initiating activating mutation in the KRAS gene. These p53 mutations frequently result in expression of a stable protein, p53 R175H , rather than complete loss of protein expression. In this study we elucidate the functions of mutant p53 (Trp53 R172H ), compared to knockout p53 (Trp53 fl ), in a mouse model of PDAC. First we find that although Kras G12D is one of the major oncogenic drivers of PDAC, most Kras G12D -expressing pancreatic cells are selectively lost from the tissue, and those that remain form premalignant lesions. Loss, or mutation, of Trp53 allows retention of the Kras G12D -expressing cells and drives rapid progression of these premalignant lesions to PDAC. This progression is consistent with failed growth arrest and/or senescence of premalignant lesions, since a mutant of p53, p53 R172P , which can still induce p21 and cell cycle arrest, is resistant to PDAC formation. Second, we find that despite similar kinetics of primary tumor formation, mutant p53 R172H , as compared with genetic loss of p53, specifically promotes metastasis. Moreover, only mutant p53 R172H -expressing tumor cells exhibit invasive activity in an in vitro assay. Importantly, in human PDAC, p53 accumulation significantly correlates with lymph node metastasis. In summary, by using 'knock-in' mutations of Trp53 we have identified two critical acquired functions of a stably expressed mutant form of p53 that drive PDAC; first, an escape from Kras G12D -induced senescence/ growth arrest and second, the promotion of metastasis.
What We Have Learned About Pancreatic Cancer From Mouse Models
Gastroenterology, 2012
P ancreatic ductal adenocarcinoma (PDA) is one of the most devastating malignancies worldwide. A total of 43,140 new cases (ranked 10th) and 36,800 deaths (ranked 4th) from pancreatic cancer were estimated to occur in the United States during 2010, with an overall 5-year survival rate of just 6%. 1 This dire clinical situation exists despite recent advances in our understanding of the genetics and biology of PDA. Most patients with advanced PDA either do not respond, or respond only transiently, to systemic chemotherapy and radiotherapy. Although a few patients with PDA undergo potentially curative surgery, most PDAs ultimately recur. Over the past decade, genetically engineered mouse models (GEMMs) of PDA have been created. We describe how these models have enabled a detailed investigation of PDA biology, including tumor development and progression, and the role of inflammation and the tumor microenvironment. We also discuss how mouse models of PDA are being used to develop new therapeutic and diagnostic approaches. Conditional Kras Models of Pancreatic Cancer Although approaches to generate mouse models of pancreatic cancer started in the late 1980s, 2,3 the GEMM that most closely resembles human disease was established in 2003. 4 This model is based on the LSL-Kras G12D strain of mice, which has an endogenous, conditional Kras G12D mutant allele silenced by a floxed transcriptional STOP cassette (Lox-Stop-Lox or LSL) inserted upstream of the targeted Exon1. Removal of this LSL by directing expression of Cre recombinase with adenoviral-Cre allows expression of oncogenic Kras G12D in the lung. 5 Likewise, LSL-Kras G12D mice crossed with mice that express Cre recombinase under the control of the Pdx1 or Ptf1a/P48 promoters develop pancreatic ductal cancer. 4 Such compound mutant mice (Pdx1-Cre;LSL-Kras G12D and Ptf1a/P48-Cre;LSL-Kras G12D) develop a spectrum of preneoplasms with complete penetrance, termed pancreatic intraepithelial neoplasias (PanINs) (Figure 1). As in patients, PanINs develop in these mice along a specific pattern of progression, and a subset of older mice develop PDA. The PanINs that develop in mice resembled those of patients in that they express mucins, the epithelial protein cytokeratin-19, and components of signaling pathways that include Cyclooxygenase (Cox)-2, MMP-7, and Hes1. 4 This GEMM supported a PanIN-to-PDA model of pancreatic cancer progression that was first proposed by Hruban et al. 6,7 In this model, activating mutations in the Kras gene, which are found in more than 90% of human PDAs, initiate PDA formation by inducing development of low-grade PanIN lesions. Human PanINs are believed to progress to PDA following the acquisition of additional epigenetic and genetic somatic alterations, including inactivation or point mutation of p16/CDKN2A (Ͼ95%), TP53 (50%-75%), and the transforming growth factor (TGF)- pathway components DPC4/SMAD4 (55%), TGFRI (Ͻ5%), and TGFRII (Ͻ5%). 8-11 Studies of GEMMs of PDA incorporating these additional mutant alleles have supported the genetic basis of progression. These GEMMs included compound mutant mice that express a conditionally oncogenic Kras allele in the pancreatic compartment, in combination with the monoallelic and biallelic loss of the p16 Ink4a /p19 Arf and p53 genes, 12,13 the concomitant expression of dominant-negative forms of p53 (that contain Li Fraumeni point mutations), 14 or the ablation of the type II TGF- receptor (Tgfbr2). 15 These compound mutant mice develop invasive and metastatic PDA, with some characteristic features associated with each genotype, and can be used to determine the molecular mechanisms by which different subtypes of PDA develop and investigate differences in responses to therapeutic strategies 16 (Figure 1). In addition to PanINs, which are the most common and best characterized pancreatic preneoplasms, several GEMMs develop cystic preneoplasms, including intraductal papillary mucinous neoplasms (IPMNs) and mu
Biochemical and Biophysical Research Communications, 2009
Chronic pancreatitis increases by 16 fold the risk of developing pancreatic ductal adenocarcinoma (PDAC), one of the deadliest human cancers. It also appears to accelerate cancer progression in genetically engineered mouse models. We now report that in a mouse model where oncogenic Kras is activated in all pancreatic cell types, two brief episodes of acute pancreatitis caused rapid PanIN progression and accelerated pancreatic cancer development. Thus, a brief inflammatory insult to the pancreas, when occurring in the context of oncogenic Kras G12D , can initiate a cascade of events that dramatically enhances the risk for pancreatic malignant transformation.
Pancreatology, 2019
Pancreatic ductal adenocarcinoma (PDAC) is among the dangerous human cancers, is the 10th highly prevalent cancer, and the fourth sole cause of cancer-related mortality in the United States of America. Notwithstanding the significant commitment, the forecast for people with this burden continues to have a five-year survival rate of just 4e6%. The most critical altered genes within PDAC consist of K-ras the proto-oncogene which is usually mutationally activated above 90% cases and tumor suppressors likeTrp53 are altered at 55%. To face the burden of pancreatic ductal adenocarcinoma, a variety of genetically engineered pancreatic cancer mice models have been created over the last past years. These models have distinctive features and are not all appropriate for preclinical studies. In this review, we focus on differences between two mice models K-ras LSL.G12D/þ ;Pdx-1-Cre(KC) and K-ras LSL.G12D/þ ; Trp53 R172H/þ ; Pdx-1-Cre(KPC) in terms of their modeling biology and their clinical relevance.
Cancer Cell Line Based Drug to Control Pancreatic Cancer with Concomitant KRAS Mutation
KRAS gene is a recurrently mutated gene pair in various cancers, including pancreatic adenocarcinoma. We aim to depict the omics landscape of a KRAS mutation and find potential novel drugs for pancreatic cancer patients with KRAS mutations. This study considers the cancer genome atlas and cancer cell line encyclopedia information for the KRAS mutation analysis in a multi-omics manner. We found that the genomics and transcriptomics patterns of a KRAS mutation are significantly different compared to the corresponding non-mutated pancreatic adenocarcinoma. Pancreatic cancer's prognosis is directly associated with a specific KRAS mutation and its protein's structure instability. Our analysis confirmed that Irinotecan could be a potential drug for pancreatic adenocarcinoma patients with KRAS G12D mutation.