Identification of Sox9-Dependent Acinar-to-Ductal Reprogramming as the Principal Mechanism for Initiation of Pancreatic Ductal Adenocarcinoma
TL;DR: It is suggested that ductal and stem-like centroacinar cells are surprisingly refractory to oncogenic transformation, whereas acinar cells readily form PDA precursor lesions with ductal features, and formation of acinar-derived premalignant lesions depends on ectopic induction of the ductal gene Sox9.
About: This article is published in Cancer Cell.The article was published on 2012-12-11 and is currently open access. It has received 556 citations till now. The article focuses on the topics: KRAS.
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TL;DR: The hallmarks of cancer conceptualization is a heuristic tool for distilling the vast complexity of cancer phenotypes and genotypes into a provisional set of underlying principles as mentioned in this paper , which are used to understand mechanisms of cancer development and malignant progression, and apply that knowledge to cancer medicine.
Abstract: The hallmarks of cancer conceptualization is a heuristic tool for distilling the vast complexity of cancer phenotypes and genotypes into a provisional set of underlying principles. As knowledge of cancer mechanisms has progressed, other facets of the disease have emerged as potential refinements. Herein, the prospect is raised that phenotypic plasticity and disrupted differentiation is a discrete hallmark capability, and that nonmutational epigenetic reprogramming and polymorphic microbiomes both constitute distinctive enabling characteristics that facilitate the acquisition of hallmark capabilities. Additionally, senescent cells, of varying origins, may be added to the roster of functionally important cell types in the tumor microenvironment. SIGNIFICANCE: Cancer is daunting in the breadth and scope of its diversity, spanning genetics, cell and tissue biology, pathology, and response to therapy. Ever more powerful experimental and computational tools and technologies are providing an avalanche of "big data" about the myriad manifestations of the diseases that cancer encompasses. The integrative concept embodied in the hallmarks of cancer is helping to distill this complexity into an increasingly logical science, and the provisional new dimensions presented in this perspective may add value to that endeavor, to more fully understand mechanisms of cancer development and malignant progression, and apply that knowledge to cancer medicine.
1,838 citations
TL;DR: It is shown that the lifetime risk of cancers of many different types is strongly correlated with the total number of divisions of the normal self-renewing cells maintaining that tissue’s homeostasis, suggesting that only a third of the variation in cancer risk among tissues is attributable to environmental factors or inherited predispositions.
Abstract: Some tissue types give rise to human cancers millions of times more often than other tissue types. Although this has been recognized for more than a century, it has never been explained. Here, we show that the lifetime risk of cancers of many different types is strongly correlated (0.81) with the total number of divisions of the normal self-renewing cells maintaining that tissue’s homeostasis. These results suggest that only a third of the variation in cancer risk among tissues is attributable to environmental factors or inherited predispositions. The majority is due to “bad luck,” that is, random mutations arising during DNA replication in normal, noncancerous stem cells. This is important not only for understanding the disease but also for designing strategies to limit the mortality it causes.
1,519 citations
Royal Netherlands Academy of Arts and Sciences1, Cold Spring Harbor Laboratory2, Lustgarten Foundation3, Stony Brook University4, Watson School of Biological Sciences5, University Medical Center Utrecht6, Utrecht University7, Memorial Sloan Kettering Cancer Center8, Johns Hopkins University School of Medicine9
TL;DR: Comprehensive transcriptional and proteomic analyses of murine pancreatic organoids revealed genes and pathways altered during disease progression that demonstrate that organoids are a facile model system to discover characteristics of this deadly malignancy.
1,488 citations
Cites background from "Identification of Sox9-Dependent Ac..."
...…have been proposed for the development of PDA, with the pancreatic acinar cell hypothesized to be amajor contributor to PDA initiation (De La O et al., 2008; Gidekel Friedlander et al., 2009; Guerra et al., 2003; Habbe et al., 2008; Kopp et al., 2012; Morris et al., 2010; Sawey et al., 2007)....
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TL;DR: The prospect is raised that phenotypic plasticity and disrupted differentiation is a discrete hallmark capability, and that nonmutational epigenetic reprogramming and polymorphic microbiomes both constitute distinctive enabling characteristics that facilitate the acquisition of hallmark capabilities.
Abstract: The hallmarks of cancer conceptualization is a heuristic tool for distilling the vast complexity of cancer phenotypes and genotypes into a provisional set of underlying principles. As knowledge of cancer mechanisms has progressed, other facets of the disease have emerged as potential refinements. Herein, the prospect is raised that phenotypic plasticity and disrupted differentiation is a discrete hallmark capability, and that nonmutational epigenetic reprogramming and polymorphic microbiomes both constitute distinctive enabling characteristics that facilitate the acquisition of hallmark capabilities. Additionally, senescent cells, of varying origins, may be added to the roster of functionally important cell types in the tumor microenvironment. SIGNIFICANCE: Cancer is daunting in the breadth and scope of its diversity, spanning genetics, cell and tissue biology, pathology, and response to therapy. Ever more powerful experimental and computational tools and technologies are providing an avalanche of "big data" about the myriad manifestations of the diseases that cancer encompasses. The integrative concept embodied in the hallmarks of cancer is helping to distill this complexity into an increasingly logical science, and the provisional new dimensions presented in this perspective may add value to that endeavor, to more fully understand mechanisms of cancer development and malignant progression, and apply that knowledge to cancer medicine.
1,480 citations
Memorial Sloan Kettering Cancer Center1, University of Ulsan2, Johns Hopkins University3, Emory University4, University of Glasgow5, Utrecht University6, Jichi Medical University7, Japanese Foundation for Cancer Research8, Technische Universität München9, Dartmouth College10, University of Bonn11, Kyoto University12, University of Paris13, University of Düsseldorf14
TL;DR: International experts met to discuss recent advances and to revise the 2004 recommendations for assessing and reporting precursor lesions to invasive carcinomas of the pancreas, including pancreatic intraepithelial neoplasia (PanIN), intraductal papillary mucinous neoplasms (IPMN), mucinous cystic neoplasm, and other lesions.
Abstract: International experts met to discuss recent advances and to revise the 2004 recommendations for assessing and reporting precursor lesions to invasive carcinomas of the pancreas, including pancreatic intraepithelial neoplasia (PanIN), intraductal papillary mucinous neoplasm (IPMN), mucinous cystic neoplasm, and other lesions. Consensus recommendations include the following: (1) To improve concordance and to align with practical consequences, a 2-tiered system (low vs. high grade) is proposed for all precursor lesions, with the provision that the current PanIN-2 and neoplasms with intermediate-grade dysplasia now be categorized as low grade. Thus, "high-grade dysplasia" is to be reserved for only the uppermost end of the spectrum ("carcinoma in situ"-type lesions). (2) Current data indicate that PanIN of any grade at a margin of a resected pancreas with invasive carcinoma does not have prognostic implications; the clinical significance of dysplasia at a margin in a resected pancreas with IPMN lacking invasive carcinoma remains to be determined. (3) Intraductal lesions 0.5 to 1 cm can be either large PanINs or small IPMNs. The term "incipient IPMN" should be reserved for lesions in this size with intestinal or oncocytic papillae or GNAS mutations. (4) Measurement of the distance between an IPMN and invasive carcinoma and sampling of intervening tissue are recommended to assess concomitant versus associated status. Conceptually, concomitant invasive carcinoma (in contrast with the "associated" group) ought to be genetically distinct from an IPMN elsewhere in the gland. (5) "Intraductal spread of invasive carcinoma" (aka, "colonization") is recommended to describe lesions of invasive carcinoma invading back into and extending along the ductal system, which may morphologically mimic high-grade PanIN or even IPMN. (6) "Simple mucinous cyst" is recommended to describe cysts >1 cm having gastric-type flat mucinous lining at most minimal atypia without ovarian-type stroma to distinguish them from IPMN. (7) Human lesions resembling the acinar to ductal metaplasia and atypical flat lesions of genetically engineered mouse models exist and may reflect an alternate pathway of carcinogenesis; however, their biological significance requires further study. These revised recommendations are expected to improve our management and understanding of precursor lesions in the pancreas.
561 citations
References
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TL;DR: It is found that physiological levels of Kras(G12D) induce ductal lesions that recapitulate the full spectrum of human pancreatic intraepithelial neoplasias (PanINs), putative precursors to invasive pancreatic cancer.
2,251 citations
"Identification of Sox9-Dependent Ac..." refers background or methods in this paper
...To test this idea, we crossed the well-characterized Ptf1aCre;KrasG12D model of PanIN formation (Hingorani et al., 2003) with mice harboring a Cre-inducible Sox9 transgene (CAG-Sox9, hereafter referred to as Sox9OE)....
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...Because previous studies have modeled PDA initiation mostly by expressing oncogenic Kras in all cell types of the pancreas (Aguirre et al., 2003; Hingorani et al., 2003, 2005), little is known about its cell of origin....
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...The significance of Krasmutations for disease initiation has been demonstrated in mice, where expression of the constitutively active Kras allele induces PanINs and after a significant latency period also PDA (Hingorani et al., 2003)....
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...To test this idea, we crossed the well-characterized Ptf1a;Kras model of PanIN formation (Hingorani et al., 2003) with mice harboring a Cre-inducible Sox9 transgene (CAG-Sox9, hereafter referred to as Sox9)....
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...The significance of Krasmutations for disease initiation has been demonstrated in mice, where expression of the constitutively active KrasG12D allele induces PanINs and after a significant latency period also PDA (Hingorani et al., 2003)....
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TL;DR: Targeted concomitant endogenous expression of Trp53(R172H) and Kras(G12D) to the mouse pancreas reveals the cooperative development of invasive and widely metastatic carcinoma that recapitulates the human disease.
2,082 citations
"Identification of Sox9-Dependent Ac..." refers methods in this paper
...Because previous studies have modeled PDA initiation mostly by expressing oncogenic Kras in all cell types of the pancreas (Aguirre et al., 2003; Hingorani et al., 2003, 2005), little is known about its cell of origin....
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TL;DR: A multicenter historical cohort study of 2015 subjects with chronic pancreatitis who were recruited from clinical centers in six countries finds that pancreatitis may be a risk factor for pancreatic cancer, but the magnitude of the relation between these two diseases is unclear.
Abstract: Background The results of case-control studies and anecdotal reports suggest that pancreatitis may be a risk factor for pancreatic cancer, but there have been no studies of sufficient size and power to assess the magnitude of the relation between these two diseases. Methods and Results We undertook a multicenter historical cohort study of 2015 subjects with chronic pancreatitis who were recruited from clinical centers in six countries. A total of 56 cancers were identified among these patients during a mean (±SD) follow-up of 7.4 ±6.2 years. The expected number of cases of cancer calculated from country-specific incidence data and adjusted for age and sex was 2.13, yielding a standardized incidence ratio (the ratio of observed to expected cases) of 26.3 (95 percent confidence interval, 19.9 to 34.2). For subjects with a minimum of two or five years of follow-up, the respective standardized incidence ratios were 16.5 (95 percent confidence interval, 11.1 to 23.7) and 14.4 (95 percent confidence interval, 8...
1,528 citations
TL;DR: Evidence is also accumulating that cancers of distinct subtypes within an organ may derive from different 'cells of origin', and the identification of these crucial target cell populations may allow earlier detection of malignancies and better prediction of tumour behaviour.
Abstract: Both solid tumours and leukaemias show considerable histological and functional heterogeneity. It is widely accepted that genetic lesions have a major role in determining tumour phenotype, but evidence is also accumulating that cancers of distinct subtypes within an organ may derive from different 'cells of origin'. These cells acquire the first genetic hit or hits that culminate in the initiation of cancer. The identification of these crucial target cell populations may allow earlier detection of malignancies and better prediction of tumour behaviour, and ultimately may lead to preventive therapies for individuals at high risk of developing cancer.
1,346 citations
"Identification of Sox9-Dependent Ac..." refers background in this paper
...Since numerous tumors have been shown to originate from tissue stem cells (Visvader, 2011), it has been proposed that CACs are the cell of origin for PanINs and PDA (Miyamoto et al....
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...Since numerous tumors have been shown to originate from tissue stem cells (Visvader, 2011), it has been proposed that CACs are the cell of origin for PanINs and PDA (Miyamoto et al., 2003; Stanger et al., 2005)....
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TL;DR: The path to meaningful clinical progress has never been clearer to improve PDAC patient survival and a deeper understanding of cancer cell biology, particularly altered cancer cell metabolism and impaired DNA repair processes, is providing novel therapeutic strategies that show strong preclinical activity.
Abstract: With 5-year survival rates remaining constant at 6% and rising incidences associated with an epidemic in obesity and metabolic syndrome, pancreatic ductal adenocarcinoma (PDAC) is on track to become the second most common cause of cancer-related deaths by 2030. The high mortality rate of PDAC stems primarily from the lack of early diagnosis and ineffective treatment for advanced tumors. During the past decade, the comprehensive atlas of genomic alterations, the prominence of specific pathways, the preclinical validation of such emerging targets, sophisticated preclinical model systems, and the molecular classification of PDAC into specific disease subtypes have all converged to illuminate drug discovery programs with clearer clinical path hypotheses. A deeper understanding of cancer cell biology, particularly altered cancer cell metabolism and impaired DNA repair processes, is providing novel therapeutic strategies that show strong preclinical activity. Elucidation of tumor biology principles, most notably a deeper understanding of the complexity of immune regulation in the tumor microenvironment, has provided an exciting framework to reawaken the immune system to attack PDAC cancer cells. While the long road of translation lies ahead, the path to meaningful clinical progress has never been clearer to improve PDAC patient survival.
1,220 citations