MYC Instructs and Maintains Pancreatic Adenocarcinoma Phenotype

Sodir, Nicole M.; Kortlever, Roderik M.; Barthet, Valentin J.A.; Campos, Tânia Maria Mendonça; Pellegrinet, Luca; Kupczak, Steven; Anastasiou, Panayiotis; Swigart, Lamorna Brown; Soucek, Laura; Arends, Mark J.; Littlewood, Trevor D.; Evan, Gérard I.

doi:10.1158/2159-8290.cd-19-0435

Cited by 139 publications

(131 citation statements)

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“…More recently and in the same line of reasoning, Omomyc expression in PDAC-bearing mice (pdx1-Cre;LSL-KRas G12D ;p53ER TAM ;TRE-Omomyc;CMV-rtTA) was shown to trigger quantitative regression of these highly aggressive tumors and of their extensive fibroinflammatory stroma (Figure 2), reiterating the point that Myc holds a key role in the coordination of the cross-talk between tumors and their microenvironment [72].…”

Section: Omomyc Efficacy and Side Effects In Vivomentioning

confidence: 59%

“…Expression of the Omomyc transgene has remarkable therapeutic impact in 5 different genetically engineered mouse models of cancer, from left to right: papilloma, inv-Myc-ER TAM (top panel) and inv-Myc-ER TAM /Omomyc (bottom panel), adapted from [56]; insulinoma, RIP1-Tag2;TRE-Omomyc;CMV-rtTA -dox (top) and +dox (bottom), adapted from [70]; lung adenocarcinoma, LSL-Kras G12D ;p53ER TAM ;TRE-Omomyc;CMV-rtTA -dox (top) and +dox (bottom), adapted from [71]; glioma, GFAP-V12 Ha-Ras;TRE-Omomyc;CMV-rtTA -dox (top) and +dox (bottom) adapted from[67]; and pancreatic ductal adenocarcinoma, pdx1-Cre;LSL-KRas G12D ;p53ER TAM ;TRE-Omomyc;CMV-rtTA -dox (top) and +dox (bottom), adapted from[72]. All panels represent tissue sections stained with either an anti-GFAP antibody (glioma) or with hematoxylin and eosin (rest of the panels).…”

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confidence: 99%

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Blocking Myc to Treat Cancer: Reflecting on Two Decades of Omomyc

Massó-Vallés

Soucek

2020

Cells

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107

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First designed and published in 1998 as a laboratory tool to study Myc perturbation, Omomyc has come a long way in the past 22 years. This dominant negative has contributed to our understanding of Myc biology when expressed, first, in normal and cancer cells, and later in genetically-engineered mice, and has shown remarkable anti-cancer properties in a wide range of tumor types. The recently described therapeutic effect of purified Omomyc mini-protein-following the surprising discovery of its cell-penetrating capacity-constitutes a paradigm shift. Now, much more than a proof of concept, the most characterized Myc inhibitor to date is advancing in its drug development pipeline, pushing Myc inhibition into the clinic.

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Section: Omomyc Efficacy and Side Effects In Vivomentioning

confidence: 59%

mentioning

confidence: 99%

Blocking Myc to Treat Cancer: Reflecting on Two Decades of Omomyc

Massó-Vallés

Soucek

2020

Cells

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107

109

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“…As fibroblasts evolved in part to facilitate wound repair, this may reflect a conserved mechanism by which mesenchymal cells signal to the epithelial compartment to promote regeneration and healing, as MYC has been previously implicated in the wound-healing process (Schäfer and Werner, 2007;Su et al, 2018;Zanet et al, 2005), as have MYC-regulated bioenergetics (Shyh-Chang et al, 2013). While previous studies have demonstrated a critical role for MYC in regulation of the tumor microenvironment (Kortlever et al, 2017;Sodir et al, 2011Sodir et al, , 2020, our findings suggest the existence of a feedback loop, in which cues from the fibroinflammatory microenvironment in turn augment MYC protein level and oncogenic activity. As PDAC rarely harbors PI-3K mutations (Cancer Genome Atlas Research Network, 2017), it was not entirely surprising that external signals can increase AKT phosphorylation in PDAC cells.…”

Section: Resultsmentioning

confidence: 99%

Acidic fibroblast growth factor underlies microenvironmental regulation of MYC in pancreatic cancer

Bhattacharyya

Oon

Kothari

et al. 2020

Journal of Experimental Medicine

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Despite a critical role for MYC as an effector of oncogenic RAS, strategies to target MYC activity in RAS-driven cancers are lacking. In genetically engineered mouse models of lung and pancreatic cancer, oncogenic KRAS is insufficient to drive tumorigenesis, while addition of modest MYC overexpression drives robust tumor formation, suggesting that mechanisms beyond the RAS pathway play key roles in MYC regulation and RAS-driven tumorigenesis. Here we show that acidic fibroblast growth factor (FGF1) derived from cancer-associated fibroblasts (CAFs) cooperates with cancer cell–autonomous signals to increase MYC level, promoter occupancy, and activity. FGF1 is necessary and sufficient for paracrine regulation of MYC protein stability, signaling through AKT and GSK-3β to increase MYC half-life. Patient specimens reveal a strong correlation between stromal CAF content and MYC protein level in the neoplastic compartment, and identify CAFs as the specific source of FGF1 in the tumor microenvironment. Together, our findings demonstrate that MYC is coordinately regulated by cell-autonomous and microenvironmental signals, and establish CAF-derived FGF1 as a novel paracrine regulator of oncogenic transcription.

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“…Given that the status of the RAS-MYC oncogenic axis is important for the regenerative program, which is involved in PDAC initiation, 22,23 we investigated whether the RAS-MYC oncogenic axis is altered in KCS mice. We found that the expression of c-Myc expression was significantly decreased in KCS mice compared to control mice ( Supplementary Figure 8).…”

Section: Suppression Of Pancreatic Ductal Adenocarcinoma Formation Bymentioning

confidence: 99%

SETDB1 Inhibits p53-Mediated Apoptosis and Is Required for Formation of Pancreatic Ductal Adenocarcinomas in Mice

et al. 2020

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Setdb1 p53 P ancreatic ductal adenocarcinoma (PDAC) is one of the most dismal malignancies, with an extremely poor prognosis. 1 In order to further improve the prognosis, it is crucial to elucidate the molecular mechanisms underlying PDAC initiation and progression. Recent studies have revealed that epigenetic abnormalities exhibit a great influence on the characteristics of cancer development in addition to genetic abnormalities. 2-4 One form of epigenetic regulation, known as histone modification, contributes to tumorigenesis by affecting the expression of oncogenes/tumor suppressor genes. In fact, previous reports have shown that histone methyltransferases suppress pancreatic cancer by regulating glucose/fatty acid metabolism and promoting pancreatic regeneration. 5,6 Setdb1 serves as a histone 3 lysine 9 trimethyltransferase. Trimethylation of histone 3 lysine 9 (H3K9me3) is a repressive chromatin modification. 7 Setdb1 plays different functional roles through gene silencing. It helps to control heterochromatin formation 8 and contributes to stem cell maintenance, 9 embryonic development, and endogenous proviral silencing. 10 Recently, an in vivo study revealed that the amplification of Setdb1 accelerates the development of melanoma, 11 and SETDB1 has been shown to promote tumorigenesis in various human cancers, including lung, 12 liver, 13,14 and breast cancers. 15 Furthermore, a wholeexome sequencing study revealed a copy number amplification mutation of SETDB1 in PDAC patients. 16 These findings indicate a role of Setdb1 in PDAC initiation and progression. However, the functional role of Setdb1 in PDAC remains elusive. Therefore, in this study, we aimed to investigate the impact of Setdb1 deletion on Kras-induced pancreatic tumorigenesis and elucidate the in vivo role of Setdb1 in PDAC formation in mouse models. Materials and Methods Mice Experimental animals were generated by crossing Ptf1a Cre (gift from Y. Kawaguchi, Kyoto University, Kyoto, Japan), 17 Kras G12D (gift from D. Tuveson, Cold Spring Harbor Laboratory, Cold Spring Harbor, NY), 18 Setdb1 flox (gift from Y. Shinkai, Riken, Saitama, Japan), 10 and p53 flox (purchase from Jackson Laboratory, Bar Harbor, ME; JAX strain 008462). Acute pancreatitis was induced at 6 weeks of age by injecting cerulein (2 mg/injection diluted in phosphate-buffered saline; Sigma-Aldrich, St Louis, MO) intraperitoneally on 2 consecutive days once every hour for 8 hours each day. 19 Clinical Samples Forty-eight surgically resected specimens of pancreatic cancer tissues were obtained from patients who had been admitted to Kyoto University Hospital. Written informed consent was obtained from all patients and the protocol was approved by the Ethics Committee of Kyoto University.

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MYC Instructs and Maintains Pancreatic Adenocarcinoma Phenotype

Cited by 139 publications

References 123 publications

Blocking Myc to Treat Cancer: Reflecting on Two Decades of Omomyc

Blocking Myc to Treat Cancer: Reflecting on Two Decades of Omomyc

Acidic fibroblast growth factor underlies microenvironmental regulation of MYC in pancreatic cancer

SETDB1 Inhibits p53-Mediated Apoptosis and Is Required for Formation of Pancreatic Ductal Adenocarcinomas in Mice

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