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Increased protein synthesis plays an etiologic role in diverse cancers. Here, we demonstrate that METTL13 (methyltransferase-like 13) dimethylation of eEF1A (eukaryotic elongation factor 1A) lysine 55 (eEF1AK55me2) is utilized by Ras-driven cancers to increase translational output and promote tumorigenesis in vivo. METTL13-catalyzed eEF1A methylation increases eEF1A's intrinsic GTPase activity in vitro and protein production in cells. METTL13 and eEF1AK55me2 levels are upregulated in cancer and negatively correlate with pancreatic and lung cancer patient survival. METTL13 deletion and eEF1AK55me2 loss dramatically reduce Ras-driven neoplastic growth in mouse models and in patient-derived xenografts (PDXs) from primary pancreatic and lung tumors. Finally, METTL13 depletion renders PDX tumors hypersensitive to drugs that target growth-signaling pathways. Together, our work uncovers a mechanism by which lethal cancers become dependent on the METTL13-eEF1AK55me2 axis to meet their elevated protein synthesis requirement and suggests that METTL13 inhibition may constitute a targetable vulnerability of tumors driven by aberrant Ras signaling.

Amplification of chromosomal region 8p11-12 is a common genetic alteration that has been implicated in the aetiology of lung squamous cell carcinoma (LUSC).sup.1-3. The FGFR1 gene is the main candidate driver of tumorigenesis within this region.sup.4. However, clinical trials evaluating FGFR1 inhibition as a targeted therapy have been unsuccessful.sup.5. Here we identify the histone H3 lysine 36 (H3K36) methyltransferase NSD3, the gene for which is located in the 8p11-12 amplicon, as a key regulator of LUSC tumorigenesis. In contrast to other 8p11-12 candidate LUSC drivers, increased expression of NSD3 correlated strongly with its gene amplification. Ablation of NSD3, but not of FGFR1, attenuated tumour growth and extended survival in a mouse model of LUSC. We identify an LUSC-associated variant NSD3(T1232A) that shows increased catalytic activity for dimethylation of H3K36 (H3K36me2) in vitro and in vivo. Structural dynamic analyses revealed that the T1232A substitution elicited localized mobility changes throughout the catalytic domain of NSD3 to relieve auto-inhibition and to increase accessibility of the H3 substrate. Expression of NSD3(T1232A) in vivo accelerated tumorigenesis and decreased overall survival in mouse models of LUSC. Pathological generation of H3K36me2 by NSD3(T1232A) reprograms the chromatin landscape to promote oncogenic gene expression signatures. Furthermore, NSD3, in a manner dependent on its catalytic activity, promoted transformation in human tracheobronchial cells and growth of xenografted human LUSC cell lines with amplification of 8p11-12. Depletion of NSD3 in patient-derived xenografts from primary LUSCs containing NSD3 amplification or the NSD3(T1232A)-encoding variant attenuated neoplastic growth in mice. Finally, NSD3-regulated LUSC-derived xenografts were hypersensitive to bromodomain inhibition. Thus, our work identifies NSD3 as a principal 8p11-12 amplicon-associated oncogenic driver in LUSC, and suggests that NSD3-dependency renders LUSC therapeutically vulnerable to bromodomain inhibition. The histone H3K36 methyltransferase NSD3, which is associated with the common 8p11-12 chromosomal amplification, is an oncogenic driver in lung squamous cell carcinoma., Author(s): Gang Yuan [sup.1] , Natasha M. Flores [sup.2] , Simone Hausmann [sup.2] , Shane M. Lofgren [sup.2] , Vladlena Kharchenko [sup.3] , Maria Angulo-Ibanez [sup.4] [sup.5] , Deepanwita Sengupta [...]

Pancreatic ductal adenocarcinoma (PDAC) is one of the most lethal human cancers and shows resistance to any therapeutic strategy used. Here we tested small-molecule inhibitors targeting chromatin regulators as possible therapeutic agents in PDAC. We show that JQ1, an inhibitor of the bromodomain and extraterminal (BET) family of proteins, suppresses PDAC development in mice by inhibiting both MYC activity and inflammatory signals. The histone deacetylase (HDAC) inhibitor SAHA synergizes with JQ1 to augment cell death and more potently suppress advanced PDAC. Finally, using a CRISPR-Cas9-based method for gene editing directly in the mouse adult pancreas, we show that de-repression of p57 (also known as KIP2 or CDKN1C) upon combined BET and HDAC inhibition is required for the induction of combination therapy-induced cell death in PDAC. SAHA is approved for human use, and molecules similar to JQ1 are being tested in clinical trials. Thus, these studies identify a promising epigenetic-based therapeutic strategy that may be rapidly implemented in fatal human tumors.

Few therapies are currently available for patients with KRAS-driven cancers, highlighting the need to identify new molecular targets that modulate central downstream effector pathways. Here we found that the microRNA (miRNA) cluster including miR181ab1 is a key modulator of KRAS-driven oncogenesis. Ablation of Mir181ab1 in genetically engineered mouse models of Kras-driven lung and pancreatic cancer was deleterious to tumor initiation and progression. Expression of both resident miRNAs in the Mir181ab1 cluster, miR181a1 and miR181b1, was necessary to rescue the Mir181ab1-loss phenotype, underscoring their nonredundant role. In human cancer cells, depletion of miR181ab1 impaired proliferation and 3D growth, whereas overexpression provided a proliferative advantage. Lastly, we unveiled miR181ab1-regulated genes responsible for this phenotype. These studies identified what we believe to be a previously unknown role for miR181ab1 as a potential therapeutic target in 2 highly aggressive and difficult to treat KRAS-mutated cancers., Introduction KRAS is one of the most commonly mutated oncogenes in human cancer (1) and is a key oncogenic driver in many lung and most pancreatic cancers (2-5). KRAS induces [...]

Although the concept of tumor heterogeneity was established several decades ago, the interest in this topic is still unbroken. With the identification of inter- and intratumoral genomic rearrangements and the detection of cancer stem cells (CSCs) through phenotypic variations of cancer cells there are increasing options for pancreatic cancer therapy. Indeed, some pre-clinical studies have shown promising results in the treatment of drug-resistant CSCs, whereby a few strategies were already tested in clinical trials. Basically, CSCs are influenced by the tumor microenvironment and an epigenetic reprogramming to gain stem cell-like characteristics. Targeting options inhibiting the epithelial-mesenchymal crosstalk or promoting epigenetic-driven differentiation of CSCs to a less aggressive phenotype raised the possibilities of further therapeutic applications, which will be discussed in this review. [ABSTRACT FROM AUTHOR]

Our understanding of pancreatic ductal adenocarcinoma (PDAC) is shifting away from a disease of malignant ductal cells-only, toward a complex system where tumor evolution is a result of interaction of cancer cells with their microenvironment. This change has led to intensification of research focusing on the fibrotic stroma of PDAC. Pancreatic stellate cells (PSCs) are the main fibroblastic cells of the pancreas which are responsible for producing the desmoplasia in chronic pancreatitis (CP) and PDAC. Clinically, the effect of desmoplasia is two-sided; on the negative side it is a hurdle in the diagnosis of PDAC because the fibrosis in cancer resembles that of CP. It is also believed that PSCs and pancreatic fibrosis are partially responsible for the therapy resistance in pancreatic cancer. On the positive side, a fibrotic pancreas is safer to operate on compared to a fatty and soft pancreas which is prone for postoperative pancreatic fistula. In this review the impact of pancreatic fibrosis on diagnosis of pancreatic cancer and surgical decisions are discussed from a clinical point of view. [ABSTRACT FROM AUTHOR]

Molecular mechanisms underlying adaptive targeted therapy resistance in pancreatic ductal adenocarcinoma (PDAC) are poorly understood. Here, we identify SETD5 as a major driver of PDAC resistance to MEK1/2 inhibition (MEKi). SETD5 is induced by MEKi resistance and its deletion restores refractory PDAC vulnerability to MEKi therapy in mouse models and patient-derived xenografts. SETD5 lacks histone methyltransferase activity but scaffolds a co-repressor complex, including HDAC3 and G9a. Gene silencing by the SETD5 complex regulates known drug resistance pathways to reprogram cellular responses to MEKi. Pharmacological co-targeting of MEK1/2, HDAC3, and G9a sustains PDAC tumor growth inhibition in vivo. Our work uncovers SETD5 as a key mediator of acquired MEKi therapy resistance in PDAC and suggests a context for advancing MEKi use in the clinic. • SETD5 is an epigenetic driver of pancreatic cancer resistance to MEK1/2 inhibition • SETD5 has no intrinsic methylation activity on histones, including at H3 lysine 36 • A SETD5 co-repressor complex regulates a network of drug resistance pathways • Co-targeting of MEK1/2 and the SETD5 complex results in sustained tumor inhibition In pancreatic ductal adenocarcinoma (PDAC), a major roadblock in therapies targeting the KRAS-MAPK pathway, such as MEK1/2 inhibition (MEKi), is the rapid emergence of resistance. Wang et al. identify a clinically actionable epigenetic pathway mediated by SETD5 to drive PDAC resistance to MEKi. [ABSTRACT FROM AUTHOR]

The etiological role of NSD2 enzymatic activity in solid tumors is unclear. Here we show that NSD2, via H3K36me2 catalysis, cooperates with oncogenic KRAS signaling to drive lung adenocarcinoma (LUAD) pathogenesis. In vivo expression of NSD2 E1099K , a hyperactive variant detected in individuals with LUAD, rapidly accelerates malignant tumor progression while decreasing survival in KRAS-driven LUAD mouse models. Pathologic H3K36me2 generation by NSD2 amplifies transcriptional output of KRAS and several complementary oncogenic gene expression programs. We establish a versatile in vivo CRISPRi-based system to test gene functions in LUAD and find that NSD2 loss strongly attenuates tumor progression. NSD2 knockdown also blocks neoplastic growth of PDXs (patient-dervived xenografts) from primary LUAD. Finally, a treatment regimen combining NSD2 depletion with MEK1/2 inhibition causes nearly complete regression of LUAD tumors. Our work identifies NSD2 as a bona fide LUAD therapeutic target and suggests a pivotal epigenetic role of the NSD2-H3K36me2 axis in sustaining oncogenic signaling. [Display omitted] • High NSD2 and H3K36me2 levels common to lung cancer and correlate with poor prognosis • NSD2-selective H3K36me2 catalysis promotes rapid malignant tumor progression in vivo • A versatile CRISPRi-based in vivo system developed to test gene function in LUAD • NSD2 knockdown combined with MEK1/2 inhibitor results in sustained tumor regression NSD2 is a key epigenetic enzyme that generates the canonical histone modification H3K36me2. Sengupta et al. show that NSD2 hyperactivity promotes aggressive malignant lung tumor pathogenesis in vivo and uncover a mechanism by which lung cancers become dependent on an NSD2-H3K36me2 axis to sustain transcriptional programs driving tumorigenesis. [ABSTRACT FROM AUTHOR]

Small cell lung cancer (SCLC) is the most fatal form of lung cancer, with dismal survival, limited therapeutic options, and rapid development of chemoresistance. We identified the lysine methyltransferase SMYD3 as a major regulator of SCLC sensitivity to alkylation-based chemotherapy. RNF113A methylation by SMYD3 impairs its interaction with the phosphatase PP4, controlling its phosphorylation levels. This cross-talk between posttranslational modifications acts as a key switch in promoting and maintaining RNF113A E3 ligase activity, essential for its role in alkylation damage response. In turn, SMYD3 inhibition restores SCLC vulnerability to alkylating chemotherapy. Our study sheds light on a novel role of SMYD3 in cancer, uncovering this enzyme as a mediator of alkylation damage sensitivity and providing a rationale for small-molecule SMYD3 inhibition to improve responses to established chemotherapy., Significance: SCLC rapidly becomes resistant to conventional chemotherapy, leaving patients with no alternative treatment options. Our data demonstrate that SMYD3 upregulation and RNF113A methylation in SCLC are key mechanisms that control the alkylation damage response. Notably, SMYD3 inhibition sensitizes cells to alkylating agents and promotes sustained SCLC response to chemotherapy. This article is highlighted in the In This Issue feature, p. 2007., (©2022 The Authors; Published by the American Association for Cancer Research.)

Pancreatic ductal adenocarcinoma (PDAC) is a devastating disease with an extremely poor prognosis. Inflammatory processes have emerged as key mediators of pancreatic cancer development and progression. In genetically engineered mouse models, induction of pancreatitis accelerates PDAC development, and patients with chronic pancreatitis are known to have a higher risk of developing pancreatic cancer. In recent years, much effort has been given to identify the underlying mechanisms that contribute to inflammation-induced tumorigenesis. Many inflammatory pathways have been identified and inhibitors have been developed in order to prevent cancer development and progression. In this chapter, we discuss the role of inflammatory pathways in the initiation and progression of pancreatic cancer as well as the role of inhibitors used in treatment and prevention of pancreatic cancer.

Human lung cancer is a disease with high incidence and accounts for most cancer-related deaths in both men and women. Metastasis is a common event in non-small cell lung carcinoma (NSCLC), diminishing the survival chance of the patients with this type of tumor. It has been shown that MYC is involved in the development of metastasis from NSCLC, but the mechanism underlying this switch remained to be identified. Here, we focus on GATA4 as a MYC target in the development of metastasis with origin in lung adenocarcinoma, the most common type of NSCLC. Epigenetic alterations at the GATA4 promoter level were observed after MYC expression in lung adenocarcinoma in vivo and in vitro. Such alterations include site-specific demethylation that accompanies the displacement of the MYC-associated zinc finger protein (MAZ) from the GATA4 promoter, which leads to GATA4 expression. Histone modification analysis of the GATA4 promoter revealed a switch from repressive histone marks to active histone marks after MYC binding, which corresponds to active GATA4 expression. Our results thus identify a novel epigenetic mechanism by which MYC activates GATA4 leading to metastasis in lung adenocarcinoma, suggesting novel potential targets for the development of antimetastatic therapy.

Our understanding of pancreatic ductal adenocarcinoma (PDAC) is shifting away from a disease of malignant ductal cells-only, toward a complex system where tumor evolution is a result of interaction of cancer cells with their microenvironment. This change has led to intensification of research focusing on the fibrotic stroma of PDAC. Pancreatic stellate cells (PSCs) are the main fibroblastic cells of the pancreas which are responsible for producing the desmoplasia in chronic pancreatitis (CP) and PDAC. Clinically, the effect of desmoplasia is two-sided; on the negative side it is a hurdle in the diagnosis of PDAC because the fibrosis in cancer resembles that of CP. It is also believed that PSCs and pancreatic fibrosis are partially responsible for the therapy resistance in pancreatic cancer. On the positive side, a fibrotic pancreas is safer to operate on compared to a fatty and soft pancreas which is prone for postoperative pancreatic fistula. In this review the impact of pancreatic fibrosis on diagnosis of pancreatic cancer and surgical decisions are discussed from a clinical point of view.