Krishna Seshu Tummala

Harvard University

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Nabeel Bardeesy

Harvard University

Mirian Fernández-Vaquero

German Cancer Research Center

Lei Shi

Massachusetts General Hospital

Emily Kessler

Yale University

Meiqi Luo

Sidney Kimmel Cancer Center

Vajira Weeresekara

Massachusetts General Hospital

Brandon Nicolay

Massachusetts General Hospital

Rodrigo Saad Berreta

Rush University Medical Center

Russell W. Jenkins

Massachusetts General Hospital

Vindhya Vijay

Center for Cancer Research

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Harvard University

Massachusetts General Hospital

Center for Cancer Research

Spanish National Cancer Research Centre

Broad Institute

University of Virginia

Massachusetts Institute of Technology

Centro de Investigación del Cáncer

Centro Nacional de Epidemiología

Cancer Research Center

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Statin prevents cancer development in chronic inflammation by blocking interleukin 33 expression

Nature Communications (2024)

Jong Ho Park Mahsa Mortaja Heehwa G. Son X Zhao Lauren M. Sloat

Abstract Chronic inflammation is a major cause of cancer worldwide. Interleukin 33 (IL-33) is a critical initiator of cancer-prone chronic inflammation; however, its induction mechanism by environmental causes of chronic inflammation is unknown. Herein, we demonstrate that Toll-like receptor (TLR)3/4-TBK1-IRF3 pathway activation links environmental insults to IL-33 induction in the skin and pancreas inflammation. An FDA-approved drug library screen identifies pitavastatin to effectively suppress IL-33 expression by blocking TBK1 membrane recruitment/activation through the mevalonate pathway inhibition. Accordingly, pitavastatin prevents chronic pancreatitis and its cancer sequela in an IL-33-dependent manner. The IRF3-IL-33 axis is highly active in chronic pancreatitis and its associated pancreatic cancer in humans. Interestingly, pitavastatin use correlates with a significantly reduced risk of chronic pancreatitis and pancreatic cancer in patients. Our findings demonstrate that blocking the TBK1-IRF3-IL-33 signaling axis suppresses cancer-prone chronic inflammation. Statins present a safe and effective prophylactic strategy to prevent chronic inflammation and its cancer sequela.

Blocking (statistics)

10.1038/s41467-024-48441-8

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[14C]-Tryptophan Metabolic Tracing in Liver Cancer Cells

BIO-PROTOCOL (2015)

Krishna Seshu Tummala Nabil Djouder

Nicotinamide adenine dinucleotide (NAD+) is a coenzyme for many NAD+-consuming proteins with diverse biological functions. Oscillations in NAD+ levels may influence several cellular signaling pathways. NAD+ synthesis via Preiss-Handler route (salvage reactions) has been extensively reported. However, the contribution of L-tryptophan/kynurenine catabolism in de novo NAD+ synthesis is poorly understood. Using L-[14C]-tryptophan tracing in four liver cancer cell lines and siRNA-mediated silencing of arylformamidase (AFMID), a key enzyme involved in L-tryptophan degradation, we demonstrate the contribution of L-tryptophan catabolism in de novo synthesis of NAD+ pools. NAD+ modulation is therefore important in maintaining cellular homeostasis and appropriate cellular functions according to nutrients availability.

Catabolism

Kynurenine pathway

10.21769/bioprotoc.1582

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Molecular and cellular mechanisms of hepatocarcinogenesis

Krishna Seshu Tummala

Tesis doctoral inedita leida en la Universidad Autonoma de Madrid, Faculta de Ciencias, Departamento de Biologia molecular. Fecha de lectura: 27-10-2014

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Supplementary Figure from Mutant IDH Inhibits IFNγ–TET2 Signaling to Promote Immunoevasion and Tumor Maintenance in Cholangiocarcinoma

Meng‐Ju Wu Lei Shi Juan Dubrot Joshua Merritt Vindhya Vijay

Supplementary Figure from Mutant IDH Inhibits IFNγ–TET2 Signaling to Promote Immunoevasion and Tumor Maintenance in Cholangiocarcinoma

10.1158/2159-8290.22541395.v1

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Editorial: Metabolism and Epigenetics

Frontiers in Genetics (2022)

Carlos Sebastián Joaquim S. L. Vong Manasi K. Mayekar Krishna Seshu Tummala Indrabahadur Singh

EDITORIAL article Front. Genet., 10 March 2022Sec.Epigenomics and Epigenetics https://doi.org/10.3389/fgene.2022.877538

10.3389/fgene.2022.877538

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ISL2 is a putative tumor suppressor whose epigenetic silencing reprograms the metabolism of pancreatic cancer

Developmental Cell (2022)

Harun Öztürk Harun Cingoz Turan Tufan Jiekun Yang Sara J. Adair

10.1016/j.devcel.2022.04.014

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Data from Mutant IDH Inhibits IFNγ–TET2 Signaling to Promote Immunoevasion and Tumor Maintenance in Cholangiocarcinoma

Meng‐Ju Wu Lei Shi Juan Dubrot Joshua Merritt Vindhya Vijay

<div>AbstractIsocitrate dehydrogenase 1 mutations (mIDH1) are common in cholangiocarcinoma. (R)-2-hydroxyglutarate generated by the mIDH1 enzyme inhibits multiple α-ketoglutarate–dependent enzymes, altering epigenetics and metabolism. Here, by developing mIDH1-driven genetically engineered mouse models, we show that mIDH1 supports cholangiocarcinoma tumor maintenance through an immunoevasion program centered on dual (R)-2-hydroxyglutarate–mediated mechanisms: suppression of CD8+ T-cell activity and tumor cell–autonomous inactivation of TET2 DNA demethylase. Pharmacologic mIDH1 inhibition stimulates CD8+ T-cell recruitment and interferon γ (IFNγ) expression and promotes TET2-dependent induction of IFNγ response genes in tumor cells. CD8+ T-cell depletion or tumor cell–specific ablation of TET2 or IFNγ receptor 1 causes treatment resistance. Whereas immune-checkpoint activation limits mIDH1 inhibitor efficacy, CTLA4 blockade overcomes immunosuppression, providing therapeutic synergy. The findings in this mouse model of cholangiocarcinoma demonstrate that immune function and the IFNγ–TET2 axis are essential for response to mIDH1 inhibition and suggest a novel strategy for potentiating efficacy.Significance:Mutant IDH1 inhibition stimulates cytotoxic T-cell function and derepression of the DNA demethylating enzyme TET2, which is required for tumor cells to respond to IFNγ. The discovery of mechanisms of treatment efficacy and the identification of synergy by combined CTLA4 blockade provide the foundation for new therapeutic strategies.See related commentary by Zhu and Kwong, p. 604.This article is highlighted in the In This Issue feature, p. 587</div>

10.1158/2159-8290.c.6549628.v1

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Supplementary table from Mutant IDH Inhibits IFNγ–TET2 Signaling to Promote Immunoevasion and Tumor Maintenance in Cholangiocarcinoma

Meng‐Ju Wu Lei Shi Juan Dubrot Joshua Merritt Vindhya Vijay

Supplementary table from Mutant IDH Inhibits IFNγ–TET2 Signaling to Promote Immunoevasion and Tumor Maintenance in Cholangiocarcinoma

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10.1158/2159-8290.22541389

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Supplementary table from Mutant IDH Inhibits IFNγ–TET2 Signaling to Promote Immunoevasion and Tumor Maintenance in Cholangiocarcinoma

Meng‐Ju Wu Lei Shi Juan Dubrot Joshua Merritt Vindhya Vijay

Supplementary table from Mutant IDH Inhibits IFNγ–TET2 Signaling to Promote Immunoevasion and Tumor Maintenance in Cholangiocarcinoma

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10.1158/2159-8290.22541389.v1

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Oncogene-induced NAD+ depletion in tumorigenesis

Oncoscience (2015)

Krishna Seshu Tummala Nabil Djouder

A proto-oncogene (hereafter simplified as oncogene) has the potential to initiate cancer. Oncogenes are often mutated and/or their products are expressed at high levels in various types of cancer. Several mechanisms and features of oncogenesis have been extensively discussed in the review of Hanahan and Weinberg “hallmarks of cancer: the next generation” [1]. Fundamentally, oncogenes give an unlimited proliferative advantage to cells which generates replicative stress and, leads to the genetic heterogeneity of the cell population. Thus, cancer is the disease of the genome and, targeting the terminal phase often results in cancer recurrence. Several ongoing preclinical studies and clinical trials propose to target the proliferation process [2,3]. Specific inhibitors of the replicative stress were successfully validated for cancer treatment in mice [4]. This type of therapy clearly induces cancer cell death but unfortunately creates an irreversible genotoxic stress in healthy cells, which may lead to their transformation, consequent cellular dysfunctions and secondary cancer. There is a clear need of developing new therapies. Understanding the critical early event and dissecting the step-wise progression of tumorigenesis would help us to design more efficient therapeutic interventions to prevent and treat cancer. In particular because, metabolic alterations are common fundamental characteristics of oncogenes and in this context, represent an essential hallmark of cancer, tackling primary metabolic defects can be an elegant approach to prevent and cure cancer. We summarize in this short editorial a recent example reported in Tummala et al. of how targeting the metabolic defects prior to the high cellular proliferation and DNA damage can eradicate hepatocellular carcinoma (HCC) and prevent pancreatic cancer development [5]. HCC is the most frequent primary liver neoplasm which often arises in the predisposing liver disease states. HCC accounts for approximately 800,000 deaths each year and, making it the second most lethal cause of cancer worldwide (GLOBOCAN 2008 v2.0). Various therapeutic approaches to the treatment of advanced HCC have been unsuccessfully implemented. One of the most beneficial HCC treatment is so far the well known kinase inhibitor Sorafenib that improves patient survival of a maximum of 2 to 3 months [2,6]. Thus, limited and inefficient therapeutic options render the curative treatment of the disease almost impossible. Although several pathways and molecular players were reported in HCC development, the lack of animal models that recapitulate the full spectrum of the human disease progression may impede the development of suitable therapies. Despite detailed etiological and clinical features, the pathogenesis of HCC is not well understood. The comprehension of the disease, identifying clinically relevant therapeutic targets and the generation of efficient medicines require powerful genetic tools that mimic the human clinical stages. In a recent study of our lab, we generated genetically engineered mouse models (GEMMs) of Unconventional prefoldin RPB5 interactor (URI) loss- and gain-of-function [5,7]. Development of tumors in the murine liver after ectopic URI expression in the whole body motivated us to study its role and function in liver disease. Hepatocytic specific URI expression leads to spontaneous, heterogenous and aggressive tumors after 65 weeks of age, through a multistep process that recapitulate the human features of HCC. We propose that URI is as an oncogene essential for liver tumorigenesis and, URI GEMMs represent unique genetic models to appropriately address the mechanisms of HCC development and explore novel therapeutic avenues. At the early stages, we demonstrate that DNA damage is the critical initiating event leading to dysplastic lesions and aggressive HCC. Interestingly, while apoptosis-induced compensatory proliferation is suggested to initiate liver tumors, in our model, abolishing apoptosis and increasing genotoxic stress by inactivating p53, accelerates tumor formation and death of mice. Thus, oncogenic URI-induced genotoxic stress, rather than excessive liver injury is essential to initiate the liver tumorigenic process. In support of this, chromosomal abnormalities represent the most reliable clinical aspect to determine precancerous stages of HCC [8]. Next, using global quantitative transcriptomic and proteomic analysis, we demonstrate that prior to DNA damage, URI downregulates the L-tryptophan/kynurenine catabolism pathway and thus, leads to the inhibition of de novo NAD+ synthesis. The decrease in total NAD+ levels consequently provokes DNA damage (Figure). Although it remains unclear how decreased in NAD+ concentrations causes genotoxic stress, preliminary results indicate that the DNA repair protein poly-ADP-ribose polymerase (PARP) activity may be affected. We do not completely exclude that NAD+ depletion may affect Sirts activity. Furthermore, because NAD+ is a cofactor for inosine monophosphate dehydrogenase implicated in dNTPs synthesis, NAD+ deficits can also lead to insufficient dNTP production that may contribute to DNA damage during high replication. Replenishing the NAD+ levels by nicotinamide riboside (NR), a derivative of vitamin B3, prevented and abolished DNA damage and aggressive tumor formation [5]. Figure 1 Scheme representing hepatocyte specific hURI expression leading to DNA damage and liver tumorigensesis Based on previous observations and extending our work to other oncogenes known to induce tumors on the basis of DNA damage, we demonstrate that c-Myc expression in pancreas induced NAD+ depletion through a net reduction in tryptophan catabolism. Enzymes implicated in tryptophan degradation are downregulated by c-Myc over-expression. NAD+ depletion is apparently involved in the formation of pancreatic tumors. Importantly, these tumors could be tackled when NAD+ levels were enhanced by NR supplementation [5]. We propose that NAD+ depletion is a common molecular mechanistic basis for oncogene-induced DNA damage and tumor development. NR seems therefore to be an efficient therapy for the treatment of various cancers in which predictive and prognostic factors can be identified as oncogene-associated genotoxic stress. Clinical trials with NR for treatment of such cancers are under consideration. However, developing a methodological screen to find more efficient and stable NAD+ “boosters” and, understanding the mechanisms of NAD+ depletion-dependent DNA damage would offer a broad spectrum of new possibilities to decisively prevent and cure cancer in human beings. The development of drug discovery platform based on screening of new compounds that enable to abolish DNA damage by increasing NAD+ levels can thus be an exciting investment in the war against cancer.

10.18632/oncoscience.154

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Citations (6)