Lipogenic Tumor Research Articles

Abstract LB138: DAXX interacts with sterol regulatory element-binding proteins (SREBPs) to promote oncogenic lipogenesis and tumorigenesis in triple-negative breast cancer

Abstract Elevated lipid metabolism including lipogenesis is a major metabolic feature in cancer cells. In breast and other cancer types, genes involved in lipogenesis are highly upregulated, but the mechanisms that control their expression remain poorly understood. DAXX modulates gene expression through binding to numerous transcription factors although the functional impact of these diverse interactions remains to be defined. Our recent analysis indicates that DAXX is overexpressed in diverse cancer types and metastases. However, mechanisms underlying DAXX’s oncogenic function remains elusive. Using global integrated transcriptomic and lipidomic analyses, we show that DAXX plays a key role in lipid metabolism in triple-negative breast cancer (TNBC) cells. DAXX depletion attenuates, while its overexpression enhances, lipogenic gene expression, lipid synthesis and tumor growth. Mechanistically, DAXX interacts with SREBP1 and SREBP2 and activates SREBP-mediated transcription. DAXX associates with lipogenic gene promoters through SREBPs. Underscoring the critical roles for the DAXX-SREBP interaction for lipogenesis, SREBP2 knockdown attenuates tumor growth in cells with DAXX overexpression, and a DAXX mutant unable to bind SREBPs are incapable of promoting lipogenesis and tumor growth. In TNBC patients, DAXX expression levels are increased in breast cancer brain metastasis and correlate with poor patient survival. Our results identify the DAXX-SREBP axis as an important pathway for tumorigenesis in TNBC. (This work is supported by Florida Department of Health Grants.) Citation Format: Iqbal Mahmud, Guimei Tian, Tarun Hutchison, Brandon Kim, Daiqing Liao. DAXX interacts with sterol regulatory element-binding proteins (SREBPs) to promote oncogenic lipogenesis and tumorigenesis in triple-negative breast cancer [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2022; 2022 Apr 8-13. Philadelphia (PA): AACR; Cancer Res 2022;82(12_Suppl):Abstract nr LB138.

Abstract 3595: DSP-0692, a selective SCD inhibitor, enhances the anti-tumor activity of anti-PD1 antibody

Abstract SCD (Stearoyl-CoA Desaturase), a key enzyme for lipid metabolism, is overexpressed in various types of cancer and plays an important role in cancer cell proliferation. We have previously shown that the identification and the functional characterization of DSP-0692, a novel and selective SCD inhibitor. SCD expression was induced in tumor cells cultured in sphere conditions, which were resistant to conventional agents within therapeutic concentration. DSP-0692 showed strong growth inhibition when tumor cells were cultured in sphere conditions, but had little impact on cells cultured under adherent conditions. In addition, DSP-0692 decreased the expression of stemness-related genes in tumor cells as well as in tumor tissues. Treatment with DSP-0692 suppressed tumor growth in multiple models both in single agent or in combination with conventional chemotherapies. DSP-0692 also inhibited WNT/beta-catenin signaling pathway through two different mechanisms (inhibition of Wnt3A secretion and nuclear translocation of beta-catenin). DSP-0692 exhibited lower IC50 value to sphere cells carrying mutations related to WNT/beta-catenin signaling pathway than those without these mutations. Blockade of the coinhibitory checkpoint molecule PD-1 has emerged as an effective treatment for many cancers. However, despite successes in the clinical setting, only a limited subpopulation respond to PD-1 blockade. We hypothesized that the deregulated lipid metabolism of tumor cells and microenvironment function as a barrier to antitumor immunity, and therefore that normalization of lipid metabolism with DSP-0692 might restore response to immunotherapy. Combination of DSP-0692 with anti-PD-1 antibody in the syngeneic CT-26 colon model, a resistant model to anti-PD-1 antibody, augmented tumor regressions relative to each single agent alone. DSP-0692 induced PD-L1 and PD-L2 expression in CT-26 cells, indicating that it is one of a mechanism of restoration of the effect of anti-PD-1 antibody. Our data suggest that remodeling the lipogenic tumor microenvironment has potential to convert patients resistant to immunotherapy into those who may receive clinical benefit of immunotherapy. Citation Format: Eiji Sugaru, Yudai Furuta, Yoshikazu Nagagaki, Satoshi Ikeda, Yuichi Fukunaga, Hiroki Umehara, Tsuguteru Otsubo, Manabu Watanabe, Shingo Tojo, Miki Hashizume, Yasushi Matsuki, Hitoshi Ban. DSP-0692, a selective SCD inhibitor, enhances the anti-tumor activity of anti-PD1 antibody [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2019; 2019 Mar 29-Apr 3; Atlanta, GA. Philadelphia (PA): AACR; Cancer Res 2019;79(13 Suppl):Abstract nr 3595.

The FUS-DDIT3 Interactome in Myxoid Liposarcoma

Myxoid liposarcoma is a malignant lipogenic tumor that develops in deep soft tissues. While local control rates are good, current chemotherapy options remain ineffective against metastatic disease. Myxoid liposarcoma is characterized by the FUS-DDIT3 fusion oncoprotein that is proposed to function as an aberrant transcription factor, but its exact mechanism of action has remained unclear. To identify the key functional interacting partners of FUS-DDIT3, this study utilized immunoprecipitation-mass spectrometry (IP-MS) to identify the FUS-DDIT3 interactome in whole cell lysates of myxoid liposarcoma cells, and results showed an enrichment of RNA processing proteins. Further quantitative MS analyses of FUS-DDIT3 complexes isolated from nuclear lysates showed that members of several chromatin regulatory complexes were present in the FUS-DDIT3 interactome, including NuRD, SWI/SNF, PRC1, PRC2, and MLL1 COMPASS-like complexes. Co-immunoprecipitation validated the associations of FUS-DDIT3 with BRG1/SMARCA4, BAF155/SMARCC1, BAF57/SMARCE1, and KDM1A. Data from this study provides candidates for functional validation as potential therapeutic targets, particularly for emerging epigenetic drugs.

Abstract 192: Targeting stearoyl CoA desaturase 1 (SCD1) in hepatobilliary carcinoma

Abstract Background: The paucity of effective therapeutic agents for hepatocellular cancer (HCC) underscores the critical need for more effective therapeutic strategies. Recent studies indicate lipid biosynthesis and desaturation is required for HCC survival. Targeting these may prove beneficial because such changes contribute to therapeutic resistance. Stearoyl CoA desaturase (SCD1), a key mediator of fatty acid (FA) biosynthesis and rate-limiting in conversion of saturated fatty acids (SFAs) to mono-unsaturated fatty acids (MUFAs), is upregulated in HCC and many other cancers. As such, we therapeutically targeted a novel lipogenic tumor survival mechanism mediated by SCD1 as a means to combat the chemoresistance associated with HCC. In so doing, we evaluated a novel lead SCD1 inhibitor in HCC. Methods: Paraffin embedded patient HCC tissues were examined for SCD1 expression. Using combined computational and synthetic chemistry approaches, we synthesized four novel specific SCD1 inhibitors with SSI-4 being the lead SCD1 inhibitor. HCC cell lines were examined using proliferation assays for response to SSI-4. IC50 concentrations for blocking SCD1 enzyme activity was determined. Blood half-life and bioavailability of single dose SSI-4 was determined. Mechanisms of action of SCD1 were examined that included Endoplasmic reticulum (ER) stress. In vivo, antitumor activity was determined using HCC patient derived xenograft (PDX) mouse models. Results: We identified elevated SCD1 mRNA and protein in HCCs tissues. SSI-4 dose-dependently inhibits cell proliferation in HCC cell lines with specificity demonstrated by oleic acid (MUFA) co-culture. Single dose oral gavage SSI-4 demonstrated a half-life of ~4 hours and excellent oral bioavailability. SSI-4 was well tolerated with long-term daily dosing. SSI-4 treatment of HCC cells and tumors led to endoplasmic reticulum (ER) stress followed by apoptotic cell death. Single agent SSI-4 demonstrated antitumor activity in HCC PDX mouse models with suppression of ER stress regulated proteins. Conclusions: Targeting a novel lipid metabolic pathway in HCC may provide effective therapy for aggressive HCC. Citation Format: John Alton Copland, Laura A. Marlow, Ilah Bok, James L. Miller, Matsuda Akiko, Yan W. Asmann, Vivekananda Sarangi, Steven R. Alberts, Kabir Mody, Lewis R. Roberts, Mark J. Truty, Tushar C. Patel. Targeting stearoyl CoA desaturase 1 (SCD1) in hepatobilliary carcinoma [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2017; 2017 Apr 1-5; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2017;77(13 Suppl):Abstract nr 192. doi:10.1158/1538-7445.AM2017-192

Inhibition of Acetyl-CoA Carboxylase 1 (ACC1) and 2 (ACC2) Reduces Proliferation and De Novo Lipogenesis of EGFRvIII Human Glioblastoma Cells.

Tumor cell proliferation and migration processes are regulated by multiple metabolic pathways including glycolysis and de novo lipogenesis. Since acetyl-CoA carboxylase (ACC) is at the junction of lipids synthesis and oxidative metabolic pathways, we investigated whether use of a dual ACC inhibitor would provide a potential therapy against certain lipogenic cancers. The impact of dual ACC1/ACC2 inhibition was investigated using a dual ACC1/ACC2 inhibitor as well as dual siRNA knock down on the cellular viability and metabolism of two glioblastoma multiform cancer cell lines, U87 and a more aggressive form, U87 EGFRvIII. We first demonstrated that while ACCi inhibited DNL in both cell lines, ACCi preferentially blunted the U87 EGFRvIII cellular proliferation capacity. Metabolically, chronic treatment with ACCi significantly upregulated U87 EGFRvIII cellular respiration and extracellular acidification rate, a marker of glycolytic activity, but impaired mitochondrial health by reducing maximal respiration and decreasing mitochondrial ATP production efficiency. Moreover, ACCi treatment altered the cellular lipids content and increased apoptotic caspase activity in U87 EGFRvIII cells. Collectively these data indicate that ACC inhibition, by reducing DNL and increasing cellular metabolic rate, may have therapeutic utility for the suppression of lipogenic tumor growth and warrants further investigation.

The Values and Limitations of FDG-PET/CT for Diagnosis of Hibernoma.

Hibernoma is a rare benign lipogenic tumor of brown fat that develops in a wide variety of locations. Although the features of hibernoma demonstrated by MRI resemble those of liposarcoma, recent FDG-PET/CT studies have documented higher radiotracer uptake than liposarcoma, suggesting that FDG/PET/CT is useful for differentiating hibernoma from liposarcoma. Here we report two cases of hibernoma that showed relatively lower SUVs than those reported previously, lying within the range for liposarcoma. Our findings emphasize that hibernoma needs to be included in the differential diagnosis of any fat-containing tumor showing intense accumulation by FDG-PET/CT. Although it is unlikely that such a rare condition could be reasonably diagnosed on the basis of MRI and FDG-PET/CT alone due to possible SUV overlap between hibernoma and liposarcoma, it is important to recognize this extremely rare lipogenic tumor for accurate diagnosis and appropriate management.

Coactivation of AKT and β-catenin in mice rapidly induces formation of lipogenic liver tumors.

Obesity is a risk factor for development of certain cancers but the basis for this risk is unclear. In this study, we developed a novel mouse model that demonstrates directly how lipogenic phenotypes commonly associated with diet-induced metabolic syndromes can influence hepatic cancer development. Activated AKT and β-catenin (AKT/CAT) genes were hydrodynamically codelivered using the Sleeping Beauty transposon to initiate liver tumorigenesis. AKT/CAT and MET/CAT combination induced microscopic tumor foci by 4 weeks, whereas no tumorigenesis resulted from delivery of AKT, MET, or CAT alone. Primary AKT/CAT tumor cells were steatotic (fatty) hepatocellular adenomas which progressed to hepatocellular carcinomas (HCC) upon in vivo passage, whereas primary MET/CAT tumors emerged directly as frank HCC. Conversion of AKT/CAT tumor cells to frank HCC during passage was associated with induction of the human HCC marker α-fetoprotein and the stem cell marker CD133. Using hierarchical clustering and gene set enrichment analysis, we compared the primary murine AKT/CAT and MET/CAT tumors to a panel of 53 human HCCs and determined that these two mouse models could be stratified as distinct subtypes associated in humans with poor clinical prognosis. The chief molecular networks identified in primary and passaged AKT/CAT tumors were steatosis and lipid metabolic pathways, respectively. Our findings show how coactivation of the AKT and CAT pathways in hepatocytes can efficiently model development of a lipogenic tumor phenotype. Furthermore, we believe that our approach could speed the dissection of microenvironmental factors responsible for driving steatotic-neoplastic transformation to frank carcinoma, through genetic modification of existing immunodefined transgenic models.

Significance of LRP and PPAR-γ Expression in Lipomatous Soft Tissue Tumors

Background:Molecular mechanism of differentiation in lipogenic tumor is still unknown in detail. Low-density lipoprotein receptor-related protein (LRP) and peroxisome proliferator-activated receptor gamma (PPAR-γ), representative regulatory molecules of lipogenic differentiation, have been reported today as multi-functional molecules and to modulate tumorigenesis in various kind of cancer. To date, diagnostic and therapeutic significance of the expression of these molecules in lipogenic tumors are not defined. Methods:The immunohistochemical expression status of LRP and PPAR-γ in various grades of 54 lipogenic tumors was analyzed. Correlation between the expression levels and the differentiation of the tumors was confirmed. For statistical analyses, the Kruskal-Wallis test, the Steel-Dwass test and the Mann–Whitney U test were used. Results:LRP and PPAR-γ expression was detected in 50 (92.6%) and 44 (81.5%) cases, respectively. The expression level in LRP was significantly higher in cases with well differentiated liposarcoma, pleomorphic liposarcoma and dedifferentiated liposarcoma than in lipoma. Compared with lipoma or well differentiated liposarcoma, significant elevation in expression level of PPAR-γ was confirmed in myxoid liposarcoma, pleomorphic liposarcoma, dedifferentiated liposarcoma and the differentiated area of dedifferentiated liposarcoma. Conclusion:The up-regulation of LRP and PPAR-γ in higher grade cases, i.e. less differentiated tumors than in low grade cases was shown, suggesting the candidate role of these molecules as tumor progression modulators rather than regulatory molecules of differentiation in lipogenic tumors.

Overlapping Features Between Dedifferentiated Liposarcoma and Undifferentiated High-Grade Pleomorphic Sarcoma

Dedifferentiated liposarcoma (DDL), occurring in up to 10% of well differentiated liposarcoma cases, has similar histologic features to that of undifferentiated high-grade pleomorphic sarcoma (UHGPS); the former develops in a background of atypical lipomatous tumors/well differentiated liposarcoma, whereas the latter shows no specific line of differentiation. The retroperitoneum and thigh represent the most common anatomic locations for both the sarcomas. Despite their morphologic similarity, the issue of whether these 2 sarcomas share overlapping immunohistochemical and molecular features has not been well studied. We examined the expression of the lipogenic tumor-related markers peroxisome proliferator-activated receptor gamma (PPAR-gamma), CDK4, and MDM2 in 15 cases of DDL and 45 cases of retroperitoneal/thigh UHGPS. Patients with DDL ranged from 31 to 82 years (mean 63 y) with a male:female ratio of 5:3. Patients with UHGPS ranged from 14 to 80 years (mean 52 y) with a male:female ratio of 3:2. All 15 DDLs expressed CDK4 and MDM2 (100%), and 8 of 15 cases expressed PPAR-gamma (53%). Twenty-three of 45 (51%) UHGPS expressed at least 1 of these 3 markers. We also studied MDM2 and CDK4 gene amplification by fluorescence in situ hybridization in 28 immunohistochemically positive cases, including 5 DDLs and 23 UHGPSs. All 5 cases of DDL showed MDM2 and/or CDK4 amplification (100%), whereas 6 of 45 UHGPSs showed MDM2 and/or CDK4 amplification (13%). Our results demonstrate that (1) the lipogenic tumor markers CDK4 and MDM2 can be used as surrogate immunohistochemical markers for the diagnosis of malignant lipomatous tumors with high sensitivity; (2) approximately 26% of retroperitoneal/thigh UHGPS cases that were positive for PPAR-gamma, CDK4, or MDM2 by immunohistochemistry showed characteristic CDK4 and MDM2 gene amplification, suggesting that a subset of UHGPS cases represent DDL despite lacking histologic evidence of lipoblasts.

Liposarcoma with radiologically biphasic patterns

Liposarcoma is a one of the common soft tissue sarcomas, and is estimated to represent 16–18% of sarcomas in adults. According to the World Health Organization, this tumor is mainly classified into five subtypes: well-differentiated, dedifferentiated, myxoid/round, pleomorphic and mixed-type. Previous papers have reported that radiological information for liposarcoma is correlated with the radiological and histopathological findings. In liposarcoma, when biphasic patterns composed of a lipogenic tumor with a sarcomatous appearance are found on radiological examination of computed tomography and/or magnetic resonance imaging, dedifferentiated liposarcoma, defined as a “malignant adipocytic neoplasm showing transition from atypical lipomatous tumor/well-differentiated liposarcoma to non-lipogenic sarcoma of variable histological grade”, is usually considered.