My laboratory studies the role of de novo lipogenesis in colorectal cancer (CRC) initiation and progression. A large number of preclinical studies, including ours, have demonstrated that Fatty Acid Synthase (FASN), a key enzyme of de novo lipogenesis, is a critical component of tumor cell survival and proliferation for a wide range of cancers, making it an attractive target for cancer therapy.
Using tissue microarray analysis, our group demonstrated that an increased expression of FASN is associated with higher CRC stage. Our studies are the first to demonstrate the importance of FASN upregulation in the development of CRC metastasis. We showed that shRNA-mediated inhibition of FASN significantly reduced lung and hepatic metastases in nude mice and inhibited angiogenesis in an orthotopic CRC mouse model. Our recent work suggests that overexpression of FASN promotes a metabolic switch that fuels bioenergetic pathways to enhance cancer cell survival and support metastasis, particularly under energy stress conditions. More importantly, we showed that even in the presence of exogenous fatty acids CRC cells preferentially oxidize endogenous fatty acids synthesized by FASN, thus providing further evidence of the crucial role of de novo lipid synthesis in CRC progression.
Current research projects in the laboratory has on the following goals:
1. To determine the functional importance of FASN in patient-derived xenograft (PDX) models. We utilize PDX models established from resected human CRC tissues to determine the effect of a novel FASN inhibitor (3V-Biosciences) on tumor growth as a monotherapy or in combination with other therapeutic agents. We utilize targeted next-generation sequencing with a panel of 198 cancer-associated genes to identify mutational profiles of tumors and correlate them to the response to FASN-targeted therapy. Identified “driver mutations” are also used to guide the choices of targeted therapies. We use stable isotope-resolved metabolomics (SIRM) analysis to evaluate the effect of FASN inhibition on tumor metabolism in vivo. Our goal is to identify a subset of patients that would benefit from FASN-targeted therapy and ascertain unique metabolic vulnerabilities and genetic biomarkers that can further guide the development of targeted therapies for CRC.
2. To elucidate the molecular mechanisms of regulation of metastasis by FASN-mediated alteration of sphingolipid metabolism. We found that inhibition of de novo fatty acid synthesis decreased the level of sphingosine kinases (SPHKs) and their product S1P and selectively altered levels of other sphingolipids in CRC cells. We utilize primary CRC cells and in vivo metastatic models to understand the effect of FASN-mediated sphingolipid metabolism on CRC metastasis, and mass spectrometry-based targeted metabolomics to delineate the effect of FASN on sphingolipid composition in CRC cells.
3. To determine the role of CD36 in CRC. We found that membrane localization of CD36, a fatty acid translocase, is associated with metastatic CRC and expression/localization of CD36 is regulated by the level of FASN expression. We utilize PDX models, primary CRC cells, human CRC specimens, and multiple molecular biology techniques including the CRISPR–Cas gene-editing system to understand the role of CD36 and determine the mechanisms of its regulation by FASN in this disease. We also investigate the role of CD36 in developing resistance to FASN Inhibition.
4. To elucidate the effect of FASN on CRC initiation and progression using genetically modified mouse models. We utilize C57BL/6J-ApcMin and FASN/Apc/Cre mouse models to determine the effect of FASN and diet on tumor initiation and progression and animal survival.
Rostov State University
BS Biology, Chemistry Minor, Teacher Certification
North Caucasus Personnel Center
BBA, Business & Public Administration
University of Kentucky
Department of Biomedical Pharmacology
- Jafari, N.; Drury, J ; Morris, AJ ; Onono, FO ; Stevens, PD ; Gao, T.; Liu, J.; Wang, C.; Lee, EY ; Weiss, HL ; Evers, BM ; Zaytseva, YY "<i>De Novo</i> Fatty Acid Synthesis-Driven Sphingolipid Metabolism Promotes Metastatic Potential of Colorectal Cancer." Molecular cancer research : MCR 17, 1 (2019): 140-152. [PubMed Link] | [ Full text ]
- Huang, X.; Ye, Q.; Chen, M.; Li, A.; Mi, W.; Fang, Y.; Zaytseva, YY ; O'Connor, KL ; Vander Kooi, CW ; Liu, S.; She, QB "N-glycosylation-defective splice variants of neuropilin-1 promote metastasis by activating endosomal signals." Nature communications 10, 1 (2019): 3708. [PubMed Link] | [ Full text ]
- Sinner, HF ; Johnson, J.; Rychahou, PG ; Watt, DS ; Zaytseva, YY ; Liu, C.; Evers, BM "Novel chemotherapeutic agent, FND-4b, activates AMPK and inhibits colorectal cancer cell proliferation." PloS one 14, 10 (2019): e0224253. [PubMed Link] | [ Full text ]
- Stevens, PD ; Wen, YA ; Xiong, X.; Zaytseva, YY ; Li, AT ; Wang, C.; Stevens, AT ; Farmer, TN ; Gan, T.; Weiss, HL ; Inagaki, M.; Marchetto, S.; Borg, JP ; Gao, T. "Erbin Suppresses KSR1-Mediated RAS/RAF Signaling and Tumorigenesis in Colorectal Cancer." Cancer research 78, 17 (2018): 4839-4852. [PubMed Link] | [ Full text ]
- Zaytseva, YY ; Rychahou, PG ; Le, AT ; Scott, TL ; Flight, RM ; Kim, JT ; Harris, J.; Liu, J.; Wang, C.; Morris, AJ ; Sivakumaran, TA ; Fan, T.; Moseley, H.; Gao, T.; Lee, EY ; Weiss, HL ; Heuer, TS ; Kemble, G.; Evers, M. "Preclinical evaluation of novel fatty acid synthase inhibitors in primary colorectal cancer cells and a patient-derived xenograft model of colorectal cancer." Oncotarget 9, 37 (2018): 24787-24800. [PubMed Link] | [ Full text ]
- Wang, Q.; Zhou, Y.; Rychahou, P.; Harris, JW ; Zaytseva, YY ; Liu, J.; Wang, C.; Weiss, HL ; Liu, C.; Lee, EY ; Evers, BM "Deptor Is a Novel Target of Wnt/β-Catenin/c-Myc and Contributes to Colorectal Cancer Cell Growth." Cancer research 78, 12 (2018): 3163-3175. [PubMed Link] | [ Full text ]
- Wen, YA ; Xiong, X.; Zaytseva, YY ; Napier, DL ; Vallee, E.; Li, AT ; Wang, C.; Weiss, HL ; Evers, BM ; Gao, T. "Downregulation of SREBP inhibits tumor growth and initiation by altering cellular metabolism in colon cancer." Cell death & disease 9, 3 (2018): 265. [PubMed Link] | [ Full text ]
- Rychahou, P.; Bae, Y.; Reichel, D.; Zaytseva, YY ; Lee, EY ; Napier, D.; Weiss, HL ; Roller, N.; Frohman, H.; Le, AT ; Mark Evers, B. "Colorectal cancer lung metastasis treatment with polymer-drug nanoparticles." Journal of controlled release : official journal of the Controlled Release Society 275, (2018): 85-91. [PubMed Link] | [ Full text ]
- Mitov, MI ; Harris, JW ; Alstott, MC ; Zaytseva, YY ; Evers, BM ; Butterfield, DA "Temperature induces significant changes in both glycolytic reserve and mitochondrial spare respiratory capacity in colorectal cancer cell lines." Experimental cell research 354, 2 (2017): 112-121. [PubMed Link] | [ Full text ]
- Wen, YA ; Xing, X.; Harris, JW ; Zaytseva, YY ; Mitov, MI ; Napier, DL ; Weiss, HL ; Mark Evers, B.; Gao, T. "Adipocytes activate mitochondrial fatty acid oxidation and autophagy to promote tumor growth in colon cancer." Cell death & disease 8, 2 (2017): e2593. [PubMed Link] | [ Full text ]
- Li, J.; Song, J.; Zaytseva, YY ; Liu, Y.; Rychahou, P.; Jiang, K.; Starr, ME ; Kim, JT ; Harris, JW ; Yiannikouris, FB ; Katz, WS ; Nilsson, PM ; Orho-Melander, M.; Chen, J.; Zhu, H.; Fahrenholz, T.; Higashi, RM ; Gao, T.; Morris, AJ ; Cassis, LA ; Fan, TW ; Weiss, HL ; Dobner, PR ; Melander, O.; Jia, J.; Evers, BM "An obligatory role for neurotensin in high-fat-diet-induced obesity." Nature 533, 7603 (2016): 411-5. [PubMed Link] | [ Full text ]
- Vilchez, V.; Turcios, L.; Zaytseva, Y.; Stewart, R.; Lee, EY ; Maynard, E.; Shah, MB ; Daily, MF ; Tzeng, CW ; Davenport, D.; Castellanos, AL ; Krohmer, S.; Hosein, PJ ; Evers, BM ; Gedaly, R. "Cancer stem cell marker expression alone and in combination with microvascular invasion predicts poor prognosis in patients undergoing transplantation for hepatocellular carcinoma." American journal of surgery 212, 2 (2016): 238-45. [PubMed Link] | [ Full text ]
- Kim, JT ; Liu, C.; Zaytseva, YY ; Weiss, HL ; Townsend CM, Jr ; Evers, BM "Neurotensin, a novel target of Wnt/β-catenin pathway, promotes growth of neuroendocrine tumor cells." International journal of cancer 136, 6 (2015): 1475-81. [PubMed Link] | [ Full text ]
- Rychahou, P.; Haque, F.; Shu, Y ; Zaytseva, Y.; Weiss, HL ; Lee, EY ; Mustain, W.; Valentino, J.; Guo, P.; Evers, BM "Delivery of RNA nanoparticles into colorectal cancer metastases following systemic administration." ACS nano 9, 2 (2015): 1108-16. [PubMed Link] | [ Full text ]
- Zaytseva, YY ; Harris, JW ; Mitov, MI ; Kim, JT ; Butterfield, DA ; Lee, EY ; Weiss, HL ; Gao, T.; Evers, BM "Increased expression of fatty acid synthase provides a survival advantage to colorectal cancer cells via upregulation of cellular respiration." Oncotarget 6, 22 (2015): 18891-904. [PubMed Link] | [ Full text ]
- Valentino, JD ; Li, J.; Zaytseva, YY ; Mustain, WC ; Elliott, VA ; Kim, JT ; Harris, JW ; Campbell, K.; Weiss, H.; Wang, C.; Song, J.; Anthony, L.; Townsend CM, Jr ; Evers, BM "Cotargeting the PI3K and RAS pathways for the treatment of neuroendocrine tumors." Clinical cancer research : an official journal of the American Association for Cancer Research 20, 5 (2014): 1212-22. [PubMed Link] | [ Full text ]
- Zaytseva, YY ; Elliott, VA ; Rychahou, P.; Mustain, WC ; Kim, JT ; Valentino, J.; Gao, T.; O'Connor, KL ; Neltner, JM ; Lee, EY ; Weiss, HL ; Evers, BM "Cancer cell-associated fatty acid synthase activates endothelial cells and promotes angiogenesis in colorectal cancer." Carcinogenesis 35, 6 (2014): 1341-51. [PubMed Link] | [ Full text ]
- Elliott, VA ; Rychahou, P.; Zaytseva, YY ; Evers, BM "Activation of c-Met and upregulation of CD44 expression are associated with the metastatic phenotype in the colorectal cancer liver metastasis model." PloS one 9, 5 (2014): e97432. [PubMed Link] | [ Full text ]
- Gulhati, P.; Zaytseva, YY ; Valentino, JD ; Stevens, PD ; Kim, JT ; Sasazuki, T.; Shirasawa, S.; Lee, EY ; Weiss, HL ; Dong, J.; Gao, T.; Evers, BM "Sorafenib enhances the therapeutic efficacy of rapamycin in colorectal cancers harboring oncogenic KRAS and PIK3CA." Carcinogenesis 33, 9 (2012): 1782-90. [PubMed Link] | [ Full text ]
- Zaytseva, YY ; Rychahou, PG ; Gulhati, P.; Elliott, VA ; Mustain, WC ; O'Connor, K.; Morris, AJ ; Sunkara, M.; Weiss, HL ; Lee, EY ; Evers, BM "Inhibition of fatty acid synthase attenuates CD44-associated signaling and reduces metastasis in colorectal cancer." Cancer research 72, 6 (2012): 1504-17. [PubMed Link] | [ Full text ]
- Zaytseva, YY ; Valentino, JD ; Gulhati, P.; Evers, BM "mTOR inhibitors in cancer therapy." Cancer letters 319, 1 (2012): 1-7. [PubMed Link] | [ Full text ]
- Valentino, JD ; Elliott, VA ; Zaytseva, YY ; Rychahou, PG ; Mustain, WC ; Wang, C.; Gao, T.; Evers, BM "Novel small interfering RNA cotargeting strategy as treatment for colorectal cancer." Surgery 152, 2 (2012): 277-85. [PubMed Link] | [ Full text ]
- Zaytseva, YY ; Wallis, NK ; Southard, RC ; Kilgore, MW "The PPARgamma antagonist T0070907 suppresses breast cancer cell proliferation and motility via both PPARgamma-dependent and -independent mechanisms." Anticancer research 31, 3 (2011): 813-23. [PubMed Link] | [ Full text ]
- Silva, SR ; Zaytseva, YY ; Jackson, LN ; Lee, EY ; Weiss, HL ; Bowen, KA ; Townsend CM, Jr ; Evers, BM "The effect of PTEN on serotonin synthesis and secretion from the carcinoid cell line BON." Anticancer research 31, 4 (2011): 1153-60. [PubMed Link] | [ Full text ]
- Talbert, DR ; Allred, CD ; Zaytseva, YY ; Kilgore, MW "Transactivation of ERalpha by Rosiglitazone induces proliferation in breast cancer cells." Breast cancer research and treatment 108, 1 (2008): 23-33. [PubMed Link] | [ Full text ]
- Zaytseva, YY ; Wang, X.; Southard, RC ; Wallis, NK ; Kilgore, MW "Down-regulation of PPARgamma1 suppresses cell growth and induces apoptosis in MCF-7 breast cancer cells." Molecular cancer 7, (2008): 90. [PubMed Link] | [ Full text ]