Igor Garkavtsev
Assistant Professor, Radiation Oncology
Garkavtsev Lab

Garkavtsev Lab Research

Regulation of Metastasis

My research focuses on mechanisms governing tumor progression, with primary emphasis on the identification and characterization of novel tumor suppressor genes. We are particularly interested in understanding how these genes are involved in the regulation of brain tumor angiogenesis and invasion. A detailed understanding of this regulation may lead to the rational selection of molecular targets for anti-cancer drug development. 

Stress granule involvement in cancer progression

Breast tumors contain tumorigenic cancer cells, termed “tumor-initiating cells” (TICs), which are capable of both replenishing themselves and giving rise to populations of nontumorigenic breast cancer cells (non-TICs). However, the molecular mechanisms responsible for breast tumor initiation remain poorly understood. We used a chemical screening strategy to identify small molecules that enhance the effect of chemotherapeutic agents on TIC-enriched breast cancer cells. We found proteins that interact with the lead compound C108, including the stress granule-associated protein, GTPase-activating protein (SH3 domain)-binding protein 2, G3BP2. G3BP2 regulates breast tumor initiation through the stabilization of Squamous cell carcinoma antigen recognized by T cells 3 (SART3) mRNA, which leads to increased expression of the pluripotency transcription factors Octamer-binding protein 4 (Oct-4) and Nanog Homeobox (Nanog). Our findings suggest that G3BP2 is important for the process of breast cancer initiation. Furthermore, these data suggest a possible connection between stress granule formation and tumor initiation in breast cancer cells.

[Gupta N, Badeaux M, Liu Y, Naxerova K, Sgroi D, Munn LL, Jain RK, Garkavtsev I. Stress granule-associated protein G3BP2 regulates breast tumor initiation. Proc Natl Acad Sci U S A 2017, 114:1033-1038]

Discovery of small molecule that inhibit metastasis of triple-negative breast cancers.

SLPI has been implicated in the progression and metastasis of certain cancers. However, the effects of SLPI seem to be tumor-specific and the mechanisms remain poorly defined. We discovered that highly metastatic, triple-negative breast cancer (TNBC) 4T1 cells secrete more SLPI compared to their non-metastatic counterparts. Furthermore, SLPI secretion directly correlated with spontaneous lung metastasis from 4T1 tumors orthotopically implanted in mice. Consistent with our experimental results, we also found that higher SLPI expression levels correlate with worse clinical outcome in basal/TNBC patients. Using high-throughput screening we identified a novel compound, C74, which significantly inhibits SLPI secretion. C74 administration in our mouse model slows the growth of primary 4T1 tumors and inhibits their dissemination to the lung. We also discovered that SLPI physically interacts with the retinoblastoma tumor suppressor protein (Rb) and releases FoxM1 from the Rb-FoxM1 complex, which may activate FoxM1 target genes involved in breast cancer metastasis.

[Kozin S, Maimon N, Wang R, Gupta N, Munn L, Jain R.K, and Garkavtsev I.. Secretory leukocyte protease inhibitor (SLPI) as a potential target for inhibiting metastasis of triple-negative breast cancers. Oncotarget 2017; 8:108292-108302]

Lab News

National Foundation for Cancer Research conducts Salisbury Award Competition

Dr. Garkavtsev's second runner-up project, delivered in conjunction with his laboratory's director, Rakesh Jain, Ph.D., involves improving cancer treatment by targeting cancer stem cells and immunosuppression.

NFCR announcement

Selected Publications (from total of 28)

Munn LL, Garkavtsev I
SLPI: a new target for stopping metastasis.
Aging (Albany NY). 2018;10(1):13-14 - PMID: 29356683 - PMCID: PMC5811255 - DOI: 10.18632/aging.101372
Kozin SV, Maimon N, Wang R, Gupta N, Munn L, Jain RK, Garkavtsev I
Secretory leukocyte protease inhibitor (SLPI) as a potential target for inhibiting metastasis of triple-negative breast cancers.
Oncotarget. 2017;8(65):108292-108302 - PMID: 29312532 - PMCID: PMC5752445 - DOI: 10.18632/oncotarget.22660
Gupta N, Badeaux M, Liu Y, Naxerova K, Sgroi D, Munn LL, Jain RK, Garkavtsev I
Stress granule-associated protein G3BP2 regulates breast tumor initiation.
Proc Natl Acad Sci U S A. 2017;114(5):1033-1038 - PMID: 28096337 - PMCID: PMC5293063 - DOI: 10.1073/pnas.1525387114
Han S, Ma X, Zhao Y, Zhao H, Batista A, Zhou S, Zhou X, Yang Y, Wang T, Bi J, Xia Z, Bai Z, Garkavtsev I, Zhang Z
Identification of Glypican-3 as a potential metastasis suppressor gene in gastric cancer.
Oncotarget. 2016;7(28):44406-44416 - PMID: 27259271 - PMCID: PMC5190106 - DOI: 10.18632/oncotarget.9763
Wong HK, Shimizu A, Kirkpatrick ND, Garkavtsev I, Chan AW, di Tomaso E, Klagsbrun M, Jain RK
Merlin/NF2 regulates angiogenesis in schwannomas through a Rac1/semaphorin 3F-dependent mechanism.
Neoplasia. 2012;14(2):84-94 - PMID: 22431917 - PMCID: PMC3306254 - DOI: 10.1593/neo.111600
Garkavtsev I, Chauhan VP, Wong HK, Mukhopadhyay A, Glicksman MA, Peterson RT, Jain RK
Dehydro-alpha-lapachone, a plant product with antivascular activity.
Proc Natl Acad Sci U S A. 2011;108(28):11596-601 - PMID: 21709229 - PMCID: PMC3136298 - DOI: 10.1073/pnas.1104225108
Perentes JY, Kirkpatrick ND, Nagano S, Smith EY, Shaver CM, Sgroi D, Garkavtsev I, Munn LL, Jain RK, Boucher Y
Cancer cell-associated MT1-MMP promotes blood vessel invasion and distant metastasis in triple-negative mammary tumors.
Cancer Res. 2011;71(13):4527-38 - PMID: 21571860 - DOI: 10.1158/0008-5472.CAN-10-4376
Nelson GM, Padera TP, Garkavtsev I, Shioda T, Jain RK
Differential gene expression of primary cultured lymphatic and blood vascular endothelial cells.
Neoplasia. 2007;9(12):1038-45 - PMID: 18084611 - PMCID: PMC2137938 - DOI: 10.1593/neo.07643
Kozin SV, Winkler F, Garkavtsev I, Hicklin DJ, Jain RK, Boucher Y
Human tumor xenografts recurring after radiotherapy are more sensitive to anti-vascular endothelial growth factor receptor-2 treatment than treatment-naive tumors.
Cancer Res. 2007;67(11):5076-82 - PMID: 17545583 - DOI: 10.1158/0008-5472.CAN-06-3664
Garkavtsev I, Boucher Y
An intact ING1-P53 pathway can potentiate the cytotoxic effects of taxol.
Cancer Biol Ther. 2005;4(1):48-9 - PMID: 15711122 - DOI: 10.4161/cbt.4.1.1572
Winkler F, Kozin SV, Tong RT, Chae SS, Booth MF, Garkavtsev I, Xu L, Hicklin DJ, Fukumura D, di Tomaso E, Munn LL, Jain RK
Kinetics of vascular normalization by VEGFR2 blockade governs brain tumor response to radiation: role of oxygenation, angiopoietin-1, and matrix metalloproteinases.
Cancer Cell. 2004;6(6):553-63 - PMID: 15607960 - DOI: 10.1016/j.ccr.2004.10.011
Garkavtsev I, Kozin SV, Chernova O, Xu L, Winkler F, Brown E, Barnett GH, Jain RK
The candidate tumour suppressor protein ING4 regulates brain tumour growth and angiogenesis.
Nature. 2004;428(6980):328-32 - PMID: 15029197 - DOI: 10.1038/nature02329
Fukumura D, Ushiyama A, Duda DG, Xu L, Tam J, Krishna V, Chatterjee K, Garkavtsev I, Jain RK
Paracrine regulation of angiogenesis and adipocyte differentiation during in vivo adipogenesis.
Circ Res. 2003;93(9):e88-97 - PMID: 14525808 - PMCID: PMC2755542 - DOI: 10.1161/01.RES.0000099243.20096.FA
Ohiro Y, Garkavtsev I, Kobayashi S, Sreekumar KR, Nantz R, Higashikubo BT, Duffy SL, Higashikubo R, Usheva A, Gius D, Kley N, Horikoshi N
A novel p53-inducible apoptogenic gene, PRG3, encodes a homologue of the apoptosis-inducing factor (AIF).
FEBS Lett. 2002;524(1-3):163-71 - PMID: 12135761 - DOI: 10.1016/s0014-5793(02)03049-1
Garkavtsev I
Suppression of the novel growth inhibitor p33ING1 promotes neoplastic transformation
Nat Genet. 1999;23(3):373 - PMID: 10545957 - DOI: 10.1038/15566