• Regulation of Ovarian Cancer Metastasis

    We study the regulation of metastatic colonization of ovarian cancer through the reciprocal interactions between cancer cells and the metastatic microenvironment

  • Lab News

    5/18/19: Anirban participated in Rumble for the Cure to raise awareness about cancer and raise funds for American Cancer Society. It was a 90 mile ride involving 238 motorcycles.

     

    5/15/19: Yiming won the 1st prize for best poster at the IUSCC Cancer Research Day. He was also chosen to give a talk on his research. Congratulations Yiming!!!

     

    1/7/19: Melissa Halprin joins the lab as an undergraduate researcher. Welcome Melissa!

     

    12/15/18: First year CMCB graduate student Ishara Moulana joins the lab to pursue her Ph.D. Welcome Ishara!

     

    11/7/18: Congratulations Yiming for passing your prelims with flying colors!

     

    7/16/18: A warm welcome to Kartikeya who joins the group today as a postdoctoral scholar.

     

    5/17/18: We are featured in a New York Times article by Susan Gubar: https://nyti.ms/2k1tEoS

     

    5/3/18: Congratulations Yiming for being awarded the honorable mention prize in the IU Simon Cancer Center's Cancer Research Day!!!

     

    5/1/18: A warm welcome to Mohamed who joins the group today as a visiting scholar.

  • Research Projects

    Role of reciprocal interactions between cancer cells and their microenvironment in regulation of ovarian cancer metastasis.

    Ovarian cancer is the most lethal of all gynecologic malignancies primarily because most ovarian cancer patients present with extensive metastasis when they are first diagnosed. There has been no significant improvement in survival rates over the last three decades. Metastasis is responsible for most cancer related deaths and is one of the least understood aspects of the disease. Therefore, it is imperative to understand the process of ovarian cancer metastasis and devise new therapies targeting metastatic disease. Ovarian cancer has a unique metastasis, which rarely takes the hematogenous route. During the process of abdominal dissemination, the cancer cells floating in the peritoneal fluid have to attach to the mesothelial cells lining the peritoneal organs and interact with the microenvironment at the site of metastasis to successfully establish metastatic colonies. The cross talk between the cancer cells with the microenvironment of the metastasis site and the regulation of the initial steps of colonization is crucial and largely unknown.

     

    My laboratory seeks to understand the paracrine and juxtacrine interactions between cancer cells and their microenvironment that regulate metastatic colonization in ovarian cancer. We are using in vitro organotypic 3D culture models (Figure 1), live 3D time lapse microscopy and mouse xenograft models of metastasis along with cell and molecular biological approaches to study the reciprocal interactions between the metastasizing cancer cells with their microenvironment at the site of metastasis. We are specifically interested in the regulation of key microRNAs and transcription factors by these paracrine/juxtacrine interactions and the mechanism by which they drive metastatic colonization in ovarian cancer. We have developed novel assays like a plug homing assay, a 3D time-lapse confocal microscopy based assay for co-invasion of cancer cells along with stromal cells and a proximal culture method to study paracrine signaling.

    Time lapse confocal imaging of invasion of ovarian cancer cells (green) through a monolayer of mesothelial cells (red)

    Time lapse confocal imaging of co-invasion of ovarian cancer cells (green) and cancer associated fibroblasts (red) through matrigel.

    Immunofluorescence imaging of cocultured OVCAR3 cells (green) and cancer associated fibroblasts (red).

    Yiming's immunofluorescence image made it to the cover of "The Tumor Microenvironment of High Grade Serous Ovarian Cancer".

    Proximal Culture Method: We have developed a novel Proximal Culture method to study paracrine signaling between cancer cells and their microenvironment (J. Vis. Exp. (138), e58144).

  • Our team

    Subramanyam Dasari, Ph.D.

    Postdoctoral Scholar

    Yiming Fang, B.S.

    Graduate Student

    Taruni Pandhiri

    Undergraduate Student

    Melissa Halprin

    Undergraduate Student

    Aneesha Anand

    Undergraduate Student

    Past Members

    Sunil Tomar (Postdoc)

    Kartikeya Tiwari (Postdoc)

    Mohamed A. Abd El Aziz, M.D. (Visiting Scholar)

    Ishara Moulana (Graduate Student)

    James Haley (MS Student)

    Sen Xiong (Undergrad student)

    Joshua Scantland (MD student)

  • Publications

    1. Mitra S., Tiwari K., Podicheti R., Pandhiri T., Rusch D.B., Bonetto A., Zhang C., Mitra A.K. Transcriptome Profiling Reveals Matrisome Alteration as a Key Feature of Ovarian Cancer Progression. Cancers 2019, 11, 1513. https://www.mdpi.com/549026 
    2. Abd El Aziz M.A., Agarwal K., Dasari S., Mitra A.K. Productive Cross-Talk with the Microenvironment: A Critical Step in Ovarian Cancer Metastasis. Cancers 2019, 11, 1608. https://www.mdpi.com/557784 
    3. Mitra AK, Yang-Hartwich Y. Tumor microenvironment and immunology of ovarian cancer: 12th Biennial Rivkin Center Ovarian Cancer Research Symposium. Int J Gynecol Cancer. 2019, 29(Suppl 2):s12-s15. PMID: 31462543.
    4. Dasari S, Fang Y and Mitra AK. Cancer Associated Fibroblasts: Naughty Neighbors That Drive Ovarian Cancer Progression. Cancers 2018, 10(11), 406. https://doi.org/10.3390/cancers10110406 
    5. Wang Y, Zong X, Mitra S, Mitra AK, Matei D, Nephew KP. IL-6 mediates platinum-induced enrichment of ovarian cancer stem cells. JCI Insight. 2018 Dec 6;3(23). pii: 122360. doi: 10.1172/jci.insight.122360. [Epub ahead of print] PubMed PMID: 30518684.
    6. Dasari, S., Pandhiri, T., Haley, J., Lenz, D., Mitra, A. K. A Proximal Culture Method to Study Paracrine Signaling Between Cells. J. Vis. Exp. (138), e58144, doi:10.3791/58144 (2018).   http://www.jove.com/video/58144
    7. Tomar S, Plotnik JP, Haley J, Scantland J, Dasari S, Sheikh Z, Emerson R, Lenz D, Hollenhorst PC, Mitra AK. ETS1 induction by the microenvironment promotes ovarian cancer metastasis through focal adhesion kinase. Cancer Lett. 2017 Nov 22;414:190-204. PubMed PMID: 29174800. (Link to full article: https://doi.org/10.1016/j.canlet.2017.11.012)
    8. Mitra S*, Mitra AK*. Potential role of antiestrogens in treating ovarian cancer. Transl Cancer Res 2017;6(Suppl 3):S614-S616. doi: 10.21037/tcr.2017.05.30. Editorial.* Corresponding Authors.
    9. Mitra AK (2016). Ovarian Cancer Metastasis: A Unique Mechanism of Dissemination, Tumor Metastasis, Dr. Ke Xu (Ed.), InTech, DOI: 10.5772/64700. Available from: https://www.intechopen.com/books/tumor-metastasis/ovarian-cancer-metastasis-a-unique-mechanism-of-dissemination
    10. Sundaram KM, Zhang Y, Mitra AK, Kouadio JK, Gwin K, Kossiakoff AA, Roman BB, Lengyel E, Piccirilli JA. Prolactin Receptor-Mediated Internalization of Imaging Agents Detects Epithelial Ovarian Cancer with Enhanced Sensitivity and Specificity. Cancer research. 2017; 77(7):1684-1696. PMID: 28202518.
    11. Haley J, Tomar S, Pulliam N, Xiong S, Perkins SM, Karpf AR, Mitra S, Nephew KP, Mitra AK. Functional characterization of a panel of high-grade serous ovarian cancer cell lines as representative experimental models of the disease. Oncotarget. 2016, 7(22): 32810-20.
    12. Mittal K, Choi da H, Klimov S, Pawar S, Kaur R, Mitra AK, Gupta MV, Sams R, Cantuaria G, Rida PC, Aneja R. A centrosome clustering protein, KIFC1, predicts aggressive disease course in serous ovarian adenocarcinomas. J Ovarian Res. 2016, 9:17. (PMID: 26992853).
    13. Mitra AK*, Davis DA, Tomar S, Roy L, Gurler H, Xie J, Lantvit DD, Cardenas H, Fang  F, Liu Y, Loughran E, Yang J, Sharon  S*, Emerson RE, Cowden Dahl KD*, Barbolina M*, Nephew KP*, Matei D* and Burdette J*. In vivo tumor growth of high-grade serous ovarian cancer cell lines. Gynecologic Oncology 2015, 138:372-7 (PMID: 26050922).* Corresponding Authors.
    14. Kohlhapp FJ, Mitra AK, Lengyel E, Peter ME. MicroRNAs as mediators and communicators between cancer cells and the tumor microenvironment. Oncogene. 2015, 34(48):5857-68. Review. (PMID:25867073).
    15. Mitra AK*, Chiang CY, Tiwari P, Tomar S, Watters KM, Peter ME, and Lengyel E*. Microenvironment-induced downregulation of miR-193b drives ovarian cancer metastasis. Oncogene (In Press).* Corresponding Authors.
    16. Kenny HA, Lal-Nag M, White EA, Shen M, Chiang CY, Mitra AK, Zhang Y, Curtis M, Schryver E, Bettis S, Jadhav A, Boxer MB, Li Z, Ferrer M, and Lengyel E. High throughput screening using a physiologically-relevant primary human three-dimensional organotypic culture predicts in vivo efficacy. Nat Commun 2015, 6:6220.
    17. Lengyel E, Litchfield LM, Mitra AK, Nieman KM, Mukherjee A, Zhang Y, Johnson A, Bradaric M, Lee WS, and Romero IL. Metformin inhibits ovarian cancer growth and increases sensitivity to paclitaxel in mouse models. Am J Obstet Gynecol. 2014, pii: S0002-9378(14)01081-3.
    18. Zhang Y, Kenny HA, Swindell EP, Mitra AK, Hankins PL, Ahn RW, Gwin K, Mazar AP, O’Halloran TV, and Lengyel E. Urokinase Plasminogen Activator System Targeted Delivery of Nanobins as a Novel Ovarian Cancer Therapeutics. Mol Cancer Ther. 2013, 12:2628-39.
    19. Mitra AK, Zillhardt M, Hua YJ, Tiwari P, Peter ME, and Lengyel E. microRNAs mediate cancer cell-induced reprogramming of normal fibroblasts into cancer associated fibroblasts. Cancer Discovery. 2012, 2:1100-8.
    20. Commentary on this article by Chou and Werb: Cancer Discovery 2012, 2:1078-80
    21. Mitra AK, Sawada K, Tiwari P, Mui K, Gwin K, and Lengyel E. Ligand-independent activation of c-Met by fibronectin and α5β1-integrin regulates ovarian cancer invasion and metastasis. Oncogene. 2011, 30:1566-76.
    22. Romero IL, Lee WS, Mitra AK, Gordon IO, Zhao Y,  Leonhardt P, Penicka P, Mui KL, Krausz TN, Greene GL, and Lengyel E. The effects of 17β-estradiol and a selective estrogen receptor modulator, bazedoxifene, on ovarian carcinogenesis. Gynecologic Oncology. 2012, 124:134-41.
    23. Kenny HA, Nieman KM, Mitra AK, and Lengyel E. The First Line of Intra-abdominal Metastatic Attack: Breaching the Mesothelial Cell Layer. Cancer Discovery. 2011, 1:100-102.
    24. Kaur S, Kenny HA, Jagadeeswaran S, Zillhardt MR, Montag AG, Kistner E, Yamada SD, Mitra AK, and Lengyel E. b3-integrin expression on tumor cells inhibits tumor progression, reduces metastasis, and is associated with a favorable prognosis in patients with ovarian cancer. American Journal of Pathology. 2009, 175:2184-96.
    25. Sawada K, Mitra AK, Radjabi AR, Bhaskar V, Kistner EO, Tretiakova M, Jagadeeswaran S, Montag A, Becker A, Kenny HA, Peter ME, Ramakrishnan V, Yamada SD, Lengyel E. Loss of E-cadherin promotes ovarian cancer metastasis via alpha 5-integrin, which is a therapeutic target. Cancer Research. 2008, 68:2329-39.
    26. Mitra AK, Krishna M. Fractionated and acute irradiation induced signaling in a murine tumor. Journal of Cellular Biochemistry. 2007, 101:745-52.
    27. Mitra AK, Singh RK, Krishna M. MAP kinases: differential activation following in vivo and ex vivo irradiation. Molecular and Cellular Biochemistry. 2007, 294:65-72.
    28. Mitra AK, Krishna M. Radiation-induced bystander effect: activation of signaling molecules in K562 erythroleukemia cells. Journal of Cellular Biochemistry. 2007, 100:991-7.
    29. Mitra AK, Bhat N, Sarma A, Krishna M. Alteration in the expression of signaling parameters following carbon ion irradiation. Molecular and Cellular Biochemistry. 2005, 276:169-73.
    30. Mitra AK, Sarma A, Krishna M, Verma NC. Expression of NF-kappaB and ERK following heavy ion irradiation. Journal of Environmental Pathology, Toxicology and Oncology. 2004, 23:53-9.
    31. Mitra AK, Krishna M. In vivo modulation of signaling factors involved in cell survival. Journal of Radiation Research (Tokyo). 2004, 45:491-5.
    32. Mitra AK, Singh RK, Narang H, Maurya SK, Krishna M. Differential activation of signaling factors following low and high doses of gamma irradiation in vivo. International Journal of Low Radiation. 2004, 1:358-367.
    33.  Hebbar SA*, Mitra AK*, George KC, Verma NC. Caffeine ameliorates radiation-induced skin reactions in mice but does not influence tumour radiation response. Journal of Radiological Protection. 2002, 22:63-9. ( *Both authors have contributed equally)
  • Research Funding

    Ovarian Cancer Academy Award

    From the Department of Defense (DoD) Ovarian Cancer Research Program (OCRP)

    Pilot Award from The Marsha Rivkin Center for Ovarian Cancer Research

    Pilot Award from Colleen's Dream Foundation

    https://www.colleensdream.org

    Ralph W. and Grace M. Showalter Research Award

    CTSI Core Pilot Grant