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Research at Mass General
A major effort in Dr. Rueda’s laboratory has been in the identification and functional characterization of gynecologic cancer stem cells. Recent experiments conducted in collaboration with Dr. Rosemary Foster provide evidence to support the concept that both human endometrial and ovarian cancers contain a rare subpopulation of tumor-initiating cells, which have stem/progenitor like properties (Cell Cycle 2008; 7:242-249; 2009; 27:2875-83; Cancer Research 2009; 69:8241-8.).
Drs. Rueda and Foster are actively optimizing strategies to better isolate these rare cells, define their stem-like properties, determine how they are regulated, how their local environment may influence them, whether they are resistant to current radiation or chemotherapy and ultimately how we may target them.
Another component of Dr. Rueda’s research is the molecular interrogation of human gynecologic tumors to test novel anti-cancer drugs in a pre clinical setting. This research is part of an active consortium with Dr. Darrell Borger of the Translational Research Laboratory (MGH Cancer Center) and Dr. Whitfield Growdon (VCRB MGH Obstetrics and Gynecology Department).
Together they have been actively developing strategies for real-time identification of novel cell signaling pathways that contribute to malignant transformation (Gyn Onc 2008; 111:289-297), the pathology of the disease and/or chemoresistance and recurrence in gynecologic cancers.
Once identified, they are testing new biologics and determining their efficacy in primary ovarian and/or endometrial tumor explant and short-term cell culture models. The results of this research will hopefully contribute to development of strategies designed to provide patients personalized therapy.
A long standing basic science theme of Dr. Rueda’s research has been defining the functional significance of mediators of cell proliferation and/or differentiation in ovarian and uterine biology. This is a critical step in the dynamic cellular changes associated with the hormone mediated menstrual cycle. Inactivation of specific cell cycle regulators can promote cellular hyperplasia and malignant transformation.
Dr. Rueda’s team has been working to identify novel hormone mediated cell cycle regulators and their interacting proteins to determine their functional significance in the regulation of the cell cycle, cell proliferation, differentiation and/or apoptosis (Cancer Res 2004;202-8; Can Biol Ther 2005;103-107; Can Biol Ther 2007;15:7).
It is well recognized that endometriosis is a polygenic disease with complex multifactorial etiologies affecting reproductive-aged women. Although this disorder is commonly treated in clinical practice, the mechanisms by which ectopic endometrium is disseminated and proliferates, is not completely understood.
There are a number of different factors, which have been implicated in either the genesis or the propagation of endometriosis. They include but are not limited to prostaglandins, cytokines, growth factors, chemokines, cell adhesion molecules and steroid hormones.
It is, however, difficult to investigate the functional role of these factors without adequate in vivo model systems. Dr. Styer and Dr. Rueda continue to develop and exploit existing mouse models which have been manipulated to ‘mimic’ the human disease in order that they may study the effect of specific factors on the growth of ectopic endometrium (Endocrinology 2008; 149:506-514).
The mouse model was chosen to incorporate the power of mouse genetics. Using mutant mouse strains that are devoid or over express one or more of the factors described above they should be able to delineate their cause an effect relationships with the pathogenesis of the disease.
Using this strategy in tandem with gene and protein analysis Dr. Styer and Dr. Rueda hope to gain a better understanding of the underlying mechanisms of endometriosis. This information will also serve to develop more effective alternative treatment modalities.
Bo Rueda, PhDDirector, Vincent Center for Reproductive Biology, Massachusetts General Hospital Director, Clinical Fellows Research Program, Department of Obstetrics and Gynecology, Massachusetts General Hospital Director, Deborah Kelly Center for Outcomes Research, Massachusetts General Hospital Associate Professor, Department of Obstetrics, Gynecology and Reproductive Biology, Harvard Medical School Affiliated Faculty, Harvard Stem Cell Institute Affiliated Faculty, Massachusetts General Hospital Cancer Center
Rosemary Foster, PhD Whitfield Growdon, MDAaron Styer, MD
Silvia Fatima Hernandez, PhD Chiara Bellio, PhD Linah Al-Alem, PhD
Celeste DiGloria, Clinical Research Coordinator II Bianca Zarrella, Research Technician II
Murphy K, Mitchell C.The interplay of host immunity and environment on risk for bacterial vaginosis and associated reproductive health outcomes. Journal of Infectious Diseases. 2016 Apr 7
Hernandez SF, Chisholm S, Borger D, Foster R, Rueda BR, Growdon WB. Ridaforolimus improves the anti-tumor activity of dual HER2 blockade in uterine serous carcinoma in vivo models with HER2 gene amplification and PIK3CA mutation. Gynecol Oncol. 2016 Apr 1. pii: S0090-8258(16)30083- X. doi: 10.1016/j.ygyno.2016.03.027. [Epub ahead of print]
Karmon AE, Cardozo ER, Souter I, Gold J, Petrozza JC, Styer AK. Donor TSH level is associated with clinical pregnancy among oocyte donation cycles. Journal of Assisted Reproduction Genet. 2016 Feb 4. [Epub ahead of print]
Le HG, Saeed H, Mantagos IS, Mitchell CM, Goverman J, Chodosh J. Burn unit care of Stevens Johnson syndrome/toxic epidermal necrolysis: A survey. Burns. 2016 Jan
Cardozo ER, Karmon AE, Gold J, Petrozza JC, Styer AK. Reproductive outcomes in oocyte donation cycles are associated with donor BMI. Human Reproduction. 2016 Feb; 31(2):385-92. doi: 10.1093/humrep/dev298. Epub 2015 Dec 17.
Mitchell C, on behalf of MsFlash Network. “Estrogen Metabolites and the Vaginal Microbiome Following 8 Weeks of Low‐Dose Estradiol, Venlafaxine, or Placebo for Vasomotor Symptoms” Oral presentation at the North American Menopause Society Annual Meeting. Las Vegas, NV Sept 30-Oct 3, 2015.
Ticona E, Bull M, Soria J, Tapia K, Legard J, Styrchak S, Williams C, Mitchell C, La Rosa A, Coombs R, Frenkel L. Biomarkers of inflammation in HIV-infected Peruvian men and women before and during suppressive anti-retroviral therapy (ART). AIDS. 2015 Aug 24;29(13):1617-22
Mitchell C, Fredricks D, Agnew K, Hitti J. Hydrogen-peroxide producing lactobacilli are associated with lower levels of vaginal IL1β, independent of bacterial vaginosis. Sex Transm Dis. 2015 Jul;42(7):358-63.
Elisabeth J. Diver, Rosemary Foster, Bo R. Rueda, Whitfield B. Growdon.The Therapeutic Challenge of Targeting HER2 in Endometrial Cancer. The Oncologist. June 2015;20:1058–1068.
Tan A. Ince, Aurea D. Sousa, Michelle A. Jones, J. Chuck Harrell, Elin S. Agoston, Marit Krohn, Laura M. Selfors, Wenbin Liu, Ken Chen, Mao Yong, Peter Buchwald, Bin Wang, Katherine S. Hale, Evan Cohick, Petra Sergent, Abigail Witt, Zhanna Kozhekbaeva, Sizhen Gao, Agoston T. Agoston, Melissa A. Merritt, Rosemary Foster, Bo R. Rueda, Christopher P. Crum, Joan S. Brugge & Gordon B. Mills. Characterization of twenty-five ovarian tumour cell lines that phenocopy primary tumours. Nature Communications, 17 Jun 2015.
John O. Schorge, Tracilyn R. Hall, Xun C. Zhou, Amy J. Bregar, Rosemary Foster, Christopher J. Darus, Loyd A. West and Cheung Wong. Therapeutic Innovations in Ovarian Cancer Treatment: The New England Perspective. Gynecology & Obstetrics. Volume 5 • Issue 5. April 14, 2015
Yan Gao, Rosemary Foster, Xiaoqian Yang, Yong Feng, Jacson K. Shen, Henry J. Mankin, Francis J. Hornicek, Mansoor M. Amiji, Zhenfeng Duan. Up-regulation of CD44 in the development of metastasis, recurrence and drug resistance of ovarian cancer. Oncotarget, Vol. 6, No. 11, March 13, 2015
Clark RM, Lee MS, Alejandro Rauh Hain J, Hall T, Boruta DM, Del Carmen MG, Goodman A, Schorge JO, Growdon WB. Surgical Apgar Score and prediction of morbidity in women undergoing hysterectomy for malignancy. Gynecol Oncol. 2015 Mar;136(3):516-20.
Bull M, McLaughlin S, Huang H, Styrchak S, Soria J, Ticona E, LaRosa A, Mitchell C, Mullins J, Frenkel L. Low-Level HIV Viremias Originate in Part From Infected Proliferating Cells. Accepted for oral presentation to the annual Conference on Retroviruses and Opportunistic Infections, February 2015, Seattle, WA.
Whitfield B. Growdon, Jolijn Groeneweg, Virginia Byron, Celeste DiGloria, Darrell R. Borger, Rosemary Tambouret, Rosemary Foster, Ahmed Chenna, Jeff Sperinde, JohnWinslow, Bo R. Rueda. HER2 over-expressing high grade endometrial cancer expresses high levels of p95HER2 variant. Gynecologic Oncology, 17 January 2015.
Friel AM, Zhang L, Pru CA, Clark NC, McCallum ML, Blok LJ, Shioda T, Peluso JJ, Rueda BR, Pru JK. Progesterone receptor membrane component 1 deficiency attenuates growth while promoting chemosensitivity of human endometrial xenograft tumors. Cancer Lett. 2015 Jan 28;356(2 pt B):434-42.
Raj RS, Bonney EA, Phillippe M. Influenza, immune system, and pregnancy. Reprod Sci. 2014 Dec;21(12):1434-51.
Doyle JO, Lee HJ, Selesniemi K, Styer AK, Rueda BR. The impact of vitrification on murine germinal vesicle oocyte In vitro maturation and aurora kinase A protein expression. J Assist Reprod Genet. 2014 Dec;31(12):1695-702.
Groeneweg JW, Hernandez SF, Byron VF, DiGloria CM, Lopez H, Scialabba V, Kim M, Zhang L, Borger DR, Tambouret R, Foster R, Rueda BR, Growdon WB. Dual HER2 targeting impedes growth of HER2 gene-amplified uterine serous carcinoma xenografts. Clin Cancer Res. 2014 Dec 15;20(24):6517-28.
Mitchell CM, Haick A, Nkwopara E, Garcia R, Rendi M, Agnew K, Fredricks DN, Eschenbach D. Colonization of the upper genital tract by vaginal bacterial species in non-pregnant women. Am J Obstet Gynecol. 2014 Dec 16. pii: S0002-9378(14)02438-7.
Psaros C, Kagan L, Shifren JL, Willett J, Jacquart J, Alert MD, Macklin EA, Styer AK, Denninger JW, LaRoche KL, Park ER. Mind-body group treatment for women coping with infertility: a pilot study. J Psychosom Obstet Gynaecol. 2014 Dec 26:1-9.
Groeneweg JW, Foster R, Growdon WB, Verheijen R, Rueda BR. Notch signaling in serous ovarian cancer. J Ovarian Res. 2014 Nov 4;7(1):95.
Growdon W, Foster R, and Rueda B. Molecular targets in gynecologic cancers. In: Del Carmen MG, Young RH, Schorge JO and Birrer MJ, editors. Uncommon Gynecologic Cancers. West Sussex: Wiley Blackwell; Nov 2014. p. 3-17.
Kaneko-Tarui T, Commandeur AE, Patterson AL, DeKuiper JL, Petillo D, Styer AK, Teixeira JM. Hyperplasia and fibrosis in mice with conditional loss of the TSC2 tumor suppressor in Müllerian duct mesenchyme-derived myometria. Mol Hum Reprod. 2014 Nov;20(11):1126-34.
Clark RM, Lynch MP, Kolp R, Zukerberg LR, Growdon WB, Rueda BR. The N-methyl-D-aspartate receptor, a precursor to N-methyl-D-aspartate receptor encephalitis, is found in the squamous tissue of ovarian teratomas. Int J Gynecol Pathol. 2014 Nov;33(6):598-606.
Stanic AK, Kim M, Styer AK, Rueda BR. Dendritic cells attenuate the early establishment of endometriosis-like lesions in a murine model. Reprod Sci. 2014 Oct;21(10):1228-36.
Attaman J, Stanic AK, Kim M, Lynch MP, Rueda BR, Styer AK. The anti-inflammatory impact of omega-3 polyunsaturated fatty acids during the establishment of endometriosis-like lesions. Am J Reprod Immunol. 2014 Oct;72(4):392-402.
Karmon AE, Cardozo ER, Rueda BR, Styer AK. MicroRNAs in the development and pathobiology of uterine leiomyomata: does evidence support future strategies for clinical intervention? Hum Reprod Update. 2014 Sep-Oct;20(5):670-87.
Gordon D, Gardella C, Eschenbach D, Mitchell CM. High Prevalence of Sexual Dysfunction in a Vulvovaginal Specialty Clinic. J Low Genit Tract Dis. 2014 Sep 25.
He L, Guo L, Vathipadiekal V, Sergent PA, Growdon WB, Engler DA, Rueda BR, Birrer MJ, Orsulic S, Mohapatra G. Identification of LMX1B as a novel oncogene in human ovarian cancer. Oncogene. 2014 Aug 14;33(33):4226-35.
Mitchell CM, McLemore L, Westerberg K, Astronomo R, Smythe K, Gardella C, Mack M, Magaret A, Patton D, Agnew K, McElrath MJ, Hladik F, Eschenbach D. Long-term effect of depot medroxyprogesterone acetate on vaginal microbiota, epithelial thickness and HIV target cells. J Infect Dis. 2014 Aug 15;210(4):651-5.
Reed SD, Mitchell CM, Joffe H, Cohen L, Shifren JL, Newton KM, Freeman EW, Larson JC, Manson JE, LaCroix AZ, Guthrie KA. Sexual function in women on estradiol or venlafaxine for hot flushes: a randomized controlled trial. Obstet Gynecol. 2014 Aug;124(2 Pt 1):233-41.
Groeneweg JW, DiGloria CM, Yuan J, Richardson WS, Growdon WB, Sathyanarayanan S, Foster R, Rueda BR. Inhibition of notch signaling in combination with Paclitaxel reduces platinum-resistant ovarian tumor growth. Front Oncol. 2014 Jul 7;4:171.
O'Connor OJ, Diver E, McDermott S, Covarrubias DA, Shelly MJ, Growdon W, Hahn PF, Mueller PR. Palliative gastrostomy in the setting of voluminous ascites. J Palliat Med. 2014 Jul;17(7):811-21.
Mitchell C, Marrazzo J. Bacterial vaginosis and the cervicovaginal immune response. Am J Reprod Immunol. June 2014
Phillippe M. Cell-free fetal DNA--a trigger for parturition. N Engl J Med. 2014 Jun 26;370(26):2534-6.
Groeneweg JW, Hall TR, Zhang L, Kim M, Byron VF, Tambouret R, Sathayanrayanan S, Foster R, Rueda BR, Growdon WB. Inhibition of gamma-secretase activity impedes uterine serous carcinoma growth in a human xenograft model. Gynecol Oncol. 2014 Jun;133(3):607-15.
Zomorodian LM, Massawe E, Makundi JP, Mitchell CM, Eschenbach DA. Obstetric care preferences and desire for maternity waiting homes among labor and delivery patients in Arusha, Tanzania. Obstet Gynecol. 2014 May;123 Suppl 1:179S-80S.
Vargas R, Rauh-Hain JA, Clemmer J, Clark RM, Goodman A, Growdon WB, Schorge JO, Del Carmen MG, Horowitz NS, Boruta DM 2nd. Tumor size, depth of invasion, and histologic grade as prognostic factors of lymph node involvement in endometrial cancer: a SEER analysis. Gynecol Oncol. 2014 May;133(2):216-20.
Wang L, Gala M, Yamamoto M, Pino MS, Kikuchi H, Shue DS, Shirasawa S, Austin TR, Lynch MP, Rueda BR, Zukerberg LR, Chung DC. Adrenomedullin is a therapeutic target in colorectal cancer. Int J Cancer. 2014 May 1;134(9):2041-50.
Bradford LS, Rauh-Hain A, Clark RM, Groeneweg JW, Zhang L, Borger D, Zukerberg LR, Growdon WB, Foster R, Rueda BR. Assessing the efficacy of targeting the phosphatidylinositol 3-kinase/AKT/mTOR signaling pathway in endometrial cancer. Gynecol Oncol. 2014 May;133(2):346-52.
Rauh-Hain JA, Clemmer J, Clark RM, Bradford LS, Growdon WB, Goodman A, Boruta DM 2nd, Dizon DS, Schorge JO, del Carmen MG. Management and outcomes for elderly women with vulvar cancer over time. BJOG. 2014 May;121(6):719-27; discussion 727.
Guseh SH, Rauh-Hain JA, Tambouret RH, Davis M, Clark RM, Boruta DM, Goodman A, Growdon WB, Schorge JO, del Carmen MG. Transitional cell carcinoma of the ovary: a case-control study. Gynecol Oncol. 2014 Mar;132(3):649-53.
Fallon EM, Nehra D, Carlson SJ, Brown DW, Nedder AP, Rueda BR, Puder M. Evaluation of anastomotic strength and drug safety after short-term sunitinib administration in rabbits. J Surg Res. 2014 Mar; 187(1):101-6.
Foley OW, Rauh-Hain JA, Clark RM, Goodman A, Growdon WB, Boruta DM, Schorge JO, Del Carmen MG. Intraoperative radiation therapy in the management of gynecologic malignancies. Am J Clin Oncol. 2014 Mar 28.
Brady P, Imudia AN, Awonuga AO, Wright DL, Styer AK, Toth TL. Pregnancies of unknown location after in vitro fertilization: minimally invasive management with Karman cannula aspiration. Fertil Steril. 2014 Feb;101(2):420-6.
Imudia AN, Goldman RH, Awonuga AO, Wright DL, Styer AK, Toth TL. The impact of supraphysiologic serum estradiol levels on peri-implantation embryo development and early pregnancy outcome following in vitro fertilization cycles. J Assist Reprod Genet. 2014 Jan;31(1):65-71.
Rauh-Hain JA, Vargas RJ, Clemmer J, Clark RM, Bradford LS, Growdon WB, Goodman A, Boruta DM 2nd, Schorge JO, Del Carmen MG. Mucinous adenocarcinoma of the endometrium compared with endometrioid endometrial cancer: a SEER analysis. Am J Clin Oncol. 2014 Jan 2.
Roussel-Gervais A, Couture C, Langlais D, Takayasu S, Balsalobre A, Rueda BR, Zukerberg LR, Figarella-Branger D, Brue T, Drouin J. The Cables1 Gene in Glucocorticoid Regulation of Pituitary Corticotrope Growth and Cushing Disease.J Clin Endocrinol Metab. 2016 Feb;101(2):513-22. doi: 10.1210/jc.2015-3324.
Styer AK, Rueda BR The Epidemiology and Genetics of Uterine Leiomyoma. Best Pract Res Clin Obstet Gynaecol. 2016 Jul;34:3-12. doi: 10.1016/j.bpobgyn.2015.11.018
Clark NC, Friel AM, Pru CA, Zhang L, Shioda T, Rueda BR, Peluso JJ, Pru JK Progesterone receptor membrane component 1 promotes survival of human breast cancer cells and the growth of xenograft tumors. Cancer Biol Ther. 2016;17(3):262-71. doi: 10.1080/15384047.2016.1139240.
Hernandez SF, Chisholm S, Borger D, Foster R, Rueda BR, Growdon WB. Ridaforolimus improves the anti-tumor activity of dual HER2 blockade in uterine serous carcinoma in vivo models with HER2 gene amplification and PIK3CA mutation.Gynecol Oncol. 2016 Jun;141(3):570-9. doi: 10.1016/j.ygyno.2016.03.027.
Guan Y, Guo L, Zukerberg L, Rueda BR, Styer AK. MicroRNA-15b regulates reversion-inducing cysteine-rich protein with Kazal motifs (RECK) expression in human uterine leiomyoma.Reprod Biol Endocrinol. 2016 Aug 17;14(1):45. doi: 10.1186/s12958-016-0180-y.
Garrett LA, Growdon WB, Rueda BR, Foster R. Influence of a novel histone deacetylase inhibitor panobinostat (LBH589) on the growth of ovarian cancer.J Ovarian Res. 2016 Sep 15;9(1):58. doi: 10.1186/s13048-016-0267-2
Bajwa P, Nielsen S, Lombard JM, Rassam L, Nahar P, Rueda BR, Wilkinson JE, Miller RA, Tanwar PS.Oncotarget. 2016 Dec 12. doi: 10.18632/oncotarget.13919. [Epub ahead of print] Overactive mTOR signaling leads to endometrial hyperplasia in aged women and mice.
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