The world of medicine has made remarkable strides in diagnosing and treating various health conditions, but when it comes to many women’s health issues, progress is lacking.
Vincent Center for Reproductive Biology
Rueda Lab: Bo Rueda, PhD
Explore This Lab
The Rueda lab has been involved in basic, translational and clinical research focused on women’s reproductive health. The lab specializes in reproductive and cancer biology, with an emphasis on the investigation of novel signaling pathways that contribute to the pathology of benign gynecologic diseases, malignant transformation, and the contribution of cancer stem cells to the pathology of ovarian and uterine tumors. A major effort in the Rueda laboratory has been to identify and functionally characterize inherent and acquired mechanisms that contribute to metastasis, resistance, and recurrence of gynecological cancers to better inform the development and testing of novel or repurposed drugs that can target both cancer stem and non-stem tumor cells.
The Rueda Lab and its collaborators were responsible for the establishment of the VCRB/MGH GYN Tissue Repository. The repository was established to develop a collection of clinically applicable tissue and correlate biologic samples (ex. blood, ascites) collected from women diagnosed with gynecologic conditions and or gynecologic cancers along with their annotated medical information. From the inception one of our objectives was to establish an infrastructure whereby all gynecologic samples were collected under a single carefully maintained IRB approved repository protocol. Moreover, the presence of an established well-maintained repository that has appropriate management would be the best way to ensure a quality product, equitable distribution, and oversight. At present the repository has collected over 3000 samples. The VCRB/MGH Repository is led by Dr. Bo Rueda who serves as the Executive Director. Other leaders include members of the MGH Gynecologic Oncology Research Consortium (Drs. Eric Eisenhauer, David Spriggs and Cesar Castro).
This rich resource serves to support our investigators whose research is focused on developing or improving early diagnostics, defining molecular pathways contributing to the genesis of the tumors, developing pre-clinical models for testing of novel anti-cancer therapies and or combination drug strategies including primary derived organoids and xenografts, and discerning mechanisms contributing to inherent and acquired treatment resistance.
The overall success of our banking efforts is the byproduct of collegial interactions between our gyn surgeons, medical oncologists, pathology staff, gyn oncology fellows, post-doctoral fellows, clinical research coordinators, clinical support staff and research technologists. Importantly, we recognize the unselfish generosity of the patients themselves for providing informed consent which allows us to collect the discarded samples and the annotated clinical information which we hope will benefit others suffering from similar diagnoses and conditions. Similarly, we appreciate that this resource was initiated with the support of the Nile Albright Research Foundation (A.K.A Advanced Medical Research Foundation) and the Vincent Memorial Hospital Foundation.
The benefits of this effort are evidenced by the increase in clinically meaningful publications in high quality peer reviewed publications, increased extramural funding from federal funding agencies and foundations. Also of importance is that this resource serves to promote active collaborations with pharmaceutical companies to test novel anti-cancer agents while recognizing the potential for opportunities to move forward into phase I trials should they be successful.
Mass General Gynecologic Oncology Research Consortium
The Mass General Gynecologic Oncology Research Consortium (MGH Gyn ORC) was formalized to unite basic, translational and clinician scientists to engage in transformative research that will enhance our understanding of the molecular and cellular factors that contribute to the genesis, progression and resistance of gynecologic cancers enabling improved diagnosis, treatment, and prevention.
The objectives/goals of the Gyn ORC are:
- Develop and support an open interactive research infrastructure to promote the integration of knowledge, technology, resources, and personnel needed to combat gynecologic malignancies at MGH.
- Support sample and annotated data collection from our patient cohort to develop better diagnostics, understand how treatment alters the tumor landscape, and to appreciate mechanisms contributing to inherent and acquired resistance to inform clinical care.
- Develop applicable primary derived organoids and xenografts from our patients gyn malignancies for testing of novel drugs and or combination drug treatment strategies.
- Continue to develop interactive educational strategies for our clinicians in training, postdoctoral fellows, and graduate students.
- Promote diversity, equity, and inclusion with regards to appreciating how malignancies impact everyone. Recognizing how some individuals representing different communities, cultures, and or race may be differentially affected and how we might better serve those in need.
- Support and integrate Clinical and Outcomes based research to improve patient’s outcome and quality of life.
View all consortium members
- Sara Bouberhan, MD, Gynecologic Medical Oncology
- Dr. Bouberhan’s research is focused on identifying blood-based biomarkers in ovarian cancer. She is currently working on a project to detect patient-specific p53 mutations in plasma using droplet-digital PCR. This project relies on an ongoing collaboration with the Gyn Tissue Repository. Banked specimens from patients’ initial surgical resection are accessed to identify tumor-specific DNA sequences. These sequences are then used to develop customized DNA sequencing primers and detection probes which are applied to blood samples. Blood collected through the tissue banking protocol at the time of patients’ initial surgery is used as a substrate to identify circulating tumor DNA. Dr. Bouberhan also collaborates with the tissue repository team to prospectively collect blood and ascites specimens to support this and future projects.
- Amy Bregar, MD, Gynecologic Oncology
- Andrea Russo, MD, Gynecologic Radiation Oncology
- Steven Skates, PhD
- Dr. Skates has been dedicated to studying early detection of ovarian cancer including biomarker discovery and validation. He spearheaded development of multiple longitudinal early detection algorithms which were implemented in five prospective early detection clinical trials. More specifically, Dr. Skates risk of ovarian cancer algorithm has been implemented in a definitive trial of 200,000 postmenopausal women with half screened annually for up to 11 years and with ovarian cancer mortality as the “gold standard” endpoint. Dr. Skates has served as a co-investigator for multiple proposal s led MGH, BWH and DFCI based investigators on identification and validation of biomarker(s) for ovarian cancer detection. He is recruited by Gyn ORC members to develop statistical models for proposed research applications.
- David Spriggs, MD, Gynecologic Medical Oncology
- Dr. Spriggs’ research is focused on cell membrane glyco-proteins that promote the patho-biology of ovarian cancer. The serum marker, CA125, has been used to manage ovarian cancer since the 1980’s but its function(s) have yet to be completely identified. CA125 is the cleaved portion of the tethered mucin MUC16. The Spriggs Lab have provided insights into the function of MUC16.
- It is now apparent that MUC16 regulates growth, invasion and metastatic disease disease through the structure of sugars (glycosylation) on the surface of normal and cancer cells. This regulation requires interaction with specialized sugar binding proteins, Galectins, which are key components of the tumor microenvironment. We are actively developing antibodies against MUC16 and Galectin 3 for diagnosis, imaging and treatments. Our work has shown that antibodies which inhibit these cell – cell interactions can slow tumor growth and inhibit metastasis.
- Cheng Wang, PhD
- Dr. Wang’s group focuses on the identification of key regulatory proteins in the Hippo-Yap signaling pathway that regulate the normal physiology of the cervix and ovary. More importantly his team is defining how aberrant Hippo-Yap signaling can promote malignant transformation, invasive and metastatic properties.
- Recently, Dr. Wang has shown that increased Yap signaling can promote an immunotolerant environment. Delineating the mechanisms by which Yap promotes immunotolerance will allow for the development of novel treatment strategies to overcome this tumor resistant micro-environment. To accomplish these goals Dr. Cheng’s lab develops novel transgenic mouse models to determine the functional contributions of the members of the Hippo-Yap signaling pathway in cervical and ovarian cancer.
- Oladapo Yeku, MD, PhD, FACP, Gynecologic Medical Oncology
- Dr. Yeku’s research efforts are focused on delineating the functional contributions of the tumor microenvironment. Specifically, he and his team are designing and testing immunologic approaches for the management of ovarian cancer. His research utilizes syngeneic immune competent mouse models of metastatic ovarian cancer with subsequent validation in appropriate genetically engineered and xenograft models. This approach allows for analysis of the effects of this combinatorial therapy in recruiting and harnessing the hosts’ effector immune cells against cancer cells. Furthermore, this approach allows critical evaluation of the immunosuppressive cytokine, cellular and tumor microenvironment in response to therapy.
Learn more about the Tissue Repository
Delineating the diagnostic and therapeutic potential of the tumor-associated carbohydrate (TACA), sialyl-Tn in ovarian cancer. Working in collaboration with our pharma collaborators we identified and characterized mouse anti-STn specific antibodies for cancer therapeutic applications in binding assays, and in vitro, and in vivo efficacy assays. Our collaborative efforts provided evidence to support the hypothesis that an STn positive fraction recovered from OvCa cells displays cancer stem-like properties. This work was followed our teems demonstrating the efficacy of a humanized anti-STn-ADCs in in vitro and in vivo models of ovarian cancer. We recently completed additional in vivo studies illustrating the effectiveness of the anti-STn with and without cytotoxics. We now have evidence to suggest that a custom STn ELISA we developed may serve to help identify patients that an anti-STn strategy may benefit. Working with Dr. Steve Skates we are assessing whether the STn based ELISA could augment CA125 as a diagnostic and or for following treatment response. In addition, we have preliminary data that supports the concept that STn is immunosuppressive and are working to validate this finding.
Determining whether tumor cell plasticity can account for the enrichment of cancer stem cell populations post treatment. Numerous reports support the concept of a subpopulation of cancer cells that have or can obtain the capacity to gain stem like properties and are often referred to as caner stem cells (CSCs). The inherent or acquired mechanisms by which these stem-like properties might be (re)activated remains incompletely understood. Appropriately, it is believed that the tumor microenvironment contributes to this change in phenotype via crosstalk, including that cancer associated fibroblasts can influence tumor cells to acquire more stem-like properties. Similarly, it has been proposed the cytokines and/or chemokines secreted directly from bulk tumor cells might influence the stem sources. More recently, however, it was proposed that extracellular vesicles (EVs) may be responsible for sharing the necessary cellular machinery (ex. miRNAs, lncRNAs, demethylases) to influence these tumor cells to gain stem-like properties. This led us to hypothesize that EVs extruded from ovarian CSC in response to treatment might contain factors needed to convert neighboring tumor cells to become more stem-like. We are currently focusing our efforts on defining the potential mechanisms by which this could occur and with an emphasis on the direct transfer or through upregulation of methyltransferases which can promote stem like properties.
Investigating mechanisms contributing to resistance to current HER2 treatment strategies in endometrial cancer. A significant percentage of high grade endometrioid and uterine serous cancers cancer display HER2 amplifications. Utilizing in vitro and in vivo approaches, we continue to gain multi-dimensional insights into how cells may attain resistance to HER2 directed therapy. We believe this work will improve how we might apply the anti HER2 agents underdevelopment towards high grade endometrial cancer. For this we have generated or accumulated multiple HER2 resistant endometrial cancer models for which we are testing combination strategies with the intent to overcome inherent and acquired resistance to ensure a more durable response.
Provide pre-clinical rationale for identifying unique endometrial tumor molecular characteristics that will influence clinical decisions. Endometrial cancer mortality has increased over the past three decades despite medical advances in our understanding of the genomic profile and the advent of immunotherapy. Therapies for recurrent disease still have limited durability highlighting the need for novel therapeutic strategies that exploit the molecular underpinnings of an individual tumor. While encouraging anti-tumor activity has been observed utilizing immune checkpoint blockade in recurrent endometrial cancer, over 50% of women do not respond despite harboring the molecular signatures associated with response. Improved response to immune checkpoint blockade has been observed in ovarian tumors when poly-ADP-ribose polymerase (PARP) inhibitors have been used simultaneously suggesting synergistic activity. The degree of homologous repair deficiency (HRD) has only been characterized on a limited basis in endometrial cancers, but much pre-clinical data has demonstrated that genomic events, such as PIK3CA mutation and loss of PTEN create genomic instability mimicking HRD. We hypothesize that a subset of endometrial tumors harbors a significant degree of HRD that associates with the expression of immune checkpoint proteins. We are currently analyzing data derived from testing high grade endometrioid and serous endometrial carcinomas using the FoundationOne platform to detect tumor gain of function mutations, mutational burden, loss of heterozygosity, checkpoint protein RNA dosage and PD-1 expression. Associations amongst the tumor molecular characteristics will be correlated with clinical outcomes. We plan to functionally test our findings by treating correlate primary derived organoids and assessing their response. It is anticipated that these data will provide some preclinical rationale for clinical trials investigating the role of dual immune checkpoint and PARP inhibition in women with recurrent endometrial cancer.
Delineating the functional contribution of Galectin 3 to the pathology of ovarian endometrial cancers. Over the past two years we have expanded our interests in glycobiology to better understand how Galectin-3 functionally contributes to the pathology of high grade ovarian and uterine cancer. Our research efforts are focused on how it promotes an immunosuppressive environment, promotes stem like properties and influences metastasis. In doing so we have teamed up with Drs. David Spriggs and Oladapo Yeku to focus on testing small molecule inhibitors in combination with a novel anti-Gal-3 antibody-based strategy to neutralize Gal-3’s protumor properties in uterine and ovarian carcinoma.
Working with our Pharma colleagues/collaborators: We have multiple collaborative and SRA related projects whereby we are actively working with Pharma to develop and validate diagnostics/biomarkers in blood and/or tumor samples, identify new targets contributing to treatment resistant recurrent disease, testing the efficacy of novel anti-cancer agents in our pre-clinical cancer models, and developing novel drugs for treatment of gynecologic cancers.
Who We Are
Meet our team
Director, Vincent Center for Reproductive Biology, 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
Dominique Zarrella, BS
Dominique is native of Leominster, MA. She received her bachelor’s degree in Biopsychology from Tufts University. She now works as a Laboratory Technologist within Dr. Rueda’s lab where she helps with both the lab’s tissue banking efforts and bench research experiments. Dominique will be attending medical school this fall where she plans to use the experience gained in Dr. Rueda’s lab on her journey to becoming a clinician-scientist. Outside of the lab, Dominique enjoys spending time outside and with friends.
Madelyn (Maddy) Krueger, BS
Grew up in Asheville, North Carolina and obtained a bachelor’s degree in Biology from the University of North Carolina at Chapel Hill. She now works as a Research Technician in the Rueda Lab where she hopes to gain valuable research experience before going to graduate school. Outside of the lab, Madelyn enjoys painting, cheering on Boston’s sports teams, and discovering new restaurants and running trails around the city.
Venkatesh (Venky) Pooladanda, M.S. (Pharm.), Ph.D.
Venky received his doctoral degree in Pharmacology and Toxicology from National Institute of Pharmaceutical Education and Research (NIPER), Hyderabad, India where he studied the effect of acute lung inflammation on tumor metastasis. Venky also has training in immunology, nano medicine, and infectious diseases. He has the knowledge of both basic and translational research. He is passionate about academic research in immuno-oncology and is looking to translate the laboratory outcomes to clinical benefits. He loves taking on new adventures in science and explore new signaling pathways and molecular therapies. Apart from the science, he enjoys meditation and hiking.
Yusuke Matoba, MD, PhD
Dr. Matoba comes from Tokyo, Japan where he was a physician in gynecological oncology. In Japan, he was engaged in the treatment of gynecological cancer, including surgery, chemotherapy, and palliative care. He has conducted clinical research, uterine transplantation research using monkeys, and uterine regeneration research using monkeys. He joined Dr. Rueda’s lab in the VCRB eager to learn more about basic translational research, specifically to work on studies designed to delineate mechanisms contributing to transformation, immune suppression, metastatic potential, and or treatment resistance, in gynecologic tissues.
Al-Alem, L.F.; Baker, A.T.; Pandya, U.M.; Eisenhauer, E.L.; Rueda, B.R. Understanding and Targeting Apoptotic Pathways in Ovarian Cancer. Cancers. 2019 Oct 24; 11(11):1631. doi:10.3390/cancers11111631
Bellio, C.; DiGloria, C.; Spriggs, D.R.; Foster, R.; Growdon, W.B.; Rueda, B.R. The Metabolic Inhibitor CPI-613 Negates Treatment Enrichment of Ovarian Cancer Stem Cells. Cancers. 2019 Oct 29; 11(11):1678. doi:10.3390/cancers11111678
Bellio C, DiGloria C, Foster R, James K, Konstantinopoulos PA, Growdon WB, Rueda BR. PARP inhibition induces enrichment of DNA repair proficient CD133 and CD117 positive ovarian cancer stem cells. Mol Cancer Res. 2018 Nov 6. pii: molcanres.0594.2018. doi: 10.1158/1541-7786.MCR-18-0594. [Epub ahead of print] PMID:30401718.
Chiu YH, Karmon AE, Gaskins AJ, Arvizu M, Williams PL, Souter I, Rueda BR, Hauser R, Chavarro JE; Serum omega-3 fatty acids and treatment outcomes among women undergoing assisted reproduction. EARTH Study Team.Hum Reprod. 2018 Jan 1;33(1):156-165. doi: 10.1093/humrep/dex335.PMID:29136189
Cardozo ER, Foster R, Karmon AE, Lee AE, Gatune LW, Rueda BR, Styer AK. MicroRNA 21a-5p overexpression impacts mediators of extracellular matrix formation in uterine leiomyoma. Reprod Biol Endocrinol. 2018 May 11;16(1):46. doi: 10.1186/s12958-018-0364-8. PMID:29747655
Starbuck K, Al-Alem L, Eavarone DA, Hernandez SF, Bellio C, Prendergast JM, Stein J, Dransfield DT, Zarrella B, Growdon WB, Behrens J, Foster R, Rueda BR. Treatment of ovarian cancer by targeting the tumor stem cell-associated carbohydrate antigen, Sialyl-Thomsen-nouveau. Oncotarget. 2018 May 1;9(33):23289-23305. doi: 10.18632/oncotarget.25289. eCollection 2018 May 1.PMID:29796189
Eavarone DA, Al-Alem L, Lugovskoy A, Prendergast JM, Nazer RI, Stein JN, Dransfield DT, Behrens J, Rueda BR. Humanized anti-Sialyl-Tn antibodies for the treatment of ovarian carcinoma. PLoS One. 2018 Jul 27;13(7):e0201314. doi: 10.1371/journal.pone.0201314. eCollection 2018.PMID:30052649
Bregar A, Deshpande A, Grange C, Zi T, Stall J, Hirsch H, Reeves J, Sathyanarayanan S, Growdon WB, Rueda BR. Characterization of immune regulatory molecules B7-H4 and PD-L1 in low and high grade endometrial tumors. Gynecologic oncology. 2017; 145(3):446-452. PubMed [journal] PMID:28347512
Prendergast JM, Galvao da Silva AP, Eavarone DA, Ghaderi D, Zhang M, Brady D, Wicks J, DeSander J, Behrens J, Rueda BR. Novel anti-Sialyl-Tn monoclonal antibodies and antibody-drug conjugates demonstrate tumor specificity and anti-tumor activity. mAbs. 2017; 9(4):615-627. PubMed [journal] PMID: 28281872PMCID: PMC5419082
Bajwa P, Nielsen S, Lombard JM, Rassam L, Nahar P, Rueda BR, Wilkinson JE, Miller RA, Tanwar PS. Overactive mTOR signaling leads to endometrial hyperplasia in aged women and mice. Oncotarget. 2017; 8(5):7265-7275. PubMed [journal] PMID: 27980219 PMCID: PMC5352319
Garrett LA, Growdon WB, Rueda BR, Foster R. Influence of a novel histone deacetylase inhibitor panobinostat (LBH589) on the growth of ovarian cancer. Journal of ovarian research. 2016; 9(1):58. PubMed [journal] PMID: 27633667 PMCID: PMC5025559
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. Reproductive biology and endocrinology : RB&E. 2016; 14(1):45. PubMed [journal] PMID: 27530410 PMCID: PMC4988044
Styer AK, Rueda BR. The Epidemiology and Genetics of Uterine Leiomyoma. Best practice & research. Clinical obstetrics & gynaecology. 2016; 34:3-12. PubMed [journal] PMID: 26725703
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. 141(3):570-579. PubMed [journal] PMID: 27017985
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. The Journal of clinical endocrinology and metabolism. 2016; 101(2):513-22. PubMed [journal] PMID: 26695862
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 biology & therapy. 2016; 17(3):262-71. PubMed [journal] PMID: 26785864 PMCID: PMC4847980
Hernandez SF, Vahidi NA, Park S, Weitzel RP, Tisdale J, Rueda BR, Wolff EF. Characterization of extracellular DDX4- or Ddx4-positive ovarian cells. Nature medicine. 2015; 21(10):1114-6. PubMed [journal] PMID: 26444630
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