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Cancer Center

2019 Scientific Retreat

With keynote speaker Dr. Douglas Lowy, Acting Director of the National Cancer Institute

Agenda, Presentations and Speakers

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 8:00-8:30 am Registration and Breakfast
 8:30-9:00 am

Welcome, MCW Cancer Center Overview. Introductions

Dr. Hallgeir Rui and Dr. Jim Thomas, Interim Co-Directors, MCW Cancer Center

 9:00-10:00 am   

Keynote Address

Control of HPV-Associated Cancer by Vaccination and Screening

Dr. Douglas Lowy, Acting Director, NCI

 10:00-10:15 am

Break

Note: a professional photographer will be available on site to take pictures of your disease/lab/team/other group.  

 10:15-11:45 am   

Cancer Prevention and Outcomes Research Program

Program Overview, Dr. Joan Neuner
Title TBD, Dr. Kirsten Beyer
Title TBD, Dr. Melinda Stolley 
Novel Opportunities for Anal Cancer Screening Among Men. Dr. Alan Nyitray
Q&A, Discussion

 11:45 am-1:00 pm Lunch and Poster Session

Note: a professional photographer will be available on site to take pictures of your disease/lab/team/other group.  
 1:00-2:30 pm  Cancer Biology Research Program 

Program Overview, Dr. Carol Williams 
Title TBD, Carmen Bergom 
Title TBD, Michael Dwinell 
Title TBD, Ben Gantner
Title TBD, Peter LaViolette
Q&A, Discussion
 2:30-2:45 pm  Break

Note: a professional photographer will be available on site to take pictures of your disease/lab/team/other group.  
 2:45-4:15 pm  Discovery and Development Therapeutics Research Program

Program Overview, Dr. William Drobyski
Title TBD, Dr. Siegfried Janz
Title TBD, Dr. Gwen Lomberk
Title TBD, Dr. Brian Volkman
Q&A, Discussion
 4:15 5:00 pm  Cancer Collaborative Celebration, Poster and Pilot Awards, Happy Hour

Poster Session Numbers, Presenters, and Titles

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Full List of Poster Session Numbers, Presenter Names, and Titles

Basic Science Posters

1. Chen, Changliang: Furin-mediated  ovarian cancer progression and metastasis via IGF1R/Stat3 signaling axis

2. Chowdhury, Shreya Roy: SNRK-mediated metabolic reprogramming plays a crucial role in the initial stages of ovarian cancer metastasis

3. Du, Meijun: Plasma cell-free DNA genome abnormalities predict response to abiraterone acetate/prednisone and prognosis in castration-resistant prostate cancer

4. George, Jasmine: FXR1-mediated Oncogenic Adaptations via Post Transcriptional Regulation of c-MYC

5. Gronseth, Emily: Astrocyte secreted factors influence medulloblastoma tumor cell adhesion and morphology

6. He, Chenxia: Acetylation activates an alternative function of SOD2 as a stemness factor in breast cancer

7. Heimbruch, Katelyn: Cohesin Mutations in Core-Binding Factor AML

8. Jondle, Christopher: Gammaherpesvirus usurps host IL-17 signaling to support chronic infection

9. Maddirela, Dilip: Inhibition of HIF-169 Sensitizes Primary and Metastatic Liver Cancer Cells

10. Miller, Bradley: p52Shc isoform of Shc1 controls breast cancer initiation and growth

11. Norwood Toro, Laura: Adverse Effects of Chemotherapy on Human Microvascular Function

12. Ibrahim, El-Sayed & Parchur, Abdul: Tracking nanoparticle mediated colorectal cancer liver metastasis ablation therapy using R2* magnetic resonance imaging

13. Parchur, Abdul Kareem: Site-selective Plasmonic Photothermal Therapy of Colorectal Cancer Liver Metastasis

14. Schlaak, Rachel: Identifying Hereditary Factors That Modulate Radiation-Induced Cardiac Toxicity

15. Sun, Yunguang: NSG-Pro: a next generation model for breast cancer patient-derived xenografts

16. Udhane, Vindhya: Enzalutamide-Induced Jak2-Stat5 Feed-Forward Loop Promotes Therapy-Resistant Prostate Cancer Growth and Provides an Exploitable Molecular Vulnerability 

17. Yeo, Chay Teng: The regulation of oxidative metabolism by nitric oxide protects β-cells from DNA damage-induced cell death 

Translational Science and Clinical Research Posters

18. Iden, Marissa: Defining HPV integration sites of unknown significance in invasive cervical cancer

19. Izaguirre-Carbonell, Jesus: Critical Role of Jumonji Domain of JMJD1C in MLL-rearranged leukemia

20. Johnson, Alexander: Beta-adrenergic signaling and Rap1 expression and prenylation during hematopoietic cell transplantation: a randomized controlled trial of propranolol

21. Kerketta, Romica: The Early Epigenomic Landscape of Oncogenic Kras Signaling in Pancreatic Cancer  

22. Lu, Tongtong: Intraoperative imaging of breast tumor margins using a UV fluorescence scanning microscope

23. Singavi, Arun: Secondary Myeloid Malignancies after Autologous Stem Cell Transplantation for Multiple Myeloma are associated with a Distinct Mutational Profile

24. Sun, Fumou: Osteolytic disease in IL-6 and Myc dependent mouse model of human myeloma

25. Urrutia, Guillermo: Cell Cycle Dependent Inhibition of G9a Induces Cell Death via Replication Catastrophe in Pancreatic Cancer

26. Xin, Gang: A Novel Immunotherapy Overcomes Antigen Escape and Prevents Relapse (Poster will be presented by Topchyan Paytsar, the second author.)

27. Zimmermann, Michael: Process for molecular modeling and through next-generation sequencing of clinical cases 

Population Science and Community Based Research Posters

28. Ajala, Christopher: Protocol of the Prevent Anal Cancer Study of Self-Swabbing and Novel Biomakers

29. Anderson, Jeffry: Increasing Mammography Uptake through Academic-Community Partnerships in Ethnic Minority Communities

30. Engelmann, Jeff: Developing a Neural Biomarker of Smoking Cessation

31. George, Gemlyn: Patients’ perspectives on the definition of cure in chronic myeloid leukemia: A US based survey (Poster will be presented by Dr. Kathryn Flynn.)

32. Lauren Matthews: Promoting racial equity and inclusion in Milwaukee- Understanding and Reducing Cancer Disparities 

33. Olson, Jessica: An Integrative Approach to Identify Biological and Socioeconomic Contributors to Cancer Incidence and Mortality: The Advancing a Healthier Wisconsin Endowment's Cross-Cutting Component

34. Saeed, Hina: MRI-Based Radiomic Fingerprint in Cervical Cancer: A New Predictor for Progression-Free Survival

35. Thalji, Samih: Effect of Hospital Volume on Overall Survival after Surgery in Elderly Breast Cancer Patients

36. Zhou, Yuhong: Mortgage lending discrimination by race, ethnicity, and place: a national study of large US metropolitan areas

MCW Cancer Center Pilot Grant Project Posters

37. Battle, Michele: Novel roles for GATA4 in defining the squamocolumnar junction in the GI tract: Implications for Barrett’s esophagus

38. Bluemn, Theresa: ARID1B but not ARID2 is a novel tumor suppressor in MLL-AF9 leukemogenesis

39. Chaluvally-Raghavan, Pradeep: Unexpected Role of microRNAs in the Nucleus for Transcriptional activation

40. Neuner, Joan: The association of pharmacy fill synchronization with breast cancer endocrine therapy adherence

41. Spellecy, Ryan: Mistrust, the Obstruction of Medicine: Repairing the Breach between Medical Research and the African American Community in Milwaukee

Abstracts: Basic Science Posters #1 - 17

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1. Changliang Chen: Furin-mediated ovarian cancer progression and metastasis via IGF1R/Stat3 signaling axis 

Presenter: Changliang Chen, PhD, Postdoctoral Fellow

Poster Type: Student/Trainee/Junior Faculty

Mentor/PI: Sunila Pradeep, PhD

Research Program: Cancer Biology

Title: Furin-mediated  ovarian cancer progression and metastasis via IGF1R/Stat3 signaling axis

Introduction: Ovarian cancer is a devastating disease in women and the current strategies for therapeutic management are not very successful. Our data demonstrate that the changes in the matured form of proteins like Insulin Like Growth Factor 1 Receptor (IGF1R) and Mesothelin compare to the precursor form express high in cancer tissues and cell lines. Furin is a cellular endoprotease, which helps the maturation of several important precursor form of protein substrates through its proteolytic actions. However, the role of Furin as pro-cancer proteolytic enzyme is not well studied. In this study, we identified that Furin-mediated maturation of IGF1R protein is critical for the progression and metastasis of ovarian cancer through STAT3 signaling.

Objective: Furin is an understudied proteolytic enzyme in ovarian and other gynecological malignancies. In this study, we will elucidate the mechanism of action how Furin promotes ovarian cancer progression and metastasis as well as determine the effects of inhibiting Furin to disrupt the progression of ovarian cancer.  

Methods: Expression of Furin and its target genes were detected in cancer cell lines and cancer tissues by western blotting, immunohistochemistry and immunofluorescence staining. To determine the role of Furin on tumor cell migration, we used target-specific siRNAs to knockdown Furin in ovarian cancer cell lines and then performed cell migration assay, matrigel invasion assay, Cancer cells were grown in extracellular matrix for 3D culture. To determine the role of Furin in preclinical models, we have knocked down Furin in ovarian cancer cells and function, ovarian cancer orthotopic implantation animal model was used, followed by bioluminescence imaging to detect tumor growth and metastasis. 

Results: In the high-grade ovarian cancer patients, Furin is highly expressed in tumor omentum compared with normal omentum. Meanwhile, Insulin Like Growth Factor 1 Receptor (IGF1R) expression was also upregulated in the patient tumor omentum. When Furin was silenced in different ovarian cancer cell lines, cell migration, cell invasion, spheroids size and numbers were significantly reduced. It is interesting that we also found that Furin knockout downregulated the level of IGF1R and p-stat3(Tyr705). In vivo animal data showed that when Furin was knocked down, tumor weight, tumor nodules and tumor ascites were significantly reduced. We also checked Furin, IGF1R and p-stat3 expressions in animal tissues using immunohistochemistry. All these protein expressions were suppressed in Furin knockdown group.

Conclusions: Our findings yielded additional insights into newly proposed roles for Furin in ovarian cancer progression and metastasis through the maturation of IGF1R and subsequent activation of STAT3 in cancer cells. Our study demonstrated that Furin can be a new therapeutic target for ovarian cancer. Our data suggests that inhibiting the levels of Furin could modulate the tumor microenvironment and inhibit the progression and metastasis of ovarian cancer. We are expecting that our studies will improve the understanding on the role of Furin on the maturation of key precursor proteins and their contributions on ovarian cancer metastasis.

Significance: Our study suggested that Furin can be a new therapeutic target for ovarian cancer. We are expecting that our studies will have an impact on other cancers with a high level of Furin expression.  

Funding source: Our lab is supported by the grants from The Ovarian Cancer Research Fund Alliance, research funds from Women’s Health Research Program in the Department of Obstetrics and Gynecology (OBGYN), and start-up funds from the Department of Obstetrics and Gynecology at the Medical College of Wisconsin.  

2. Shreya Roy Chowdhury, SNRK-mediated metabolic reprogramming plays a crucial role in the initial stages of ovarian cancer metastasis 

Presenter:  Shreya Roy Chowdhury, PhD, Postdoctoral Fellow

Poster Type: Student/Trainee/Junior Faculty

Mentor/PI: Erin Bishop

Research Program: Cancer Biology

Title: SNRK-mediated metabolic reprogramming plays a crucial role in the initial stages of ovarian cancer metastasis

Introduction: Ovarian cancer tends to metastasize to the fat-rich areas of omentum. Reports suggest that release of free fatty acids by the omental adipocytes act as an alternate source of energy to the tumor cells and aid the process of metastasis. Nevertheless, the molecular players and the exact mechanisms underlying this switch in fuel consumption has not yet been elucidated properly. Sucrose non-fermenting related kinase (SNRK) has been reported to be a crucial regulator of energy homeostasis in adipocytes and cardiomyocytes. The role of SNRK in cancer and metastasis remains elusive. Our previous data showed that SNRK is highly expressed in primary ovarian tumors but not in the late stage metastatic samples.  

Objective: Decipher the role of SNRK in promoting ovarian cancer metastasis

Methods: Ovarian cancer cell lines A2780, SKOV3ip1, CaOV3, OV90 were used for the study. Stable cell lines were generated with SNRK knock down to study the effect of SNRK. Immunohistochemistry was used to detect the expression of SNRK in primary ovarian tumors, normal omentum and omental metastatic samples. The tumorigenic potential of SNRK was assessed by migration, invasion and proliferation assays. SNRK expression was studied by immunofluorescence imaging and western blotting. Mitochondrial membrane potential was studied by JC-1 staining and the ultrastructure was determined by transmission electron microscopy. Extracellular flux analyzer was used to study the bioenergetic profile and the status of fatty acid oxidation in the cells. Protein association studies were done by co-immunoprecipitation.

Results: Our data shows that SNRK is highly expressed near the tumor-invasive fonts but could not be detected in the advanced metastatic tissue sections. Expression analysis in a panel of cell lines revealed that SNRK shows mostly a nuclear localization. SNRK was found to be important for cellular proliferation but was noted to have an inhibitory effect on the migratory potential. Extracellular flux analysis revealed that the proliferation profile was associated with a change in the bioenergetic state of the cells with SNRK knockdown. SNRK seemed to be crucial and necessary for mitochondrial respiration as compared to cellular glycolysis. Studying the mitochondrial physiology revealed that SNRK uncouples mitochondrial respiration thereby deterring ATP production. Mitochondrial ultrastructure analysis revealed that SNRK is essential to maintain mitochondria in a fused state to assist the process of fatty acid oxidation. Knocking down SNRK led to the appearance of bigger lipid droplets in the vicinity of truncated mitochondria. To study the role of extracellular fatty acids on the expression of SNRK, we treated ovarian cancer cells with palmitic acid and found that palmitic acid led to an increase in SNRK expression in a dose dependent manner. SNRK was found to associate with Salt-Inducible Kinase 2 (SIK2), which is reported to be necessary for the initial stages of ovarian cancer metastasis.

Conclusions: Ovarian cancer cells display heterogeneity in their energetic behavior which accounts for their dependence on SNRK. Cells which are highly energetic (rely both on glycolysis and mitochondrial respiration) are more vulnerable to SNRK-mediated changes as compared to glycolytic cell lines. This implies that SNRK is a crucial regulator of mitochondrial respiration. SNRK uncouples mitochondrial respiration thereby restricting the ATP supply and propelling the cells to depend on alternate sources for energy production. 

Significance: Our data puts forward a novel role of SNRK in the initial stages of ovarian cancer metastasis. Inhibition of SNRK might help in developing new therapeutic regimens to restrict the metastatic spread of ovarian cancer.

Funding source: Wisconsin Ovarian Cancer Alliance and Cancer Center Pilot Grant

 

3. Meijun Du, Plasma cell-free DNA genome abnormalities predict response to abiraterone acetate/prednisone and prognosis in castration-resistant prostate cancer 

Presenter: Meijun Du, Research Scientist I

Poster Type: Student/Trainee/Junior Faculty

Mentor/PI: Wang, Liang, PhD

Research Program: Cancer Biology

Title: Plasma cell-free DNA genome abnormalities predict response to abiraterone acetate/prednisone and prognosis in castration-resistant prostate cancer

Introduction: Abiraterone acetate/prednisone (AA/P) is used for treatment of metastatic castration-resistant prostate cancer (mCRPC), but no molecular predictive biomarkers are known.

Objective: This study aimed to identify plasma cell-free DNA (cfDNA) based molecular biomarkers predictive of treatment resistance and/or prognostic of overall survival for mCRPC state.

Methods: We collected serial plasma specimens from 88 mCRPC patients progressing on androgen deprivation therapy (ADT) before and after 12-weeks AA/P treatment. We performed low-pass whole genome sequencing and subsequent copy number alteration (CNA) analysis in 174 plasma cfDNAs. We used Fisher’s exact test to evaluate CNAs with primary resistance. We applied Cox regression and Kaplan-Meier survival analyses to associate the CNAs with time to treatment change (TTTC) (secondary resistance) and overall survival (OS). 

Results: By comparing treatment response status, we identified CNAs in 4 genes (AR, OPHN1, ZFHX3, and PIK3CA) that showed significant association with AA/P primary resistance (False discovery rate (FDR≤0.05)). Survival analyses revealed significant association of CNAs at 11 gene loci with TTTC and at 12 gene loci with OS. Notably, amplifications at AR locus was associated with primary resistance to AA/P treatment (P=0.0039), shorter TTTC (P=0.0003) and OS (P=0.05). Interestingly, amplification of OPHN1 at AR downstream showed more significant association with primary resistance (P=0.0037), shorter TTTC (P=0.0002) and poor OS (P=0.004). To compensate for genetic heterogeneity, we built multi-gene models to predict risk of secondary resistance and OS. By combining CNAs from OPHN1, ZFHX3, PIK3CA and BRCA2, we developed a CNAs-based risk score that was significantly associated with TTTC (P=7.8E-04). We also developed another CNAs-based risk score by combining CNAs from ZFHX3, PIK3CA, and SPOP loci that predicted OS (P=0.002). These genomic risk scores were independent from known predictive and prognostic factors including circulating tumor cells (CTC), plasma tumor content, and clinical factors (age, baseline PSA level and volume of metastasis). 

Conclusions: Plasma cfDNA-based CNAs in multiple gene loci are predictive of treatment resistance to AA/P and survival in mCRPC state.

Significance: Liquid biopsy is a minimal invasive technology that may supplement tissue biopsy to predict treatment response and clinical outcome.

Funding source: NCI CA212097

4. Jasmine George, FXR1-mediated Oncogenic Adaptations via Post Transcriptional Regulation of c-MYC

Presenter: George, Jasmine, PhD, Postdoctoral Fellow

Poster Type: Student/Trainee/Junior Faculty

Mentor/PI: Chaluvally-Raghavan, Pradeep, PhD

Research Program: Cancer Biology

Title: FXR1-mediated Oncogenic Adaptations via Post Transcriptional Regulation of c-MYC

Introduction: Breast and ovarian cancers are the most lethal malignancies in women. Our data shows that Copy Number Variations of RNA binding proteins (RBPs) changes the post- transcriptional events contributes towards tumor initiation and metastasis. However, the functional role of RBPs has not been explored carefully in cancer. We identified that an RNA binding protein FXR1 is highly amplified in breast and ovarian cancers and this genomic amplification upregulates the expression of FXR1. In this study we characterized the key targets of FXR1 and its mechanism of action in breast and ovarian cancers. Our analysis and assays identified that c-MYC is the key target of FXR1 and FXR1 upregulates c-MYC levels by altering post-transcriptional and translational mechanisms. We further demonstrated that the upregulation of c-MYC through FXR1 dysregulates cell cycle, provides metabolic and proliferative advantages, and hijack pro-apoptotic mechanisms in cancer cells.

Objective: This study aims to evaluate the mechanism, how FXR1 upregulates c-MYC and other oncogenes for the growth and metastasis of cancer cells.

Methods: FXR1 expression in human breast and ovarian cancer cells and tissues were determined by Western blotting, immunohistochemistry and qPCR. We have either knocked down or overexpressed FXR1 in breast and ovarian cancer cells and performed MTT proliferation assay, colony formation assay, matrigel invasion assay, wound healing assay, protein array, cell cycle analysis, and real-time quantitative PCR (qPCR) array. We used this medium throughput qPCR arrays to determine the expression of cell cycle genes, metabolism genes and the expression of tumor suppressor genes and oncogenes differentially expressed upon the alterations of FXR1. We also performed seahorse bioassay to measure the oxygen consumption and extracellular acidification rate upon FXR1 altered cancer cells. To identify the proteins which interact with FXR1, we performed co-immunoprecipitation (CoIP) analyses followed by immunoblotting. We also performed RNA immunoprecipitation (RIP) to show the interaction between FXR1 with c-MYC mRNA.

Results: Our analysis identified that FXR1 is highly amplified in several types of human malignancies, particularly in lung, ovarian, cervical and breast cancers. We show that FXR1 is overexpressed in a panel of cancer cell lines and tissues, and the high expression of FXR1 promotes the growth, migration and invasion of cancer cells. In contrast, silencing of FXR1, reduced the proliferation, clonogenic potential, invasion, and wound healing abilities of cancer cells. We also found that the loss of FXR1 modulated the levels of apoptosis-related proteins, as well as promoted G-1 phase arrest. FXR1 silencing also reduced the glucose consumption, lactate secretion, mitochondrial membrane potential and the generation of reactive oxygen species (ROS). Importantly, we found that FXR1 expression associate with poor outcome of breast, ovarian and lung cancer patients.

Our data revealed that all the oncogenic effects mediated by FXR1 are orchestrated through c- MYC. We also found that FXR1 level associate with c-MYC expression in the tissue microarrays (TMAs) of ovarian cancer patients. Our data shows that FXR1 stabilizes c-MYC mRNA by preventing its degradation. Specifically, we showed that FXR1 improves the half-life of c-MYC transcript. Furthermore, FXR1 binding on c-MYC mRNA facilitates the recruitment of eukaryotic translation initiation factors (eIFs) to the translation initiation site and activates c-MYC translation.

Conclusions: Our results demonstrate that the RNA Binding Protein FXR1 is an unexpected driver of breast and ovarian cancers. Our study characterizes the previously unknown roles of FXR1 on the progression and metastasis of cancer cells. Herein, we identified that the oncogenic effects of FXR1 are mediated through c-MYC oncogene. Importantly, we identified that FXR1 facilitates the recruitment of translation initiation factor complex to the translation initiation site of c-MYC mRNA and enhances the translation of c-MYC protein.

Significance: Our study suggests that FXR1 is a prognostic and therapeutic target for ovarian cancer. We found that FXR1 has a critical role in the regulation of c-MYC mRNA and protein. The MYC family oncogene is dysregulated in >50% of human cancers, and this deregulation is frequently associated with poor prognosis and unfavorable patient survival. Although c-MYC inhibition would be a powerful approach for the treatment of many types of cancers, direct targeting of MYC has been a challenge for decades owing to its “undruggable” protein structure. On this background, inhibiting FXR1 using RNA interference (RNAi) approaches provide opportunities to inhibit the growth and metastasis of breast and ovarian cancer cells by inhibiting c-MYC and its target genes. FXR1 is amplified and overexpressed in other cancers like lung, esophagus and cervix. Therefore, we are expecting that our studies will have an impact on all cancers which express high levels of FXR1.

Funding source: Our lab is supported by the grants from Ovarian Cancer Research Fund Alliance (OCRFA), DoD Breast Cancer Research Program (W81XWH-18-1-0024), the Women’s Health Research Program (WHRP) at MCW, American Cancer Society’s IRG, and research funds from MCW Cancer Center.

Abstracts: Translational Science Posters #18-27

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Abstracts: Population Science Posters #28-36

Click on the + next to the presenter's name and poster title to view the abstract.  

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1. Christopher Ajala: Protocol of the Prevent Anal Cancer Study of Self Swabbing and Novel Biomakers

Presenter: Christopher Ajala, Clinical Research Coordinator

Poster Type:  Student/Trainee/Junior Faculty

Mentor/PI: Alan Nyitray

Research Program: Cancer Prevention and Outcomes

Title: Protocol of the Prevent Anal Cancer Study of Self Swabbing and Novel Biomakers

Introduction: Men who have sex with men (MSM), whether HIV-positive or HIV-negative, are at increased risk of developing anal cancer, a condition primarily caused by persistent HPV infection. Anal cancer screening in HIV-positive and HIV-negative MSM involves Digital Anal Rectal Exam (DARE) and/or Pap cytology, which may be followed by high-resolution anoscopy (HRA). It is possible that home-based self-sampling of anal canal exfoliated cells may increase compliance with screening compared to clinic-based screening.

Objective: Our study hypothesizes that there will be better compliance with home-based screening versus clinic-based screening among Milwaukee HIV-positive and HIV-negative MSM. In addition, we will use the specimens collected at home and in the clinic to test two novel biomarkers (persistent HPV infection and host DNA plus HPV DNA methylation) for detection of precancerous anal canal lesions among MSM.

Methods: Anal canal exfoliated cell specimens will be obtained from participating men by self-swab or by clinician swab at 0 and 12 months. All participants will then undergo HRA. Computer-assisted self-interviews at several time points will collect demographic and experiential data from study participants.

Significance: Study findings will increase knowledge about anal cancer screening among MSM and contribute to reduced morbidity and mortality from anal cancer.

Funding source: National Cancer Institute 

2. Jeffry Anderson: Increasing Mammography Uptake through Academic-Community Partnerships in Ethnic Minority Communities

Presenter: Jeffry Anderson, Medical Student

Poster Type: Student/Trainee/Junior Faculty

Mentor/PI: Sailaja Kamaraju

Research Program: Cancer Prevention and Outcomes

Title: Increasing Mammography Uptake through Academic-Community Partnerships in Ethnic Minority Communities

Introduction: Non-Caucasian women have a higher death rate from breast cancer, particularly African American and Hispanic women. Decreased knowledge and beliefs about breast cancer, poor social support, financial barriers, and reduced access to care contribute to delayed diagnosis in these patients. Immigrant women have lower utilization of screening practices compared to other groups of women. Community Based Academic Partnerships (CBAPs) appear to be an effective method of collaborating with communities to promote cancer awareness and screening efforts. Addressing these barriers is crucial to improving breast cancer mortality. 

Objective: Part 1: Breast health education at faith-based community centers Develop community academic partnership with ethnic minority groups in the Milwaukee area (ex. Hmong Community, Muslim Health Community Center, Sikh Temple) Identifying barriers to breast cancer screening Provide culturally appropriate breast cancer education workshops Provide free clinical breast exams to all participants Provide mobile mammography for eligible participants through Wisconsin Well Women’s program Increased mammography uptake.  Part 2: Focus groups to evaluate effectiveness of breast health education workshops Contact trusted community leaders at the sites we held workshops Conduct focus group interviews with community leaders To understand success of the workshops To understand challenges of the workshops Assess how well the workshops aligned with community needs Understand barriers to breast cancer screening which provides a cultural context for the barriers to women  

Methods: Select community partners Collect data concerning breast health education at faith-based community centers Conduct focus groups to evaluate effectiveness of breast health education workshops 

Results: 493 women attended the workshops and 375 women were included in final analysis. 32.6% of women lacked medical insurance & 34.8% of women lacked PCPs.  360 women were >40 years old and appropriate for mammography. 188 women had not received a mammogram. 75/188 were uninsured and qualified for free mammogram. 60/75 received mammogram. 113 women were privately insured and received screening mammogram through their PCP or the mobile mammography unit.  

Conclusions: CBAPs with cultural sites are an effective method of increasing screening mammography and breast health cancer knowledge among immigrant and refugee women in Milwaukee.  

Significance: Milwaukee has had a high influx of both refugees and immigrants in recent years. Ensuring these populations receive adequate screening care could decrease the breast cancer death rate.

Funding source: Susan G. Komen Foundation

3. Michele Battle: Novel Roles for GATA4 in Defining the Squamocolumnar Junction in the GI Tract, Implications for Barrett’s Esophagus  

Presenter: Michele Battle

Poster Type: Pilot Grant Awardee, <YEAR OF AWARD, AWARD FUNDING SOURCE or MECHANISM>

Research Program: Cancer Prevention and Outcomes

Title: Novel Roles for GATA4 in Defining the Squamocolumnar Junction in the GI Tract, Implications for Barrett’s Esophagus  

Introduction: Reactivation of pathways used during development to pattern tissue fate and function can play a role in disease. Our work explores the idea that abnormal re-activation of the developmentally important transcription factor GATA4 in the stratified epithelium of the esophagus contributes to the pathology of Barrett’s esophagus (BE), a premalignant metaplasia preceding esophageal adenocarcinoma (EAC). Our previous studies identified GATA4 as an essential regionalizing factor within the small intestinal epithelium. GATA4 is also differentially expressed at the squamocolumnar junction, where it is present within the columnar epithelium of the glandular stomach but is absent from the stratified epithelium of the esophagus/forestomach. In BE, this boundary is disrupted, and the esophageal stratified epithelium is replaced by columnar epithelium. The lack of GATA4 in normal esophageal epithelium and its presence in BE metaplasia along with the observation that the GATA4 gene is frequently amplified and expressed in EAC suggest a role for GATA4 in BE/EAC pathogenesis.

Objective: The objective of this study is to test the hypothesis that exclusion of GATA4 from esophageal/forestomach epithelium during development is essential to establish a normal squamocolumnar junction.  

Methods: We used Gata4 conditional knockout and knock-in mice with Sonic Hedgehog Cre to eliminate GATA4 in the columnar epithelium of the mouse hindstomach or to induce GATA4 in the stratified epithelium of mouse forestomach during development. We examined phenotypes in conditional mutants by histochemistry, immunohistochemistry, and RNA-Seq. We used ChIP-Seq to map the GATA4 binding profile in normal mouse hindstomach and combined binding data with gene expression data from mutants to identify high-confidence GATA4 direct targets implicated in human BE.

Results: We found that GATA4-deficient hindstomach epithelium was stratified rather than columnar, resembling the epithelium of the forestomach/esophagus. Conversely, GATA4-expressing forestomach contained columnar epithelium whereas control forestomach consisted solely of stratified epithelium. RNA-Seq revealed alterations in the transcriptomes of GATA4 mutants. The transcriptome of hindstomach epithelium lacking GATA4 shifted toward that of forestomach epithelium, and the transcriptome of forestomach epithelium expressing GATA4 shifted toward that of hindstomach epithelium. We found a network of esophageal and gastric transcription factors to have altered expression in GATA4 conditional mutants. One key altered factor was p63, a master regulator of stratified squamous epithelial development. Importantly, many transcripts associated with human BE were similarly mis-regulated in GATA4 conditional mutants.

Conclusions: Together, these data support the hypothesis that GATA4 has an essential role in squamocolumnar junction development. Our data suggest that GATA4 promotes columnar over stratified squamous epithelial development at the squamocolumnar junction by regulating expression of a transcription factor network, including GATA4-mediated repression of the stratified epithelial cell master regulator p63. Finally, altered expression of many BE-associated genes in GATA4 mutants further links GATA4 transcription factor function to human BE.

Significance: We expect our studies to identify the GATA4-dependent molecular mechanisms that guide normal squamocolumnar development and contribute to the molecular pathogenesis of Barrett’s esophagus. Identifying the role of GATA4 and its downstream targets in squamocolumnar development and disease has great potential to lead to new therapeutic targets and biomarkers for Barrett’s esophagus. By reducing Barrett’s esophagus, important progress can be made toward reducing esophageal cancer.  

Funding source: MCW Cancer Center Pilot Grants, <AWARD FUNDING SOURCE OR MECHANISM>

Theresa Bluemn: ARID1B but Not ARID2 is a Novel Tumor Suppressor in MLL-AF9 Leukemogenesis 
Pradeep Chaluvally-Raghavan: Unexpected Role of microRNAs in the Nucleus for Transcriptional Activation 

Abstracts: Pilot Project Posters #37-41

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