UNIVERSITY OF WISCONSIN - MADISONUNIVERSITY OF WISCONSIN - MADISONUNIVERSITY OF WISCONSIN - MADISON

Chelsie Kohns Sievers

CMP Cellular & MolecularPathology

6571 WIMR 2

Tuesday, April 18, 2017

10:00am

Research conducted under the supervision of Richard Halberg, Ph.DDepartment of Medicine

Bad Timing: Early Molecular Events Impact

Tumor Fate

Sievers CK, Kratz DJ, Zurbriggen LD, LoConte NK, Lubner SJ, Uboha N, Mulkerin D, Matkowskyj KA, and Deming DA. The multidisciplinary management of colorectal cancer: present and future paradigms. Invited review. Clinics in Colon and Rectal Surgery. 2016 Sep; 29(3):232-8. PMID: 27582648.

Sievers CK, Leystra AA, Clipson L, Dove WF, and Halberg RB. Understanding intratumoral heterogeneity: lessons from the analysis of at-risk tissue and pre-malignant lesions in the colon. [Invited commentary on: “Genomic Landscape of Colorectal Mucosa and Adenomas” by Borras E, et al.] Cancer Prevention Research. 2016 Aug;9(8):638-41. PMID: 27199343.

Kratz, J, Turk A, Sievers CK, Clipson L, Matkowskyj KA, and Deming DA. The molecular profile guides treatment options for colorectal cancer. Review. Federal Practi-tioner. 2016 May; 33(4):48S-51S.

Bacher JW*, Sievers CK*, Albrecht DM, Grimes IC, Weiss JM, Matkowskyj KA, Agni RM, Vyazunova I, Clipson L, Storts DR, Thliveris AT, Halberg RB. Improved Detection of Microsatel-lite Instability in Early Colorectal Lesions. PloS One. 2015 Aug; 10(8). PMID: 26252492.

Deming DA, Leystra AA, Nettekoven L, Sievers C, Miller D, Middlebrooks M, Clipson L, Albrecht DM, Bacher J, Washington MK, Weichert JP, Halberg RB. PIK3CA and APC mutations are synergistic in the development of intestinal cancers. Oncogene. 2014. 33(17):2245-54. PMID: 23708654.

Paul Olson TJ, Hadac JN, Sievers CK, Leystra AA, Deming DA, Zahm CD, Albrecht DM, Nomura A, Nettekoven LA, Plesh LK, Clipson L, Sullivan R, Newton MA, Schelman WR, Halberg RB. Dynamic tumor growth patterns in a novel murine model of colorectal cancer. Cancer Prevention Research. 2014 Jan; 7(1):105-13. PMID:24196829.

Sievers CK*, Shanle EK*, Bradfield CA, Xu W. Differential Action of Monohydroxylated Polycyclic Aromatic Hydrocar-bons with Estrogen Receptors α and β. Toxicological Sciences. 2013 Apr; 132(2), 359–67. PMID: 3595519.

Publications continuedSievers CK, Zou L, Pickhardt PJ, Matkowskyj K, Albrecht D, Kim D,

Moawad F, Cash BD, Reichelderfer M, Newton M, and Halberg RB. Modeling the rise of intratumoral heterogeneity in growing, static, and regressing human colorectal polyps [abstract]. In: Proceedings of the Annual Meeting of the American Association for Cancer Research; 2016 Apr 16-20; New Orleans, LA. Philadel-phia (PA): AACR; 2016. Abstract nr 1504.

Sievers CK, Pickhardt PJ, Matkowskyj K, Albrecht D, Zou L, Kim D, Lubner M, Clipson L, Reichelderfer M, and Halberg RB. Variation in Mutational Landscape Among Small Colonic Polyps with Differential Growth Fates [abstract]. In: Proceedings of the Annual Meeting of the American Association for Cancer Research; 2015 Apr 18-22; Philadelphia, PA. Philadelphia (PA): AACR; 2015. Abstract nr 4799.

Leystra AA, Luers B, Son J, Sievers CK, Wisinger AM, Schwartz AR, Zahm CD, Matkowskyj KA, Albrecht DM, Clipson L, Deming DA, Newton MA, and Halberg RB. A multiancestral model of colorec-tal cancer: in vivo evidence that early tumor heterogeneity contributes to cancer progression [abstract]. In: Proceedings of the Annual Meeting of the American Association for Cancer Research; 2016 Apr 16-20; New Orleans, LA. Philadelphia (PA): AACR; 2016. Abstract nr 2381.

Leystra AA, Wisinger AM, Zahm CD, Matkowskyj K, Sievers CK, Schwartz A, Albrecht D, Clipson L, Deming DA, Newton MA, and Halberg RB. Discrete clones cooperate to promote tumor progression through a non-cell-autonomous mechanism in intestinal cancers [abstract]. In: Proceedings of the Annual Meeting of the American Association for Cancer Research; 2015 Apr 18-22; Philadelphia, PA. Philadelphia (PA): AACR; 2015. Abstract nr 4143.

Leystra AA, Deming DA, Wisinger AM, Zahm CD, Sievers CK, Matkowskyj KA, Albrecht DM, Newton MA, Halberg RB. Transfor-mation of epithelial cells through recruitment leads to polyclon-al intestinal cancers [abstract]. In: Proceedings of the Annual Meeting of the American Association for Cancer Research; 2014 Apr 5-9; San Diego, CA. Philadelphia (PA): AACR; 2014. Abstract nr 1935.

Deming DA, Leystra AA, Nettekoven L, Sievers C, Clipson L, Albrecht DM, Bacher J, Washington MK, Weichert JP, Halberg RB. PIK3CA and APC mutations are synergistic in the development of intestinal cancers [abstract]. In: Proceedings of the Annual Meeting of the American Association for Cancer Research; 2013 Apr 6-10; Washington, DC. Philadelphia (PA): AACR; 2013. Abstract nr 2738.

Buehler J, McCullough D, Kohns C, Loving C, Lorusso A, Vincent A, Lager K, Miller C. Characterization of swine influenza virus PB1-F2 properties in swine and human cells. American Society for Virology 30th Annual Meeting, University of Minnesota, Minneapolis, MN, July 16-20. 2011.

Research Abstracts continued

Sievers CK, Vo TN, Pickhardt PJ, Pooler D, Matkowskyj K, Albrecht D, Rosemarie QR, Newton M, and Halberg RB. The timing of mutational burst events impact the growth of tumors in the colon [abstract]. In: Proceedings of the Annual Meeting of the American Association for Cancer Research; 2017 Apr 1-5; Washington, D.C. Philadelphia (PA): AACR; 2017. Abstract nr 2915.

Research Abstracts

UNIVERSITY OF WISCONSIN - MADISONUNIVERSITY OF WISCONSIN - MADISONUNIVERSITY OF WISCONSIN - MADISON

Abstract continuned

Education

University of Wisconsin - MadisonPhD Candidate in Cell and Molecular Pathology Program

Iowa State UniversityBS, Genetics

2012 - PresentMadison, WI

2007 - 2011Ames, Iowa

magna cum laude

Chelsie Kohns Sievers’s Dissertation Abstract “Bad Timing: Early Molecular Events Impact Tumor

Fate” Colorectal cancer encompasses multiple subtypes of tumors that are defined by their molecular and histological features. Historically, these features were thought to be attained by the sequential acquisition of driver mutations over time. However, this model of tumor evolution fails to account for the variability in polyp growth behavior and the ubiquitous presence of intratu-moral heterogeneity. These observations have led to new models of tumor evolution in which numer-ous molecular changes occur simultaneously during punctuation events. We sought to test this new conceptual framework by characterizing how and when crucial molecular characteristics are acquired and their impact on tumor evolution. Microsatellite instability (MSI) is common in many familial and sporadic colorectal cancers. We developed a more sensitive method for detecting MSI in tumors to determine when it is acquired. MSI can occur early in the development of adeno-mas from Lynch patients or it can occur later in the development of tumors with a serrated morphology. The early diagnosis of Lynch

Syndrome could be of immense clinical benefit as each patient has, on average, three afflicted rela-tives, many of whom go undiagnosed until they pres-ent with a cancer. Our analysis of intestinal tumors also revealed that other molecular events occur earlier than predicted. Colorectal tumors can have different fates: growth, stasis, or regression. The comparison of gene expression in growing tumors versus static tumors from mice revealed a gene signature that could distinguish between these types. The transcriptional changes were evident as soon as tumors were detectable. Similarly, in human colorectal tumors we found that subclones carrying pathogenic mutations arose when the tumors were quite small. Furthermore, we demonstrate that many of these subclonal mutations result from a very early punctuation event. Thus, our findings support the notion that early punctuation events can affect tumor fate. The finding of critical molecular events occurring very early on during tumorigenesis support the notion that some tumors might be “born to be bad.” These novel insights may lead to more efficient screening recommendations, novel screening modal-ities, and improved treatment options for patients.

PublicationsSievers CK, Zou LS, Pickhardt PJ, Matkowskyj K, Albrecht

DM, Clipson L, Bacher JW, Pooler D, Moawad FJ, Cash BD, Reichelderfer M, Vo TN, Newton MA, Larget B, and Halberg RB. Subclonal diversity arises early even in benign colorectal tumors and contributes to differential growth fates. Gut. 2016 Sep 8. [Epub ahead of print]. PMID: 27609830.

Research Experience2012 - PresentUniversity of Wisconsin - Madison, Madison, WI Doctoral Research: Dept. of MedicineResearch advisor: Dr. Richard Halberg UW-Madison•Our intent is to understand mechanisms of tumor heteroge-

neity and how this affects patient outcome using genetic mouse models of colon tumorigenesis.

2011 - 2012University of Wisconsin - Madison, Madison, WI Associate Research Specialist: Dept. of OncologyResearch advisor: Dr. Wei Xu •Our intent was to further understand the role of estrogen

receptors alpha, beta, as well as the alpha-beta heterodi-mer in breast cancer and how these can be used as targets for novel breast cancer treatments.

2010 - 2011Iowa State University, Ames, IAUndergraduate Research: Dept. of Veterinary Microbiology & Preventative MedicineResearch advisor: Dr. Cathy Miller•Our intent was to understand the function of the influenza

viral protein PB1F2 as well as how that function impacts pathogenicity in the swine host.

2009 - 2010Iowa State University , Ames, IA Undergraduate Research: Dept. of Biomedical SciencesResearch advisor: Dr. Richard Martin and Dr. Joan Howard •Our intent was to survey the incidence of helminth

resistance to anthelmintics in equine populations in Iowa.