Karl J Simin PhD
Title | Associate Professor |
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Institution | University of Massachusetts Medical School |
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Department | Molecular, Cell and Cancer Biology |
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Address | University of Massachusetts Medical School 364 Plantation Street, LRB Worcester MA 01605
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Phone | 508-856-3959 |
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vCard | Download vCard |
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Institution | UMMS - School of Medicine |
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Department | Molecular, Cell and Cancer Biology |
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Institution | UMMS - Graduate School of Biomedical Sciences |
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Department | Cancer Biology |
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Biography University of Michigan, Ann Arbor, Ann Arbor, MI, United States | BS | | Anthropology-Zoology | University of Utah School of Medicine, Salt Lake City, UT, United States | PHD | | Human Genetics |
Overview Our lab is interested in the genetic pathways involved in breast cancer malignancy. To pursue these interests, we use genomic approaches to compare and contrast tumor-derived cell lines, primary tumors from patients, and tumors from mouse models. We use a combination of cell culture experiments and in vivo genetics to directly test how perturbations in the pathways we identify from our genomic studies influence the mechanisms of tumor progression and metastasis. Our goals are to improve breast cancer diagnosis and reveal potential therapeutic targets through an improved understanding of molecular and cellular biology of tumors.
Epithelial Mesenchymal Transition and Cancer Progression
Our current research is focused on the role of tight junction complexes in regulating epithelial to mesenchymal transition (EMT) and invasive cell behavior. EMT describes processes that cause epithelial cells, which normally form sheets of interconnected cells, to dissemble their intercellular junctions, lose apical-basal polarity, and acquire mesenchymal characteristics, such as increased motility. There are many parallels to these changes observed in tumors progressing to invasive and metastatic forms, so elucidating EMT molecular pathways provides a useful framework for studying cancer progression mechanisms. EMT pathways are reused in numerous developmental stages and in adult tissues during wound healing, and as we often observe in biology, important pathways that mediate vital processes are also highly conserved across evolution. Many key EMT genes studied in mammalian cells, like TWIST, SNAIL, and SLUG, were first identified as fruit fly mutations. Comparative studies of human cell biology and experimental model systems are complementary approaches that accelerate our discovery efforts.
Understanding EMT mechanisms is not just an academic exercise, but has direct relevance to cancer biology. We and others have found that neoplastic epithelial cells have the ability to co-opt normal EMT pathways to acquire mesenchymal characteristics, such as increased motility and invasiveness. These are important properties since distant metastasis is often the cause of cancer-associated morbidity. In addition, cell morphology is evaluated in tumor staging as an indication of cellular differentiation, although the concept of EMT is not used in current clinical classification schemes. Furthermore, recent studies indicate EMT induction may also confer stem cell properties to mammary epithelial cells, which may contribute to their intractability to current therapies. Thus, elucidating the pathways of cancer-associated EMTs may yield useful diagnostic biomarkers and reveal new opportunities for therapeutic interventions. Our efforts are especially relevant to a novel breast cancer molecular subtype we call Claudin-Low tumors that we discovered in a cross-species comparison of mouse and human breast cancers. These tumors show morphological and molecular features characteristic of EMT. Ongoing studies in the lab focus on characterizing a mouse model we engineered that mimics many salient features of human Claudin-Low tumors, further characterizing primary tumors from patients, and exploring the molecular basis that uniquely distinguishes these tumors from other breast cancer subtypes.
 Bibliographic
Publications listed below are automatically derived from MEDLINE/PubMed and other sources, which might result in incorrect or missing publications.
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Carlisle AE, Lee N, Matthew-Onabanjo AN, Spears ME, Park SJ, Youkana D, Doshi MB, Peppers A, Li R, Joseph AB, Smith M, Simin K, Zhu LJ, Greer PL, Shaw LM, Kim D. Selenium detoxification is required for cancer-cell survival. Nat Metab. 2020 Jul; 2(7):603-611. PMID: 32694795.
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Gregory KJ, Roberts AL, Conlon EM, Mayfield JA, Hagen MJ, Crisi GM, Bentley BA, Kane JJ, Makari-Judson G, Mason HS, Yu J, Zhu LJ, Simin K, Johnson JPS, Khan A, Schneider BR, Schneider SS, Jerry DJ. Gene expression signature of atypical breast hyperplasia and regulation by SFRP1. Breast Cancer Res. 2019 Jun 27; 21(1):76. PMID: 31248446.
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Leonard JL, Leonard DM, Wolfe SA, Liu J, Rivera J, Yang M, Leonard RT, Johnson JPS, Kumar P, Liebmann KL, Tutto AA, Mou Z, Simin KJ. Correction: The Dkk3 gene encodes a vital intracellular regulator of cell proliferation. PLoS One. 2017; 12(9):e0184458. PMID: 28863194.
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Leonard JL, Leonard DM, Wolfe SA, Liu J, Rivera J, Yang M, Leonard RT, Johnson JPS, Kumar P, Liebmann KL, Tutto AA, Mou Z, Simin KJ. The Dkk3 gene encodes a vital intracellular regulator of cell proliferation. PLoS One. 2017; 12(7):e0181724. PMID: 28738084.
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Cojoc M, Peitzsch C, Kurth I, Trautmann F, Kunz-Schughart LA, Telegeev GD, Stakhovsky EA, Walker JR, Simin K, Lyle S, Fuessel S, Erdmann K, Wirth MP, Krause M, Baumann M, Dubrovska A. Aldehyde Dehydrogenase Is Regulated by ß-Catenin/TCF and Promotes Radioresistance in Prostate Cancer Progenitor Cells. Cancer Res. 2015 Apr 1; 75(7):1482-94. PMID: 25670168.
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Johnson JP, Kumar P, Koulnis M, Patel M, Simin K. Crucial and novel cancer drivers in a mouse model of triple-negative breast cancer. Cancer Genomics Proteomics. 2014 May-Jun; 11(3):115-26. PMID: 24969692.
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Goel HL, Pursell B, Chang C, Shaw LM, Mao J, Simin K, Kumar P, Vander Kooi CW, Shultz LD, Greiner DL, Norum JH, Toftgard R, Kuperwasser C, Mercurio AM. GLI1 regulates a novel neuropilin-2/a6ß1 integrin based autocrine pathway that contributes to breast cancer initiation. EMBO Mol Med. 2013 Apr; 5(4):488-508. PMID: 23436775.
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Kumar P, Mukherjee M, Johnson JP, Patel M, Huey B, Albertson DG, Simin K. Cooperativity of Rb, Brca1, and p53 in malignant breast cancer evolution. PLoS Genet. 2012; 8(11):e1003027. PMID: 23173005.
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D'Amato NC, Ostrander JH, Bowie ML, Sistrunk C, Borowsky A, Cardiff RD, Bell K, Young LJ, Simin K, Bachelder RE, Delrow J, Dawson A, Yee LD, Mrózek K, Clay TM, Osada T, Seewaldt VL. Evidence for phenotypic plasticity in aggressive triple-negative breast cancer: human biology is recapitulated by a novel model system. PLoS One. 2012; 7(9):e45684. PMID: 23049838.
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Rajurkar M, De Jesus-Monge WE, Driscoll DR, Appleman VA, Huang H, Cotton JL, Klimstra DS, Zhu LJ, Simin K, Xu L, McMahon AP, Lewis BC, Mao J. The activity of Gli transcription factors is essential for Kras-induced pancreatic tumorigenesis. Proc Natl Acad Sci U S A. 2012 Apr 24; 109(17):E1038-47. PMID: 22493246.
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Serber DW, Rogala A, Makarem M, Rosson GB, Simin K, Godfrey V, Van Dyke T, Eaves CJ, Bultman SJ. The BRG1 chromatin remodeler protects against ovarian cysts, uterine tumors, and mammary tumors in a lineage-specific manner. PLoS One. 2012; 7(2):e31346. PMID: 22363625.
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Lu X, Yang C, Yin C, Van Dyke T, Simin K. Apoptosis is the essential target of selective pressure against p53, whereas loss of additional p53 functions facilitates carcinoma progression. Mol Cancer Res. 2011 Apr; 9(4):430-9. PMID: 21385880.
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Lee CW, Simin K, Liu Q, Plescia J, Guha M, Khan A, Hsieh CC, Altieri DC. A functional Notch-survivin gene signature in basal breast cancer. Breast Cancer Res. 2008; 10(6):R97. PMID: 19025652.
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Lu S, Simin K, Khan A, Mercurio AM. Analysis of integrin beta4 expression in human breast cancer: association with basal-like tumors and prognostic significance. Clin Cancer Res. 2008 Feb 15; 14(4):1050-8. PMID: 18281537.
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Herschkowitz JI, Simin K, Weigman VJ, Mikaelian I, Usary J, Hu Z, Rasmussen KE, Jones LP, Assefnia S, Chandrasekharan S, Backlund MG, Yin Y, Khramtsov AI, Bastein R, Quackenbush J, Glazer RI, Brown PH, Green JE, Kopelovich L, Furth PA, Palazzo JP, Olopade OI, Bernard PS, Churchill GA, Van Dyke T, Perou CM. Identification of conserved gene expression features between murine mammary carcinoma models and human breast tumors. Genome Biol. 2007; 8(5):R76. PMID: 17493263.
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Scuderi A, Simin K, Kazuko SG, Metherall JE, Letsou A. scylla and charybde, homologues of the human apoptotic gene RTP801, are required for head involution in Drosophila. Dev Biol. 2006 Mar 1; 291(1):110-22. PMID: 16423342.
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Simin K, Hill R, Song Y, Zhang Q, Bash R, Cardiff RD, Yin C, Xiao A, McCarthy K, van Dyke T. Deciphering cancer complexities in genetically engineered mice. Cold Spring Harb Symp Quant Biol. 2005; 70:283-90. PMID: 16869764.
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Simin K, Wu H, Lu L, Pinkel D, Albertson D, Cardiff RD, Van Dyke T. pRb inactivation in mammary cells reveals common mechanisms for tumor initiation and progression in divergent epithelia. PLoS Biol. 2004 Feb; 2(2):E22. PMID: 14966529.
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Simin K, Scuderi A, Reamey J, Dunn D, Weiss R, Metherall JE, Letsou A. Profiling patterned transcripts in Drosophila embryos. Genome Res. 2002 Jul; 12(7):1040-7. PMID: 12097340.
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Weber JS, Jang W, Simin K, Lu W, Yu J, Meisler MH. High-resolution genetic, physical, and transcript map of the mnd2 region of mouse chromosome 6. Genomics. 1998 Nov 15; 54(1):107-15. PMID: 9806835.
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Ivanov IP, Simin K, Letsou A, Atkins JF, Gesteland RF. The Drosophila gene for antizyme requires ribosomal frameshifting for expression and contains an intronic gene for snRNP Sm D3 on the opposite strand. Mol Cell Biol. 1998 Mar; 18(3):1553-61. PMID: 9488472.
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Simin K, Bates EA, Horner MA, Letsou A. Genetic analysis of punt, a type II Dpp receptor that functions throughout the Drosophila melanogaster life cycle. Genetics. 1998 Feb; 148(2):801-13. PMID: 9504926.
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Letsou A, Arora K, Wrana JL, Simin K, Twombly V, Jamal J, Staehling-Hampton K, Hoffmann FM, Gelbart WM, Massagué J, et al. Drosophila Dpp signaling is mediated by the punt gene product: a dual ligand-binding type II receptor of the TGF beta receptor family. Cell. 1995 Mar 24; 80(6):899-908. PMID: 7697720.
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Year | Publications |
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1995 | 1 | 1998 | 3 | 2002 | 1 | 2004 | 1 | 2005 | 1 | 2006 | 1 | 2007 | 1 | 2008 | 2 | 2011 | 1 | 2012 | 4 | 2013 | 1 | 2014 | 1 | 2015 | 1 | 2017 | 2 | 2019 | 1 | 2020 | 1 |
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