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    Karl J Simin PhD

    TitleAssistant Professor
    InstitutionUniversity of Massachusetts Medical School
    DepartmentCancer Biology
    AddressUniversity of Massachusetts Medical School
    364 Plantation Street, LRB
    Worcester MA 01605
    Phone508-856-3959
      Other Positions
      InstitutionUMMS - Graduate School of Biomedical Sciences
      DepartmentCancer Biology

        Overview 
        Narrative

        karlsimin 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.

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        Bibliographic 
        selected publications
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        1. 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.
          View in: PubMed
        2. 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.
          View in: PubMed
        3. 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.
          View in: PubMed
        4. 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.
          View in: PubMed
        5. 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.
          View in: PubMed
        6. 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.
          View in: PubMed
        7. 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.
          View in: PubMed
        8. 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.
          View in: PubMed
        9. 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.
          View in: PubMed
        10. 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.
          View in: PubMed
        11. 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.
          View in: PubMed
        12. 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.
          View in: PubMed
        13. 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.
          View in: PubMed
        14. 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.
          View in: PubMed
        15. 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.
          View in: PubMed
        16. 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.
          View in: PubMed
        17. 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.
          View in: PubMed
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