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Karl J Simin PhD

TitleAssociate Professor
InstitutionUMass Chan Medical School
DepartmentMolecular, Cell and Cancer Biology
AddressUMass Chan Medical School
364 Plantation Street LRB
Worcester MA 01605
Phone508-856-3959
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    Other Positions
    InstitutionT.H. Chan School of Medicine
    DepartmentMolecular, Cell and Cancer Biology

    InstitutionMorningside Graduate School of Biomedical Sciences
    DepartmentCancer Biology


    Collapse Biography 
    Collapse education and training
    University of Michigan, Ann Arbor, Ann Arbor, MI, United StatesBSAnthropology-Zoology
    University of Utah School of Medicine, Salt Lake City, UT, United StatesPHDHuman Genetics

    Collapse Overview 
    Collapse 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.


     




    Collapse Bibliographic 
    Collapse selected publications
    Publications listed below are automatically derived from MEDLINE/PubMed and other sources, which might result in incorrect or missing publications. Faculty can login to make corrections and additions.
    Newest   |   Oldest   |   Most Cited   |   Most Discussed   |   Timeline   |   Field Summary   |   Plain Text
    PMC Citations indicate the number of times the publication was cited by articles in PubMed Central, and the Altmetric score represents citations in news articles and social media. (Note that publications are often cited in additional ways that are not shown here.) Fields are based on how the National Library of Medicine (NLM) classifies the publication's journal and might not represent the specific topic of the publication. Translation tags are based on the publication type and the MeSH terms NLM assigns to the publication. Some publications (especially newer ones and publications not in PubMed) might not yet be assigned Field or Translation tags.) Click a Field or Translation tag to filter the publications.
    1. Weissenrieder JS, Peura J, Paudel U, Bhalerao N, Weinmann N, Johnson C, Wengyn M, Drager R, Furth EE, Simin K, Ruscetti M, Stanger BZ, Rustgi AK, Pitarresi JR, Foskett JK. Mitochondrial Ca2+ controls pancreatic cancer growth and metastasis by regulating epithelial cell plasticity. bioRxiv. 2024 Aug 09. PMID: 39149344.
      Citations:    
    2. Murphy KC, DeMarco KD, Zhou L, Lopez-Diaz Y, Ho YJ, Li J, Bai S, Simin K, Zhu LJ, Mercurio AM, Ruscetti M. MYC and p53 alterations cooperate through VEGF signaling to repress cytotoxic T cell and immunotherapy responses in prostate cancer. bioRxiv. 2024 Jul 24. PMID: 39091883.
      Citations:    
    3. Mishra AK, Ye T, Banday S, Thakare RP, Su CT, Pham NNH, Ali A, Kulshreshtha A, Chowdhury SR, Simone TM, Hu K, Zhu LJ, Eisenhaber B, Deibler SK, Simin K, Thompson PR, Kelliher MA, Eisenhaber F, Malonia SK, Green MR. Targeting the GPI transamidase subunit GPAA1 abrogates the CD24 immune checkpoint in ovarian cancer. Cell Rep. 2024 Apr 23; 43(4):114041. PMID: 38573857.
      Citations:    
    4. Doshi MB, Lee N, Tseyang T, Ponomarova O, Goel HL, Spears M, Li R, Zhu LJ, Ashwood C, Simin K, Jang C, Mercurio AM, Walhout AJM, Spinelli JB, Kim D. Disruption of sugar nucleotide clearance is a therapeutic vulnerability of cancer cells. Nature. 2023 Nov; 623(7987):625-632. PMID: 37880368.
      Citations: 1     Fields:    Translation:HumansCells
    5. Patel SA, Cerny J, Gerber WK, Ramanathan M, Ediriwickrema A, Tanenbaum B, Hutchinson L, Meng X, Flahive J, Barton B, Gillis-Smith AJ, Suzuki S, Khedr S, Selove W, Higgins AW, Miron PM, Simin K, Woda B, Gerber JM. Prognostic heterogeneity and clonal dynamics within distinct subgroups of myelodysplastic syndrome and acute myeloid leukemia with TP53 disruptions. EJHaem. 2023 Nov; 4(4):1059-1070. PMID: 38024632.
      Citations:    
    6. Chibaya L, Murphy KC, DeMarco KD, Gopalan S, Liu H, Parikh CN, Lopez-Diaz Y, Faulkner M, Li J, Morris JP, Ho YJ, Chana SK, Simon J, Luan W, Kulick A, de Stanchina E, Simin K, Zhu LJ, Fazzio TG, Lowe SW, Ruscetti M. EZH2 inhibition remodels the inflammatory senescence-associated secretory phenotype to potentiate pancreatic cancer immune surveillance. Nat Cancer. 2023 06; 4(6):872-892. PMID: 37142692.
      Citations: 5     Fields:    Translation:AnimalsCells
    7. Spears ME, Lee N, Hwang S, Park SJ, Carlisle AE, Li R, Doshi MB, Armando AM, Gao J, Simin K, Zhu LJ, Greer PL, Quehenberger O, Torres EM, Kim D. De novo sphingolipid biosynthesis necessitates detoxification in cancer cells. Cell Rep. 2022 09 27; 40(13):111415. PMID: 36170811.
      Citations: 2     Fields:    Translation:Cells
    8. Shi Q, Herbert C, Ward DV, Simin K, McCormick BA, Ellison Iii RT, Zai AH. COVID-19 Variant Surveillance and Social Determinants in Central Massachusetts: Development Study. JMIR Form Res. 2022 Jun 13; 6(6):e37858. PMID: 35658093.
      Citations:    
    9. Meza-Segura M, Birtley JR, Maldonado-Contreras A, Mueller C, Simin KJ, Stern LJ, McCormick BA. SepA Enhances Shigella Invasion of Epithelial Cells by Degrading Alpha-1 Antitrypsin and Producing a Neutrophil Chemoattractant. mBio. 2021 12 21; 12(6):e0283321. PMID: 34724811.
      Citations: 4     Fields:    Translation:HumansCells
    10. Patel SA, Lloyd MR, Cerny J, Shi Q, Simin K, Ediriwickrema A, Hutchinson L, Miron PM, Higgins AW, Ramanathan M, Gerber JM. Clinico-genomic profiling and clonal dynamic modeling of TP53-aberrant myelodysplastic syndrome and acute myeloid leukemia. Leuk Lymphoma. 2021 12; 62(14):3348-3360. PMID: 34496723.
      Citations: 5     Fields:    Translation:Humans
    11. Nehl E, Heilman S, Ku D, Gottfried D, Farmer S, Mannino R, Tyburski E, Sullivan J, Suessmith A, Bassit L, Figueroa J, Wood A, Leong T, Rao A, Rogers B, Jerris R, Park S, Gonzalez M, Frediani J, Morris C, Levy J, Schoof N, Mavigner M, Roback J, Herzegh K, Saakadze N, Ingersoll J, Cheedarla N, Neish A, Hanberry B, Porter C, Esper A, Kempker R, Rebolledo P, McGuinness P, Balagadde F, Gore R, Koren A, Pollock N, Rogers E, Simin K, Hafer N, Picard MA, Ghezzi C, McManus D, Buchholz B, Rostad C, Claveria V, Ramachandra T, Wang YF, Washington C, Stone C, Griffiths M, Schinazi R, Chahroudi A, Vos M, Brand O, Martin G, Lam W. The RADx Tech Test Verification Core and the ACME POCT in the Evaluation of COVID-19 Testing Devices: A Model for Progress and Change. IEEE Open J Eng Med Biol. 2021 Apr 28; 2:142-151. PMID: 34192286.
      Citations:    
    12. Tomkins-Tinch CH, Daly JS, Gladden-Young A, Theodoropoulos NM, Madaio MP, Yu N, Vanguri VK, Siddle KJ, Adams G, Krasilnikova LA, Movahedi B, Bozorgzadeh A, Simin K, Lemieux JE, Luban J, Park DJ, MacInnis BL, Sabeti PC, Levitz SM. SARS-CoV-2 Reinfection in a Liver Transplant Recipient. Ann Intern Med. 2021 08; 174(8):1178-1180. PMID: 33872044.
      Citations: 8     Fields:    Translation:HumansCells
    13. 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 07; 2(7):603-611. PMID: 32694795.
      Citations: 48     Fields:    Translation:HumansAnimalsCells
    14. 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 06 27; 21(1):76. PMID: 31248446.
      Citations: 13     Fields:    Translation:HumansAnimalsCells
    15. 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.
      Citations: 1     Fields:    
    16. 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.
      Citations: 10     Fields:    Translation:AnimalsCells
    17. 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 ?-Catenin/TCF and Promotes Radioresistance in Prostate Cancer Progenitor Cells. Cancer Res. 2015 Apr 01; 75(7):1482-94. PMID: 25670168.
      Citations: 125     Fields:    Translation:HumansAnimalsCells
    18. 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.
      Citations: 7     Fields:    Translation:AnimalsCells
    19. 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/a6?1 integrin based autocrine pathway that contributes to breast cancer initiation. EMBO Mol Med. 2013 Apr; 5(4):488-508. PMID: 23436775.
      Citations: 97     Fields:    Translation:HumansAnimalsCells
    20. 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.
      Citations: 13     Fields:    Translation:HumansAnimals
    21. 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, Mr?zek 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.
      Citations: 13     Fields:    Translation:HumansAnimalsCells
    22. 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.
      Citations: 62     Fields:    Translation:Animals
    23. 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.
      Citations: 18     Fields:    Translation:HumansAnimalsCells
    24. 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.
      Citations: 2     Fields:    Translation:Animals
    25. 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.
      Citations: 62     Fields:    Translation:HumansCells
    26. 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.
      Citations: 66     Fields:    Translation:Humans
    27. 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.
      Citations: 655     Fields:    Translation:HumansAnimals
    28. 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 01; 291(1):110-22. PMID: 16423342.
      Citations: 11     Fields:    Translation:HumansAnimalsCells
    29. 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.
      Citations: 31     Fields:    Translation:HumansCells
    30. 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.
      Citations: 9     Fields:    Translation:AnimalsCells
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