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Lisa Coussens Laboratory

Summary:

The Coussens lab focuses on the role of immune cells and their mediators as critical regulators of cancer development. During the early development of cancer, many physiological processes occur in the vicinity of 'young tumor cells' that are similar to processes that occur during embryonic development and to healing of wounds in adult tissue, e.g., leukocyte recruitment and activation (inflammation), angiogenesis (development of new blood supply) and tissue remodeling. During tumor development however, instead of initiating a 'healing' response, activated leukocytes provide growth-promoting factors that typically help tumors grow. We are interested in understanding the molecular and cellular mechanisms that regulate leukocyte recruitment into neoplastic tissue, and the subsequent regulation those leukocytes exert on evolving cancer cells. To address these issues, we have taken several approaches to investigate mechanisms involved in: i. induction and maintenance of chronic inflammatory microenvironments in premalignant, malignant and metastatic tissues using murine models of human cancer development, and clinical samples obtained fresh from the operating room from patients with cancer, ii. role of leukocytes in regulating tissue remodeling, angiogenesis, immune suppression and cancer development, iii. development of novel non-invasive imaging reagents to monitor immune response in tissues/tumors. The long-term goal of this work is to translate basic observations made in the mouse, toward rational design of novel therapeutics whose aim will be to block and/or alter rate-limiting events critical for solid tumor growth, maintenance or recurrence in humans, and/or therapeutics that enhance the efficacy of standard-of-care cytotoxic therapy. Currently, we are actively utilizing transgenic mouse models of solid tumor development (non-small cell lung cancer, non-melanoma squamous, pancreatic and breast adenocarcinoma, and mesothelioma) to reveal the functional roles of adaptive and innate leukocytes during tumor development. These experimental studies are conducted in parallel with evaluation of representative human cancer specimens to affirm that mechanisms revealed in the experimental setting represent fundamental parameters of multi-stage cancer development in humans.

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Organisms and Viruses

  • 129S4-Trp53tm2Tyj ( Mus musculus )

    These mice contain a point-mutant allele of Trp53 that can be activated by Cre-mediated recombination. The conditional allele, containing LoxP sites and a transcriptional/translational STOP sequence, is functionally equivalent to a null mutation.

  • Arginase-YFP ( Mus musculus )

    "A targeting vector was designed to insert an internal ribosome entry site (IRES)-enhanced yellow fluorescent protein (eYFP) fusion protein, downstream of the endogenous stop codon of the arginase (Arg1) gene. These homozygous YARG mice are viable, fertile, and normal in size. Located in the cytoplasm of the liver and specifically in macrophages, arginase I converts L-arginine into L-ornithine and urea as the final step in the urea cycle. L-arginine can also be catabolized into nitric oxide (NO), a secreted free radical which causes tissues damage and is toxic to bacteria. Arginase I suppresses NO production by decreasing the amount of L-arginine available to the nitric oxide synthase (NOS) enzyme for conversion into NO and other reactive oxygen species (ROS). Nine days after infection with the helminth, Nippostrongylus brasiliensis, YARG mice exhibit accumulation of arginase I-expressing macrophages in the lung and peritoneum. As soon as two days after inoculation with chitin, a polysaccharide found in the exoskeleton of some invertebrates, these macrophages were also present in the lung and peritoneum. These mice may be useful for visualization of arginase-containing cells and their response to infection."

  • B6.129S4-Krastm4Tyj/J ( Mus musculus )

    "This strain carries a point mutation (G12D) in the Kras (v-Ki-ras2 Kirsten rat sarcoma viral oncogene homolog) gene whose expression is blocked by the presence of a loxP-flanked stop codon. Homozygotes die in utero. Cre-mediated recombination can excise the stop codon and permit the oncogenic protein to be expressed. Intranasal infection with an adenovirus encoding Cre results in a very high frequency of lung tumors and permits controlled timing of tumor initiation and tumor multiplicity. This strain may be useful in studies of cancer and development."

  • B6.FVB-Tg(Ipf1-cre)1Tuv ( Mus musculus )

    "Pdx-1-Cre mice exhibit a stochastic pattern of high-level Cre expression in the pancreas (Hingorani et al., 2003). When combined with Tyler Jacks' latent activatable K-ras allele, LSL-KrasG12D (Kras2, NCI Mouse Repository strain code 01XJ6), Pdx-1-Cre causes ductal lesions that recapitulate the full spectrum of human pancreatic intraepithelial neoplasias (PanINs). Some of these lesions progress to invasive and metastatic adenocarcinomas."

  • Balb/c ( Mus musculus )

    "BALB/cJ is a commonly used inbred. Key traits include a resistance to experimental autoimmune encephalomyelitis (EAE), and a susceptibility to developing the demyelinating disease upon infection with Theiler's murine encephalomyelitis virus. The BALB/cJ substrain is susceptible to Listeria, all species of Leishmania, and several species of Trypanosoma, but is resistant to experimental allergic orchitis (EAO)."

  • Batf-/- ( Mus musculus )

  • Beta actin CFP ( Mus musculus )

    "The transgene construct contains an enhanced cyan fluorescent protein gene driven by the cytomegalovirus (CMV) immediate early enhancer coupled to the chicken beta actin promoter."

  • Beta actin GFP ( Mus musculus )

    "The transgene comprises the cDNA encoding enhanced green fluorescent protein (EGFP), from the jellyfish Aequoria victoria, downstream of the "CAG promoter" -- which consists of the cytomegalovirus immediate early (CMV-EI) enhancer followed by a 1.3-kb DNA segment including the promoter, first exon and first intron of the chicken beta-actin gene, with the 3' splice junction sequence replaced by that of the rabbit hemoglobin beta gene -- and followed by the rabbit beta-hemoglobin polyadenylation signal and 3' flanking sequence."

  • C3(1)-TAg ( Mus musculus )

    "This transgene contains the rat prostatic binding protein C3 promoter (Pbpc3) and the wild-type allele of the SV40 large tumor antigen (TAg) gene. Founder c carried 6 copies of the transgene. Founders f, g, i, j, k, and l were also generated. Two transgenic lines (c and l) were produced."

  • C3(1)-TAg b-actin-GFP ( Mus musculus )

  • C3(1)-TAg-IL4-GFP ( Mus musculus )

  • C3(1)-TAg-IL4Ra-/-  ( Mus musculus )

  • C57/Bl6 ( Mus musculus )

  • C5arI-/- ( Mus musculus )

  • CatC-/- ( Mus musculus )

    "An in-frame lacZ gene and neomycin selection cassette were inserted just downstream of the transcription initiation site. Activity assays demonstrated that no functional protein is made from this allele in homozygous mice. No beta-galactosidase is expressed from this allele."

  • CD4-/- ( Mus musculus )

  • CD4-/- CD8-/- ( Mus musculus )

  • CD8-/- ( Mus musculus )

  • cfms-GFP ( Mus musculus )

    "Exon 3 was disrupted by the insertion of an in-frame cassette containing a humanized green fluorescent protein sequence and a neomycin resistance gene. While annulment of the allele in mutant mice was indicated by Western blot analysis of bone-marrow derived macrophages, expression of the green fluorescent protein could not be detected by fluorescence microscopy or flow cytometry."

  • Coll-CreER, mT/mG ( Mus musculus )

    "These mT/mG mice are useful as a Cre reporter strain; expressing red fluorescence prior to, and green fluorescence following, Cre-mediated recombination in widespread cell and tissue types."

  • Erbb2tm8(Erbb2)Mul ( Mus musculus )

  • FcRg-/- ( Mus musculus )

  • FOXP3-GFP ( Mus musculus )

    "An IRES-EGFP cassette and a floxed cre-neo autodeleter casstte were inserted into exon 11, which lies in the downstream untranslated region. Passage through the male germ line-derived ES cells resulted in deletion of the cre-neo autodeleter cassette. The presence of the EGFP cassette does not interfer with expression of the gene locus. EGFP expression occurs in Foxp3+ regulatory T cells."

  • FSP1-CreER34, mT/mG ( Mus musculus )

    "These mT/mG mice are useful as a Cre reporter strain; expressing red fluorescence prior to, and green fluorescence following, Cre-mediated recombination in widespread cell and tissue types."

  • Fvb/n ( Mus musculus )

  • IL10-GFP ( Mus musculus )

    "This reporter strain may be used to detect and monitor cells committed to interleukin 10 (IL10) production. Green fluorescent protein knocked into the gene faithfully recapitulates normal expression patterns but is preferentially observed in some populations of the intestinal tissue. Expression assayed by fluorescent-activated cell sorting (FACS) has been detected after activation in macrophages and dendritic cells as well as intraintestinal lymphocytes and lamina propria lymphocytes. Targeted allele expression is slightly reduced, as compared to wild-type."

  • IL4-GFP ( Mus musculus )

  • IL4Ra -/- ( Mus musculus )

  • Ink4a/Arf flox ( Mus musculus )

    "Exons 2 and 3 were left flanked by single loxP sites after an frt-flanked neo cassette was excised from intron 3 via FLP-mediated recombination."

  • JH-/- ( Mus musculus )

  • K14-HPV16 ( Mus musculus )

    "The transgene comprises the entire early coding sequence from wild-type human papillomavirus 16 (HPV16), extending from nucleotide (nt) 97 through nt 6152, flanked upstream by approximately 2 kilobases of DNA including the promoter/enhancer of the human keratin 14 (epidermolysis bullosa simplex, Dowling-Meara, Koebner) gene and downstream by 500 base pairs derived from the 3' untranslated sequence of the same gene, including its polyadenylation signal. The keratin 14 promoter drives expression of the transgene in basal cells of the squamous epithelium."

  • K14-HPV16 CD4-/- ( Mus musculus )

  • K14-HPV16 CD4-/-CD8-/- ( Mus musculus )

  • K14-HPV16 CD8-/- ( Mus musculus )

  • K14-HPV16/Beta actin GFP ( Mus musculus )

  • K14-HPV16/C5arI -/- ( Mus musculus )

  • K14-HPV16/C5arI -/- FcRg-/- ( Mus musculus )

  • K14-HPV16/CatC-/- ( Mus musculus )

  • K14-HPV16/FcRg-/- ( Mus musculus )

  • K14-HPV16/JH-/- ( Mus musculus )

  • K14-HPV16/Tnf tm1Gkl 1 ( Mus musculus )

  • K14-HPV16/uPA-/- ( Mus musculus )

  • Mex-TAg ( Mus musculus )

  • MMTV-lpa3 ( Mus musculus )

  • MMTV-Luciferase ( Mus musculus )

  • MMTV-PyMT ( Mus musculus )

  • MMTV-PyMT Tie2-GFP ( Mus musculus )

  • MMTV-PyMT-Batf3-/- ( Mus musculus )

  • MMTV-PyMT-IL4-GFP ( Mus musculus )

  • MMTV-PyMT-mCherry-OVA ( Mus musculus )

    mCherry-ova is unpublished transgenic. The construct inserted is the PyMT transgene along the same transcript as mCherry and ovalbumin, all driven by the MMTV promoter.

  • MMTV-PyMT-mCherry-OVA/cfms-GFP ( Mus musculus )

    mCherry-ova is unpublished transgenic. The construct inserted is the PyMT transgene along the same transcript as mCherry and ovalbumin, all driven by the MMTV promoter.

  • MMTV-PyMT/Arginase-YFP ( Mus musculus )

  • MMTV-PyMT/Beta actin GFP ( Mus musculus )

  • MMTV-PyMT/cfms-GFP ( Mus musculus )

  • MMTV-PyMT/FOXP3-GFP ( Mus musculus )

  • MMTV-PyMT/IL10-GFP ( Mus musculus )

  • MMTV-PyMT/IL4Ra ( Mus musculus )

  • MMTV-PyMT/Nur77-GFP ( Mus musculus )

  • Nf 2 +/- cfms-GFP ( Mus musculus )

  • Nf 2+/- ( Mus musculus )

  • Nur77 ( Mus musculus )

  • OT-I/Beta actin CFP ( Mus musculus )

  • OT-I/Beta actin GFP ( Mus musculus )

  • OT-II/Beta actin CFP ( Mus musculus )

  • OT-II/Beta actin GFP ( Mus musculus )

  • POET ( Mus musculus )

    A high mOVA-producing line.

  • Ptf1a[tm1.1(cre)Cvw] ( Mus musculus )

  • Tg(MMTV-cre)7Mul ( Mus musculus )

  • Tie2-GFP ( Mus musculus )

  • Tnf tm1Gkl 1 -/- ( Mus musculus )

  • uPA-/- ( Mus musculus )

  • YetCre13 ( Mus musculus )

    "The YetCre-13 allele has a bicistronic IRES-YFP-Cre reporter/recombinase cassette inserted between the translational stop codon and the 3' UTR of the interleukin 13 (Il13) gene; thus expressing the endogenous gene and the YFP-Cre fusion protein (yellow fluorescent protein/humanized [mammalian codon-optimized] Cre recombinase). These YetCre-13 mice may be useful for fluorescent reporter and/or Cre-lox studies of IL-13-expressing cells in type 2 immunity/host response to allergens and parasitic helminths. They may also be useful to track lineage-negative innate type 2 helper cells (Ih2 cells) that arise during type 2 immunity or in response to IL-25 and IL-33."


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Last updated: 2013-04-09T15:48:33.059-05:00

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