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Analysis of persistence and antibiotic response in colorectal cancer

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15 Dec 2017: Vol. 358, Issue 6369, pp. 1443-1448 DOI: 10.1126/science.aal5240
Susan Bullman
Dana-Farber Cancer Institute, Harvard Medical School, Boston, MA 02115, USA. Broad Institute of MIT and Harvard, Cambridge, MA 02142, USA.
Chandra S. Pedamallu
Dana-Farber Cancer Institute, Harvard Medical School, Boston, MA 02115, USA. Broad Institute of MIT and Harvard, Cambridge, MA 02142, USA.
Ewa Sicinska
Dana-Farber Cancer Institute, Harvard Medical School, Boston, MA 02115, USA.
Thomas E. Clancy
Brigham and Women’s Hospital, Harvard Medical School, Boston, MA 02115, USA.
Xiaoyang Zhang
Dana-Farber Cancer Institute, Harvard Medical School, Boston, MA 02115, USA. Broad Institute of MIT and Harvard, Cambridge, MA 02142, USA.
Diana Cai
Dana-Farber Cancer Institute, Harvard Medical School, Boston, MA 02115, USA. Broad Institute of MIT and Harvard, Cambridge, MA 02142, USA.
Donna Neuberg
Dana-Farber Cancer Institute, Harvard Medical School, Boston, MA 02115, USA.
Katherine Huang
Broad Institute of MIT and Harvard, Cambridge, MA 02142, USA.
Fatima Guevara
Dana-Farber Cancer Institute, Harvard Medical School, Boston, MA 02115, USA.
Timothy Nelson
Dana-Farber Cancer Institute, Harvard Medical School, Boston, MA 02115, USA.
Otari Chipashvili
Dana-Farber Cancer Institute, Harvard Medical School, Boston, MA 02115, USA.
Timothy Hagan
Dana-Farber Cancer Institute, Harvard Medical School, Boston, MA 02115, USA.
Mark Walker
Broad Institute of MIT and Harvard, Cambridge, MA 02142, USA.
Aruna Ramachandran
Dana-Farber Cancer Institute, Harvard Medical School, Boston, MA 02115, USA. Broad Institute of MIT and Harvard, Cambridge, MA 02142, USA.
Begoña Diosdado
Dana-Farber Cancer Institute, Harvard Medical School, Boston, MA 02115, USA. Broad Institute of MIT and Harvard, Cambridge, MA 02142, USA.
Garazi Serna
Vall d’Hebron University Hospital, Vall d’Hebron Institute of Oncology, Barcelona, CIBERONC, Universitat Autònoma de Barcelona, Spain.
Nuria Mulet
Vall d’Hebron University Hospital, Vall d’Hebron Institute of Oncology, Barcelona, CIBERONC, Universitat Autònoma de Barcelona, Spain.
Stefania Landolfi
Vall d’Hebron University Hospital, Vall d’Hebron Institute of Oncology, Barcelona, CIBERONC, Universitat Autònoma de Barcelona, Spain.
Santiago Ramon y Cajal
Vall d’Hebron University Hospital, Vall d’Hebron Institute of Oncology, Barcelona, CIBERONC, Universitat Autònoma de Barcelona, Spain.
Roberta Fasani
Vall d’Hebron University Hospital, Vall d’Hebron Institute of Oncology, Barcelona, CIBERONC, Universitat Autònoma de Barcelona, Spain.
Andrew J. Aguirre
Dana-Farber Cancer Institute, Harvard Medical School, Boston, MA 02115, USA. Broad Institute of MIT and Harvard, Cambridge, MA 02142, USA. Brigham and Women’s Hospital, Harvard Medical School, Boston, MA 02115, USA.
Kimmie Ng
Dana-Farber Cancer Institute, Harvard Medical School, Boston, MA 02115, USA.
Elena Élez
Vall d’Hebron University Hospital, Vall d’Hebron Institute of Oncology, Barcelona, CIBERONC, Universitat Autònoma de Barcelona, Spain.
Shuji Ogino
Dana-Farber Cancer Institute, Harvard Medical School, Boston, MA 02115, USA. Brigham and Women’s Hospital, Harvard Medical School, Boston, MA 02115, USA. Harvard T.H. Chan School of Public Health, Boston, MA 02115, USA.
Josep Tabernero
Vall d’Hebron University Hospital, Vall d’Hebron Institute of Oncology, Barcelona, CIBERONC, Universitat Autònoma de Barcelona, Spain.
Charles S. Fuchs
Yale Cancer Center, Yale School of Medicine, New Haven, CT 06520, USA.
William C. Hahn
Dana-Farber Cancer Institute, Harvard Medical School, Boston, MA 02115, USA. Broad Institute of MIT and Harvard, Cambridge, MA 02142, USA. Brigham and Women’s Hospital, Harvard Medical School, Boston, MA 02115, USA.
Paolo Nuciforo
Vall d’Hebron University Hospital, Vall d’Hebron Institute of Oncology, Barcelona, CIBERONC, Universitat Autònoma de Barcelona, Spain.
Matthew Meyerson
Dana-Farber Cancer Institute, Harvard Medical School, Boston, MA 02115, USA. Broad Institute of MIT and Harvard, Cambridge, MA 02142, USA. Brigham and Women’s Hospital, Harvard Medical School, Boston, MA 02115, USA.

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Bacteria go the distance in cancer

The bacterial species is associated with a subset of human colorectal cancers, but its role in tumorigenesis is unclear. Studying patient samples, Bullman found that and certain co-occurring bacteria were present not only in primary tumors but also in distant metastases. Preliminary evidence suggests that the bacterium is localized primarily within the metastatic cancer cells rather than in the stroma. Antibiotic treatment of mice carrying xenografts of –positive human colorectal cancer slowed tumor growth, consistent with a causal role for the bacterium in tumorigenesis.

, this issue p. 1443

Abstract

Colorectal cancers comprise a complex mixture of malignant cells, nontransformed cells, and microorganisms. is among the most prevalent bacterial species in colorectal cancer tissues. Here we show that colonization of human colorectal cancers with and its associated microbiome—including , , and species—is maintained in distal metastases, demonstrating microbiome stability between paired primary and metastatic tumors. In situ hybridization analysis revealed that is predominantly associated with cancer cells in the metastatic lesions. Mouse xenografts of human primary colorectal adenocarcinomas were found to retain viable and its associated microbiome through successive passages. Treatment of mice bearing a colon cancer xenograft with the antibiotic metronidazole reduced load, cancer cell proliferation, and overall tumor growth. These observations argue for further investigation of antimicrobial interventions as a potential treatment for patients with -associated colorectal cancer.

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Vol 358, Issue 636915 December 2017

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Analysis of persistence and antibiotic response in colorectal cancer

By Susan Bullman , Chandra S. Pedamallu , Ewa Sicinska , Thomas E. Clancy , Xiaoyang Zhang , Diana Cai , Donna Neuberg , Katherine Huang , Fatima Guevara , Timothy Nelson , Otari Chipashvili , Timothy Hagan , Mark Walker , Aruna Ramachandran , Begoña Diosdado , Garazi Serna , Nuria Mulet , Stefania Landolfi , Santiago Ramon y Cajal , Roberta Fasani , Andrew J. Aguirre , Kimmie Ng , Elena Élez , Shuji Ogino , Josep Tabernero , Charles S. Fuchs , William C. Hahn , Paolo Nuciforo , Matthew Meyerson

At least three organisms have followed this last strategy, the virus SV40 and two bacteria, Brucella abortus ( Pizarro-Cerda et al., 1998 ) and L. pneumophila ( Cheapest Cheap 2018 7 For All Mankind Woman Josefina Cropped Distressed Boyfriend Jeans Light Denim Size 26 7 For All Mankind Cheap Countdown Package e5ZbJnAdc
). In the case of SV40, this virus is taken up in small uncoated vesicles or caveoli that become continuous with a complex tubular network of smooth membranes generated as extensions of the ER ( Pelkmans et al., 2001 ; Kartenbeck et al., 1989 ). In the case of Legionella pneumophila , the causative agent of Legionnaires’ disease, the bacterium enters the cell in a phagosome that becomes surrounded by vesicles and mitochondria ( Vince Woman Smocked Floralprint Silk Crepe De Chine Shirt Cream Size M Vince Sale Fake Clearance Largest Supplier Low Cost Cheap Online 7e4Xg6n4T
). This vacuole provides an intracellular sanctuary for L. pneumophila where these bacteria are protected from lysosomal degradation. This remarkable behavior of L. pneumophila , as first described by Horwitz ( Fast Delivery Sale Online Joie Woman Offtheshoulder Embroidered Cottongauze Top Offwhite Size M Joie Cheap Looking For Cheap Sale Outlet Store bOcAf
), severely puzzled us. By what mechanisms does L. pneumophila induce vesicles to surround the phagosome? Do they protect it from fusion with lysosomes, and how does a former plasma membrane become studded with ribosomes? After all, the lipid composition and thickness of the plasma membrane and its unusual protein composition is very different from the ER. Specifically, the plasma membrane is rich in cholesterol, in amounts roughly equimolar to the sum of all the phospholipids in the membrane, and sphingolipids (such sphingomyelin and glycolipids), whereas the ER membranes lack or have extremely low concentrations of both. This results in the endoplasmic reticulum membrane being thinner than the plasma membrane, a feature that may influence differences in accumulation of transmembrane proteins ( Bretscher and Munro, 1993 ).

In this current study, we amplify and extend the morphological description of Horwitz ( Horwitz, 1983 ), revealing several previously undescribed phenomena associated with the establishment of the L. pneumophila phagosome. More specifically, we illustrate morphologically the existence of physical connections between the ER vesicles and mitochondria, and the L. pneumophila phagosome. Furthermore, we show that the thickness of the phagosomal membrane containing L. pneumophila changes to resemble an ER membrane. This is followed some hours later by the attachment of ribosomes directly to the ‘newly thinned’ phagosomal membrane. We then describe the behavior of five L. pneumophila mutants that amplify our morphological description of the wild-type L. pneumophila by emphasizing some of the changes that occur as L. pneumophila adapts to life within the macrophage. Overall, the results presented in this study support the idea that L. pneumophila subverts normal cellular processes to protect itself from proteolysis. Thus, studying the interaction of L. pneumophila with its host cell gives us the opportunity to understand additional features of basic cell biological phenomena that occur in eukaryotic cells. Study of these basic processes, which include the attachment of ER vesicles to the plasma membrane and changes in membrane composition, are some of our goals for the future. Ultimately we must determine why uninfected host macrophages behave in this fashion and how pathogens orchestrate this behavior. This report then, we hope, will stimulate others to investigate what we assume is so far an undescribed or poorly described pathway in eukaryotic cells in which the plasma membrane is converted to the ER.

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