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Filter Results:

Year

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Author

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Search Results for all work with filters:

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Work 1-3 of 3

Sorted by relevance

Article

The tyrosine phosphatase Shp-2 confers resistance to colonic inflammation by driving goblet cell function and crypt regeneration

by Jessica Gagne-Sansfacon; Ariane Langlois; Marie-Josee Langlois; Genevieve Coulombe; Sarah Tremblay; Vanessa Vaillancourt-Lavigueur; Cheng-Kui Qu; Alfredo Menendez; Nathalie Rivard

2019

Subjects
  • Health Sciences, Oncology
  • Health Sciences, Pathology
  • Biology, Cell
  • File Download
  • View Abstract

Abstract:Close

The Src homology-2 domain-containing tyrosine phosphatase 2 (SHP-2) regulates many cellular processes, including proliferation, differentiation and survival. Polymorphisms in the gene encoding SHP-2 are associated with an increased susceptibility to develop ulcerative colitis. We recently reported that intestinal epithelial cell (IEC)-specific deletion of Shp-2 in mice (Shp-2 IEC-KO ) leads to chronic colitis and colitis-associated cancer. This suggests that SHP-2-dependent signaling protects the colonic epithelium against inflammation and colitis-associated cancer development. To verify this hypothesis, we generated mice expressing the Shp-2 E76K activated form specifically in IEC. Our results showed that sustained Shp-2 activation in IEC increased intestine and crypt length, correlating with increased cell proliferation and migration. Crypt regeneration capacity was also markedly enhanced, as revealed by ex vivo organoid culture. Shp-2 activation alters the secretory cell lineage, as evidenced by increased goblet cell numbers and mucus secretion. Notably, these mice also demonstrated elevated ERK signaling in IEC and exhibited resistance against both chemical- and Citrobacter rodentium-induced colitis. In contrast, mice with IEC-specific Shp-2 deletion displayed reduced ERK signaling and rapidly developed chronic colitis. Remarkably, expression of an activated form of Braf in Shp-2-deficient mice restored ERK activation, goblet cell production and prevented colitis. Altogether, our results indicate that chronic activation of Shp-2/ERK signaling in the colonic epithelium confers resistance to mucosal erosion and colitis. © 2018 The Authors. The Journal of Pathology published by John Wiley & Sons Ltd on behalf of Pathological Society of Great Britain and Ireland.

Article

The molecular basis of breast cancer pathological phenotypes

by Yujing J Heng; Susan C Lester; Gary MK Tse; Rachel E Factor; Kimberly H Allison; Laura C Collins; Yunn-Yi Chen; Kristin C Jensen; Nicole B Johnson; Jong Cheol Jeong; Rahi Punjabi; Sandra J Shin; Kamaljeet Singh; Gregor Krings; David A Eberhard; Puay Hoon Tan; Konstanty Korski; Frederic M Waldman; David Andrew Gutman; Melinda Sanders; Jorge S Reis-Filho; Sydney R Flanagan; Deena MA Gendoo; Gregory M Chen; Benjamin Haibe-Kains; Giovanni Ciriello; Katherine A Hoadley; Charles M Perou; Andrew H Beck

2017

Subjects
  • Health Sciences, Oncology
  • Health Sciences, Pathology
  • File Download
  • View Abstract

Abstract:Close

The histopathological evaluation of morphological features in breast tumours provides prognostic information to guide therapy. Adjunct molecular analyses provide further diagnostic, prognostic and predictive information. However, there is limited knowledge of the molecular basis of morphological phenotypes in invasive breast cancer. This study integrated genomic, transcriptomic and protein data to provide a comprehensive molecular profiling of morphological features in breast cancer. Fifteen pathologists assessed 850 invasive breast cancer cases from The Cancer Genome Atlas (TCGA). Morphological features were significantly associated with genomic alteration, DNA methylation subtype, PAM50 and microRNA subtypes, proliferation scores, gene expression and/or reverse-phase protein assay subtype. Marked nuclear pleomorphism, necrosis, inflammation and a high mitotic count were associated with the basal-like subtype, and had a similar molecular basis. Omics-based signatures were constructed to predict morphological features. The association of morphology transcriptome signatures with overall survival in oestrogen receptor (ER)-positive and ER-negative breast cancer was first assessed by use of the Molecular Taxonomy of Breast C ancer International Consortium (METABRIC) dataset; signatures that remained prognostic in the METABRIC multivariate analysis were further evaluated in five additional datasets. The transcriptomic signature of poorly differentiated epithelial tubules was prognostic in ER-positive breast cancer. No signature was prognostic in ER-negative breast cancer. This study provided new insights into the molecular basis of breast cancer morphological phenotypes. The integration of morphological with molecular data has the potential to refine breast cancer classification, predict response to therapy, enhance our understanding of breast cancer biology, and improve clinical management. This work is publicly accessible at www.dx.ai/tcga_breast.

Article

PanCancer insights from The Cancer Genome Atlas: the pathologist's perspective

by Lee Cooper; Elizabeth G Demicco; Joel H Saltz; Reid T Powell; Arvind Rao; Alexander J Lazar

2018

Subjects
  • Health Sciences, Oncology
  • Health Sciences, Pathology
  • File Download
  • View Abstract

Abstract:Close

The Cancer Genome Atlas (TCGA) represents one of several international consortia dedicated to performing comprehensive genomic and epigenomic analyses of selected tumour types to advance our understanding of disease and provide an open-access resource for worldwide cancer research. Thirty-three tumour types (selected by histology or tissue of origin, to include both common and rare diseases), comprising >11 000 specimens, were subjected to DNA sequencing, copy number and methylation analysis, and transcriptomic, proteomic and histological evaluation. Each cancer type was analysed individually to identify tissue-specific alterations, and make correlations across different molecular platforms. The final dataset was then normalized and combined for the PanCancer Initiative, which seeks to identify commonalities across different cancer types or cells of origin/lineage, or within anatomically or morphologically related groups. An important resource generated along with the rich molecular studies is an extensive digital pathology slide archive, composed of frozen section tissue directly related to the tissues analysed as part of TCGA, and representative formalin-fixed paraffin-embedded, haematoxylin and eosin (H&E)-stained diagnostic slides. These H&E image resources have primarily been used to verify diagnoses and histological subtypes with some limited extraction of standard pathological variables such as mitotic activity, grade, and lymphocytic infiltrates. Largely overlooked is the richness of these scanned images for more sophisticated feature extraction approaches coupled with machine learning, and ultimately correlation with molecular features and clinical endpoints. Here, we document initial attempts to exploit TCGA imaging archives, and describe some of the tools, and the rapidly evolving image analysis/feature extraction landscape. Our hope is to inform, and ultimately inspire and challenge, the pathology and cancer research communities to exploit these imaging resources so that the full potential of this integral platform of TCGA can be used to complement and enhance the insightful integrated analyses from the genomic and epigenomic platforms. Copyright © 2017 Pathological Society of Great Britain and Ireland. Published by John Wiley & Sons, Ltd.
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