Cancer and Context

癌症与背景

基本信息

  • 批准号:
    9982211
  • 负责人:
  • 金额:
    $ 93.99万
  • 依托单位:
  • 依托单位国家:
    美国
  • 项目类别:
  • 财政年份:
    2015
  • 资助国家:
    美国
  • 起止时间:
    2015-08-01 至 2022-07-31
  • 项目状态:
    已结题

项目摘要

 DESCRIPTION (provided by applicant): Although cancer is caused by mutations in tumor suppressor and promoter genes, it is also a disease of cell behavior and cell context. The same mutations that cause transformation in one cell type are often tolerated in others and, conversely, wild type cells can phenocopy tumorigenic cells in a permissive environment. The reasons are not fully understood. However, one likely explanation is that homeostatic mechanisms in epithelia can suppress the tumorigenic phenotype. For example, if normal epithelial cells suppress proliferation of their neighbors, transformed cells might be unable to express their oncogenic potential unless they escape from the epithelial environment. We argue, therefore, that beyond the identification and cataloguing of mutations in human cancers, there is a pressing need to understand how cell context determines the responses to such mutations. Since most human cancers arise from epithelial cells or their progenitors, our over-arching goal is to determine how epithelial homeostatic mechanisms can suppress tumorigenesis, with a focus on breast cancer. We propose that transformed cells need to escape the suppressive signals generated by normal epithelial neighbors and that this is a key initiating step in tumorigenesis. How cells escape the epithelium and proliferate in ectopic sites is central to understanding cancer initiation and metastasis. Our previous studies, particularly over the last decade, have equipped us to make unique contributions to this field of cancer research. We developed a lentiviral transduction/stem cell transplantation method to study gene function in mouse mammary gland development and cancer, and developed a human organotypic culture system for breast organoids that matches in situ structures at the cellular and tissue levels with very high fidelity. These approaches, together with CRISPR gene editing technology, will be used to determine the roles of mitotic spindle mis-orientation in cancer initiation, tumor suppression by myoepithelial cells, and the subversion of mechanical tension signaling by breast cancer cells. We also collaborate with an experimental systems biologist who will use global, high-content analysis of signaling networks coupled with computational analysis, to identify key nodes that respond to homeostatic mechanisms in mammary epithelial cells. We predict that tumor initiation involves the constitutive activation of these nodes. Overal, this proposal brings multiple, state-of-the-art approaches to bear on a fundamental problem in cancer research, to understand how cell context determines phenotype.


项目成果

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IAN G MACARA其他文献

IAN G MACARA的其他文献

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{{ truncateString('IAN G MACARA', 18)}}的其他基金

Cancer and Context
癌症与背景
  • 批准号:
    10221624
  • 财政年份:
    2015
  • 资助金额:
    $ 93.99万
  • 项目类别:
Cancer and Context
癌症与背景
  • 批准号:
    8955798
  • 财政年份:
    2015
  • 资助金额:
    $ 93.99万
  • 项目类别:
Cancer and Context
癌症与背景
  • 批准号:
    9315574
  • 财政年份:
    2015
  • 资助金额:
    $ 93.99万
  • 项目类别:
Cancer and Context
癌症与背景
  • 批准号:
    9751082
  • 财政年份:
    2015
  • 资助金额:
    $ 93.99万
  • 项目类别:
Mammary Gland Morphogenesis and Breast Cancer
乳腺形态发生与乳腺癌
  • 批准号:
    8446157
  • 财政年份:
    2010
  • 资助金额:
    $ 93.99万
  • 项目类别:
Mammary Gland Morphogenesis and Breast Cancer
乳腺形态发生与乳腺癌
  • 批准号:
    8215927
  • 财政年份:
    2010
  • 资助金额:
    $ 93.99万
  • 项目类别:
Mammary Gland Morphogenesis and Breast Cancer
乳腺形态发生与乳腺癌
  • 批准号:
    8637935
  • 财政年份:
    2010
  • 资助金额:
    $ 93.99万
  • 项目类别:
Mammary Gland Morphogenesis and Breast Cancer
乳腺形态发生与乳腺癌
  • 批准号:
    8135217
  • 财政年份:
    2010
  • 资助金额:
    $ 93.99万
  • 项目类别:
Mammary Gland Morphogenesis and Breast Cancer
乳腺形态发生与乳腺癌
  • 批准号:
    7982626
  • 财政年份:
    2010
  • 资助金额:
    $ 93.99万
  • 项目类别:
MECHANISMS OF CELL POLARITY ESTABLISHMENT
细胞极性建立机制
  • 批准号:
    7932406
  • 财政年份:
    2009
  • 资助金额:
    $ 93.99万
  • 项目类别:

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