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Tumor Cell Clusters Form Intercellul...

Wrenn, Emma.

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Tumor Cell Clusters Form Intercellular Nanolumina Which Promote Collective Metastasis Via Epigen Accumulation.

紀錄類型:	書目-電子資源 : Monograph/item
正題名/作者:	Tumor Cell Clusters Form Intercellular Nanolumina Which Promote Collective Metastasis Via Epigen Accumulation./
作者:	Wrenn, Emma.
出版者:	Ann Arbor : ProQuest Dissertations & Theses, : 2021,
面頁冊數:	222 p.
附註:	Source: Dissertations Abstracts International, Volume: 82-11, Section: B.
Contained By:	Dissertations Abstracts International82-11B.
標題:	Oncology. -
電子資源:	https://pqdd.sinica.edu.tw/twdaoapp/servlet/advanced?query=28319425
ISBN:	9798728229872

Tumor Cell Clusters Form Intercellular Nanolumina Which Promote Collective Metastasis Via Epigen Accumulation.
Wrenn, Emma.

Tumor Cell Clusters Form Intercellular Nanolumina Which Promote Collective Metastasis Via Epigen Accumulation. - Ann Arbor : ProQuest Dissertations & Theses, 2021 - 222 p.

Source: Dissertations Abstracts International, Volume: 82-11, Section: B.

Thesis (Ph.D.)--University of Washington, 2021.

This item must not be sold to any third party vendors.

During development and wound healing, communities of epithelial cells can accomplish dramatic cellular rearrangements and tissue remodeling through coordinated, intercellular signaling. Recent studies have demonstrated that when tumor cells remain organized in multicellular cohorts during metastasis, they have a greatly increased likelihood of forming secondary tumors compared to single cells. These studies support the hypothesis that cancer cells may accomplish metastatic colonization through similar collective or cooperative mechanisms. However, specific molecular properties underlying the high metastatic efficiency of tumor cell clusters remain largely unknown. The purpose of my doctoral research was to identify such mechanisms, with the goal of finding new therapeutic targets against collective metastasis. To address this question, I developed techniques to manipulate single and clustered tumor cells and perform downstream molecular analyses. I devised a method of suspension organoid culture which allowed me to propagate and transduce large quantities of tumor cell clusters from the MMTV-PyMT mouse model of breast cancer for ex vivo and in vivo analyses. Using this system, I found that aggregation of single tumor cells into clusters generates >100-fold increases in macrometastasis formation (normalized to injected cell number). RNA-sequencing throughout tumor cell aggregation revealed that clustering strongly induces the expression of EGFR-related genes, including EGFR ligands. The most cluster-upregulated gene was Epgn (protein name: epigen), the most recently discovered EGFR ligand. Notably, Epgn knockdown profoundly reduced the outgrowth of lung metastases formed by injected tumor cell clusters. To better understand epigen's function in tumor cell clusters, I began by assessing its localization. Epigen was predominantly localized to cell-cell boundaries within tumor cell clusters. Super-resolution and electron microscopy showed that epigen frequently localized within intercellular spaces between cells. These cavities, which we refer to as "nanolumina", are lined with microvilli-like protrusions and bounded by cell-cell junctions. Nanolumenal junctions reduce the diffusion of epigen into the local microenvironment, allowing clusters to accumulate high concentrations of epigen between cells to facilitate potent intercellular growth signaling. Cell clusters from the aggressive basal-like 2 subset of human triple negative breast cancer also highly expressed EPGN and contained extensive intercellular nanolumina. Importantly, epigen suppression likewise reduced metastatic outgrowth by these clusters, supporting the human disease relevance of this signaling modality.

ISBN: 9798728229872Subjects--Topical Terms:

751006
Oncology.
Subjects--Index Terms:

Breast cancer

Tumor Cell Clusters Form Intercellular Nanolumina Which Promote Collective Metastasis Via Epigen Accumulation.
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