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The Association of Tissue Architecture Changes & Metabolic Heterogeneity in Epithelial Cancer Cells = = L'association des Modifications de L'architecture Tissulaire Et de L'heterogeneite Metabolique Dans Les Cellules Epitheliales Cancereuses.

紀錄類型:	書目-電子資源 : Monograph/item
正題名/作者:	The Association of Tissue Architecture Changes & Metabolic Heterogeneity in Epithelial Cancer Cells =/
其他題名:	L'association des Modifications de L'architecture Tissulaire Et de L'heterogeneite Metabolique Dans Les Cellules Epitheliales Cancereuses.
其他題名:	Association des Modifications de L'architecture Tissulaire Et de L'heterogeneite Metabolique Dans Les Cellules Epitheliales Cancereuses.
作者:	Al-Masri, Maia.
面頁冊數:	1 online resource (172 pages)
附註:	Source: Dissertations Abstracts International, Volume: 84-05, Section: B.
Contained By:	Dissertations Abstracts International84-05B.
標題:	Mechanical properties. -
電子資源:	http://pqdd.sinica.edu.tw/twdaoapp/servlet/advanced?query=30157885click for full text (PQDT)
ISBN:	9798352987162

The Association of Tissue Architecture Changes & Metabolic Heterogeneity in Epithelial Cancer Cells = = L'association des Modifications de L'architecture Tissulaire Et de L'heterogeneite Metabolique Dans Les Cellules Epitheliales Cancereuses.
Al-Masri, Maia.

The Association of Tissue Architecture Changes & Metabolic Heterogeneity in Epithelial Cancer Cells =L'association des Modifications de L'architecture Tissulaire Et de L'heterogeneite Metabolique Dans Les Cellules Epitheliales Cancereuses.Association des Modifications de L'architecture Tissulaire Et de L'heterogeneite Metabolique Dans Les Cellules Epitheliales Cancereuses. - 1 online resource (172 pages)

Source: Dissertations Abstracts International, Volume: 84-05, Section: B.

Thesis (Ph.D.)--McGill University (Canada), 2022.

Includes bibliographical references

Epithelial cells interact to form architecturally organized structures in tissues, with strict control of motility, survival, proliferation and metabolic signaling, each of which is altered during cancer progression. Loss of epithelial organization and tissue architecture is associated with the acquisition of a malignant phenotype during breast cancer initiation and throughout its progression. The changes in tissue architecture that accompany the development of breast cancer is an excellent model, that develops through architecturally different preinvasive stages that include benign lesions such as ductal carcinoma in situ (DCIS), which are risk factors for the development of invasive disease (IDC). Currently, DCIS accounts for 20% of breast cancer diagnoses, and about half are expected to progress to IDC. No clear biomarkers and histological features exist to distinguish DCIS that will or will not progress to invasive disease.Metabolic plasticity enables cancer cells to switch between glycolysis and oxidative phosphorylation to adapt to changing conditions during cancer progression, whereas metabolic dependencies limit plasticity. However, understanding how metabolic programs change during cancer progression and the influence of the architectural and mechanical environments on metabolic dependency and plasticity remained to be fully established. Accordingly, to understand a role for the architectural environment in these processes we examined metabolic heterogeneity and dependencies of cancer cells using both in vitro models, cultured in flat (two-dimensional; 2D) and organotypic (three-dimensional; 3D) environments, and an in vivo model. The hypothesis of my thesis is that tissue architecture influences metabolic programs/phenotypes in epithelial cancer cells.I first examined the impact of epithelial architecture on metabolic plasticity using 2D and 3D cultures with diverse epithelial cancer cells. The propagation of cells in flat cultures is technically simple and enables maintenance of long-term exponential growth. However, they lack architectural information that regulates many epithelial cell behaviors, which are thought to be more accurately recapitulated in organotypic cultures whereby cells can more freely associate with the microenvironment on all sides. In contrast, cells in organotypic cultures preserve mechanical cell- ECM interactions and organize into tissue-relevant architectures that regulate signaling and growth. Recent studies have noted metabolic differences between 2D and 3D cultures. In this thesis I show that cancer cells in flat 2D cultures exist in a high energy state (oxidative phosphorylation), are glycolytic, and depend on glucose and glutamine for growth. In contrast, cells in organotypic culture exhibit lower energy and glycolysis, with extensive metabolic plasticity to maintain growth during glucose or amino acid deprivation. Furthermore, our metabolomic and gene-expression data indicate that the architectural environment strongly influences signaling and metabolic pathways related to amino acid metabolism. Expression of KRASG12V in organotypic cells drives glucose dependence, however cells retain metabolic plasticity to glutamine deprivation. Finally, these data reveal that mechanical properties control metabolic plasticity, which correlates with canonical Wnt signaling.Next, I used an in vivo xenograft model of breast cancer progression and examined the heterogeneity of key metabolic enzymes. Accordingly, the mouse intra-ductal (MIND) xenograft model was established, in which ER-positive MCF7 human breast cancer cells are injected into the mouse milk duct system.

Electronic reproduction.
Ann Arbor, Mich. :
ProQuest,
2023

Mode of access: World Wide Web

ISBN: 9798352987162Subjects--Topical Terms:

3549505
Mechanical properties.
Index Terms--Genre/Form:

542853
Electronic books.

The Association of Tissue Architecture Changes & Metabolic Heterogeneity in Epithelial Cancer Cells = = L'association des Modifications de L'architecture Tissulaire Et de L'heterogeneite Metabolique Dans Les Cellules Epitheliales Cancereuses.
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504 $a Includes bibliographical references
520 $a Epithelial cells interact to form architecturally organized structures in tissues, with strict control of motility, survival, proliferation and metabolic signaling, each of which is altered during cancer progression. Loss of epithelial organization and tissue architecture is associated with the acquisition of a malignant phenotype during breast cancer initiation and throughout its progression. The changes in tissue architecture that accompany the development of breast cancer is an excellent model, that develops through architecturally different preinvasive stages that include benign lesions such as ductal carcinoma in situ (DCIS), which are risk factors for the development of invasive disease (IDC). Currently, DCIS accounts for 20% of breast cancer diagnoses, and about half are expected to progress to IDC. No clear biomarkers and histological features exist to distinguish DCIS that will or will not progress to invasive disease.Metabolic plasticity enables cancer cells to switch between glycolysis and oxidative phosphorylation to adapt to changing conditions during cancer progression, whereas metabolic dependencies limit plasticity. However, understanding how metabolic programs change during cancer progression and the influence of the architectural and mechanical environments on metabolic dependency and plasticity remained to be fully established. Accordingly, to understand a role for the architectural environment in these processes we examined metabolic heterogeneity and dependencies of cancer cells using both in vitro models, cultured in flat (two-dimensional; 2D) and organotypic (three-dimensional; 3D) environments, and an in vivo model. The hypothesis of my thesis is that tissue architecture influences metabolic programs/phenotypes in epithelial cancer cells.I first examined the impact of epithelial architecture on metabolic plasticity using 2D and 3D cultures with diverse epithelial cancer cells. The propagation of cells in flat cultures is technically simple and enables maintenance of long-term exponential growth. However, they lack architectural information that regulates many epithelial cell behaviors, which are thought to be more accurately recapitulated in organotypic cultures whereby cells can more freely associate with the microenvironment on all sides. In contrast, cells in organotypic cultures preserve mechanical cell- ECM interactions and organize into tissue-relevant architectures that regulate signaling and growth. Recent studies have noted metabolic differences between 2D and 3D cultures. In this thesis I show that cancer cells in flat 2D cultures exist in a high energy state (oxidative phosphorylation), are glycolytic, and depend on glucose and glutamine for growth. In contrast, cells in organotypic culture exhibit lower energy and glycolysis, with extensive metabolic plasticity to maintain growth during glucose or amino acid deprivation. Furthermore, our metabolomic and gene-expression data indicate that the architectural environment strongly influences signaling and metabolic pathways related to amino acid metabolism. Expression of KRASG12V in organotypic cells drives glucose dependence, however cells retain metabolic plasticity to glutamine deprivation. Finally, these data reveal that mechanical properties control metabolic plasticity, which correlates with canonical Wnt signaling.Next, I used an in vivo xenograft model of breast cancer progression and examined the heterogeneity of key metabolic enzymes. Accordingly, the mouse intra-ductal (MIND) xenograft model was established, in which ER-positive MCF7 human breast cancer cells are injected into the mouse milk duct system.
520 $a Les cellules epitheliales interagissent pour former des structures organisees architecturalement dans les tissus avec un controle strict de la motilite, survie, proliferation et signalisation metabolique, chacun des aspects etant altere au cours de la progression du cancer. Lors de l'initiation du cancer du sein et tout au long de sa progression, la perte de l'organisation epitheliale et de l'architecture tissulaire est associee a l'acquisition d'un phenotype maligne. Les changements de l'architecture tissulaire qui accompagnent le developpement du cancer du sein sont un excellent modele qui se developpe a travers des etapes preinvasives architecturalement differentes, incluant des lesions benignes, comme le carcinome canalaire in situ (CCIS) ; qui sont des facteurs de risque pour le developpement de carcinomes invasifs (CCI). Presentement, le CCIS represente 20 % des diagnostics de cancer du sein, et seulement environ la moitie deviendra CCI. Il n'existe pas de biomarqueurs ni de caracteristiques histologiques clairs pour distinguer les CCIS qui evolueront ou non vers une maladie invasive.La plasticite metabolique permet aux cellules cancereuses de changer entre la glycolyse et la phosphorylation oxydative pour s'adapter aux differentes conditions due a la progression du cancer. Pour leurs parts, les dependances metaboliques limitent la plasticite metabolique. L'evolution des programmes metaboliques durant la progression du cancer et l'influence de l'environnement architectural et mecanique sur la dependance metabolique et la plasticite restent a etablir. Pour comprendre le role de l'environnement architectural dans ces processus, nous avons examine l'heterogeneite metabolique et les dependances des cellules cancereuses en utilisant a la fois des modeles in vitro cultives dans des environnements plats (bidimensionnels ; 2D) et organotypiques (tridimensionnels ; 3D), et un modele in vivo. L'hypothese de ma est que l'architecture des tissue influence les programmes/phenotypes metaboliques dans les cellules cancereuses epitheliales.J'ai d'abord examine l'impact de l'architecture epitheliale sur la plasticite metabolique en utilisant des cultures 2D et 3D avec diverses cellules epitheliales cancereuses. La propagation des cellules dans les cultures 2D est simple techniquement et permet le maintien d'une croissance exponentielle a long terme. Cependant, ces cellules ne possedent pas les informations architecturales qui regulent plusieurs comportements des cellules epitheliales, et que l'on pense etre plus exactement reproduit dans les cultures organotypiques, puisque dans celles-ci, les cellules peuvent s'associer plus librement au microenvironnement de tous cotes. Les cellules des cultures organotypiques preservent les interactions mecaniques cellule-matrice extracellulaire et s'organisent en architectures pertinentes pour les tissus qui regulent la signalisation et la croissance. Des etudes recentes ont note des differences metaboliques entre les cultures 2D et 3D. Dans cette these, je demontre que les cellules cancereuses dans des cultures 2D plates existent dans un etat energetique eleve (phosphorylation oxydative), sont glycolytiques et dependent du glucose et de la glutamine pour leur croissance. En contrepartie, les cellules en culture organotypique presentent une energie et une glycolyse plus faibles et une grande plasticite metabolique qui leurs permettent de maintenir une croissance pendant un manque de glucose ou d'acides amines. De plus, nos donnees metaboliques et d'expression genique indiquent que l'environnement architectural influence fortement la signalisation et les voies metaboliques liees au metabolisme des acides amines.
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