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1.
Oncogenesis ; 13(1): 28, 2024 Jul 26.
Artigo em Inglês | MEDLINE | ID: mdl-39060237

RESUMO

Adult tissues set the scene for a continuous battle between cells, where a comparison of cellular fitness results in the elimination of weaker "loser" cells. This phenomenon, named cell competition, is beneficial for tissue integrity and homeostasis. In fact, cell competition plays a crucial role in tumor suppression, through elimination of early malignant cells, as part of Epithelial Defense Against Cancer. However, it is increasingly apparent that cell competition doubles as a tumor-promoting mechanism. The comparative nature of cell competition means that mutational background, proliferation rate and polarity all factor in to determine the outcome of these processes. In this review, we explore the intricate and context-dependent involvement of cell competition in homeostasis and regeneration, as well as during initiation and progression of primary and metastasized colorectal cancer. We provide a comprehensive overview of molecular and cellular mechanisms governing cell competition and its parallels with regeneration.

2.
iScience ; 27(5): 109718, 2024 May 17.
Artigo em Inglês | MEDLINE | ID: mdl-38706869

RESUMO

Cell competition plays an instrumental role in quality control during tissue development and homeostasis. Nevertheless, cancer cells can exploit this process for their own proliferative advantage. In our study, we generated mixed murine organoids and microtissues to explore the impact of cell competition on liver metastasis. Unlike competition at the primary site, the initial effect on liver progenitor cells does not involve the induction of apoptosis. Instead, metastatic competition manifests as a multistage process. Initially, liver progenitors undergo compaction, which is followed by cell-cycle arrest, ultimately forcing differentiation. Subsequently, the newly differentiated liver cells exhibit reduced cellular fitness, rendering them more susceptible to outcompetition by intestinal cancer cells. Notably, cancer cells leverage different interactions with different epithelial populations in the liver, using them as scaffolds to facilitate their growth. Consequently, tissue-specific mechanisms of cell competition are fundamental in driving metastatic intestinal cancer.

3.
Nat Commun ; 13(1): 4492, 2022 08 02.
Artigo em Inglês | MEDLINE | ID: mdl-35918345

RESUMO

The small intestine is a rapidly proliferating organ that is maintained by a small population of Lgr5-expressing intestinal stem cells (ISCs). However, several Lgr5-negative ISC populations have been identified, and this remarkable plasticity allows the intestine to rapidly respond to both the local environment and to damage. However, the mediators of such plasticity are still largely unknown. Using intestinal organoids and mouse models, we show that upon ribosome impairment (driven by Rptor deletion, amino acid starvation, or low dose cyclohexamide treatment) ISCs gain an Lgr5-negative, fetal-like identity. This is accompanied by a rewiring of metabolism. Our findings suggest that the ribosome can act as a sensor of nutrient availability, allowing ISCs to respond to the local nutrient environment. Mechanistically, we show that this phenotype requires the activation of ZAKɑ, which in turn activates YAP, via SRC. Together, our data reveals a central role for ribosome dynamics in intestinal stem cells, and identify the activation of ZAKɑ as a critical mediator of stem cell identity.


Assuntos
Mucosa Intestinal , Células-Tronco , Animais , Mucosa Intestinal/metabolismo , Intestino Delgado/metabolismo , Intestinos , Camundongos , Receptores Acoplados a Proteínas G/genética , Receptores Acoplados a Proteínas G/metabolismo , Ribossomos/metabolismo , Células-Tronco/metabolismo
4.
STAR Protoc ; 2(4): 100997, 2021 12 17.
Artigo em Inglês | MEDLINE | ID: mdl-34917977

RESUMO

Cell competition is a mechanism of interaction that dictates cell selection based on differences in cellular fitness. We designed a protocol to generate mixed murine organoids and enteroid monolayers used to study such complex cellular interactions in a mammalian system. This protocol is dedicated to follow the behavior of different cell populations over time, using (time-lapse) microscopy or transcriptome/proteome analysis. For complete details on the use and execution of this protocol, please refer to Krotenberg Garcia et al. (2021).


Assuntos
Comunicação Celular/fisiologia , Organoides/citologia , Técnicas de Cultura de Tecidos/métodos , Animais , Técnicas de Cultura de Células , Células Cultivadas , Camundongos
5.
Cell Rep ; 36(1): 109307, 2021 07 06.
Artigo em Inglês | MEDLINE | ID: mdl-34233177

RESUMO

Competitive cell interactions play a crucial role in quality control during development and homeostasis. Here, we show that cancer cells use such interactions to actively eliminate wild-type intestine cells in enteroid monolayers and organoids. This apoptosis-dependent process boosts proliferation of intestinal cancer cells. The remaining wild-type population activates markers of primitive epithelia and transits to a fetal-like state. Prevention of this cell-state transition avoids elimination of wild-type cells and, importantly, limits the proliferation of cancer cells. Jun N-terminal kinase (JNK) signaling is activated in competing cells and is required for cell-state change and elimination of wild-type cells. Thus, cell competition drives growth of cancer cells by active out-competition of wild-type cells through forced cell death and cell-state change in a JNK-dependent manner.


Assuntos
Carcinogênese/patologia , Intestinos/patologia , Organoides/patologia , Animais , Apoptose , Carcinogênese/metabolismo , Competição entre as Células , Linhagem Celular Tumoral , Feto/patologia , Sistema de Sinalização das MAP Quinases , Masculino , Camundongos Endogâmicos C57BL , Camundongos Transgênicos , Organoides/metabolismo , Receptores Acoplados a Proteínas G/metabolismo , Células-Tronco/metabolismo
6.
Cell Rep ; 32(3): 107937, 2020 07 21.
Artigo em Inglês | MEDLINE | ID: mdl-32698002

RESUMO

Calorie restriction (CR) extends lifespan through several intracellular mechanisms, including increased DNA repair, leading to fewer DNA mutations that cause age-related pathologies. However, it remains unknown how CR acts on mutation retention at the tissue level. Here, we use Cre-mediated DNA recombination of the confetti reporter as proxy for neutral mutations and follow these mutations by intravital microscopy to identify how CR affects retention of mutations in the intestine. We find that CR leads to increased numbers of functional Lgr5+ stem cells that compete for niche occupancy, resulting in slower but stronger stem cell competition. Consequently, stem cells carrying neutral or Apc mutations encounter more wild-type competitors, thus increasing the chance that they get displaced from the niche to get lost over time. Thus, our data show that CR not only affects the acquisition of mutations but also leads to lower retention of mutations in the intestine.


Assuntos
Restrição Calórica , Competição entre as Células , Intestinos/citologia , Mutação/genética , Células-Tronco/citologia , Proteína da Polipose Adenomatosa do Colo/deficiência , Proteína da Polipose Adenomatosa do Colo/metabolismo , Animais , Contagem de Células , Linhagem da Célula , Feminino , Microscopia Intravital , Masculino , Camundongos Endogâmicos C57BL
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