A single dividing cell population with imbalanced fate drives oesophageal tumour growth

Frede, Julia; Greulich, Philip; Nagy, Tibor; Simons, Benjamin D.; Jones, Philip H.

doi:10.1038/ncb3400

Cited by 65 publications

(81 citation statements)

References 62 publications

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“…Previous studies have demonstrated that clonal mutations to noncycling epithelial tissues, such as the skin epidermis or the esophageal epithelium, result in robust cellular competition that can ultimately influence the behavior and fate of their wild-type neighbors (Klein et al, 2010;Alcolea and Jones, 2015;Frede et al, 2016;Murai et al, 2018). To better understand how the Hras mutant cells are integrated into the tissue and whether their integration influences the fate of their wild-type neighbors, we performed revisit imaging of follicles over time.…”

Section: Resultsmentioning

confidence: 99%

Hair follicle regeneration suppresses Ras-driven oncogenic growth

Pineda

Gonzalez

Matte-Martone

et al. 2019

Journal of Cell Biology

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Mutations associated with tumor development in certain tissues can be nontumorigenic in others, yet the mechanisms underlying these different outcomes remains poorly understood. To address this, we targeted an activating Hras mutation to hair follicle stem cells and discovered that Hras mutant cells outcompete wild-type neighbors yet are integrated into clinically normal skin hair follicles. In contrast, targeting the Hras mutation to the upper noncycling region of the skin epithelium leads to benign outgrowths. Follicular Hras mutant cells autonomously and nonautonomously enhance regeneration, which directs mutant cells into continuous tissue cycling to promote integration rather than aberrancy. This follicular tolerance is maintained under additional challenges that promote tumorigenesis in the epidermis, including aging, injury, and a secondary mutation. Thus, the hair follicle possesses a unique, enhanced capacity to integrate and contain Hras mutant cells within both homeostatic and perturbed tissue, demonstrating that in the skin, multiple, distinct mechanisms exist to suppress oncogenic growth.

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Section: Resultsmentioning

confidence: 99%

Hair follicle regeneration suppresses Ras-driven oncogenic growth

Pineda

Gonzalez

Matte-Martone

et al. 2019

Journal of Cell Biology

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“…To track the fate of basal cells, Lrig1-cre mice were crossed with the Rosa26 flConfetti/wt (Confetti) reporter strain which labels cells with one of four possible fluorescent proteins (green, GFP, cyan, CFP, yellow, YFP or red RFP) after recombination ( Fig. S6C-D) 25,26 . In some Cre inducible mouse lines, reporter expressing clones can appear without induction with Tamoxifen.…”

Section: Clonal Dynamics In Esophageal Epitheliummentioning

confidence: 99%

The single-progenitor model as the unifying paradigm of squamous epithelial maintenance

Piedrafita

Kostiou

Wabik

et al. 2019

Preprint

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Adult tissues such as the epidermis of the skin and the epithelium lining the esophagus are continuously turned over throughout life. Cells are shed from the tissue surface and replaced by cell division. Yet, the cellular mechanisms that underpin these tissues homeostasis remain poorly established, having important implications for wound healing and carcinogenesis. Lineage tracing, in which of a cohort of proliferating cells and their descendants are genetically labelled in transgenic mice, has been used to study the fate behavior of the proliferating cells that maintain these tissues. However, based on this technique, distinct mutually irreconcilable models, differing in the implored number and hierarchy of proliferating cell types, have been proposed to explain homeostasis. To elucidate which of these conflicting scenarios should prevail, here we performed cell proliferation assays across multiple body sites in transgenic H2BGFP mouse epidermis and esophagus. Cell-cycle properties were then extracted from the H2BGFP dilution kinetics and adopted in a common analytic approach for a refined analysis of a new lineage-tracing experiment and eight published clonal data sets from esophagus and different skin territories. Our results show H2BGFP dilution profiles remained unimodal over time, indicating the absence of slow-cycling stem cells across all tissues analyzed. We find that despite using diverse genetic labelling approaches, all lineage-tracing data sets are consistent with tissues maintenance by a single population of proliferating cells. The outcome of a given division is unpredictable but, on average the likelihood of producing proliferating and differentiating cells is balanced, ensuring tissue homeostasis. The fate outcomes of sister cells are anticorrelated. We conclude a single cell population maintains squamous epithelial homeostasis.

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“…Consequently, this mutation results in the exponential expansion of the stem cell pool. It resembles the behaviour of the dividing tumour cells with a strong bias toward generating dividing over non-dividing daughter cells through cell division [83].…”

Section: Discussionmentioning

confidence: 82%

A Computational Model of Stem Cell Molecular Mechanism to Maintain Tissue Homeostasis

Khorasani

Sadeghi

Nowzari-Dalini

2020

Preprint

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Stem cells, with their capacity to self-renew and to differentiate to more specialized cell types, play a key role to maintain homeostasis in adult tissues. To investigate how, in the dynamic stochastic environment of a tissue, non-genetic diversity and the precise balance between proliferation and differentiation are achieved, it is necessary to understand the molecular mechanisms of the stem cells in decision making process. By focusing on the impact of stochasticity, we proposed a computational model describing the regulatory circuitry as a tri-stable dynamical system to reveal the mechanism which orchestrate this balance. Our model explains how the distribution of noise in genes, linked to the cell regulatory networks, controls cell decision-making to maintain homeostatic state. The noise control over tissue homeostasis is achieved by regulating the probability of differentiation and self-renewal through symmetric and/or asymmetric cell divisions. Our model reveals, when mutations due to the replication of DNA in stem cell division, are inevitable, how mutations contribute to either aging gradually or the development of cancer in a short period of time. Furthermore, our model sheds some light on the impact of more complex regulatory networks on the system robustness against perturbations.

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A single dividing cell population with imbalanced fate drives oesophageal tumour growth

Cited by 65 publications

References 62 publications

Hair follicle regeneration suppresses Ras-driven oncogenic growth

Hair follicle regeneration suppresses Ras-driven oncogenic growth

The single-progenitor model as the unifying paradigm of squamous epithelial maintenance

A Computational Model of Stem Cell Molecular Mechanism to Maintain Tissue Homeostasis

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