Periodic Reporting for period 3 - TroyCAN (Redefining the esophageal stem cell niche – towards targeting of squamous cell carcinoma)
Reporting period: 2023-03-01 to 2024-08-31
In order to establish or maintain a tissue, stem cells need to balance the choice between self-renewal and differentiation. Stem cells reside in a complex microenvironment, or niche, that is instructive in determining cell fate. However, not all stem cell niches are anatomically defined. Morphologically uniform epithelial structures such as the esophagus give rise to a single cell lineage of differentiated cells and raise questions of 1) the presence and necessity of a stem cell population to maintain the epithelium and 2) if discrete niches determining stem cell properties exist.
Understanding how stem cell fate is regulated is of considerable importance in cancer. Oncogenic lesions acquired by cells that are undergoing terminal differentiation have relatively little impact on a tissue because the cells are rapidly lost. In contrast, stem cells are permanent tissue residents and therefor have the potential to acquire further deleterious changes and form a tumor. Progenitor cells in the esophagus are suggested to be the cell-of-origin in squamous cell carcinomas, indicating that regulation of stem and cancer stem cell fates are closely linked.
Until now, we have identified and characterized Troy+ progenitor cells in the esophageal epithelium, and find that Troy+ progenitor cells are symmetrically fated. Our findings challenge the current model for how the esophageal epithelium is maintained. This is a major finding which is likely to have implications for esophageal disease and regeneration. While Troy marks symmetrically fated progenitor cells, Troy protein itself does not mediate symmetric fate. Understanding fate choices in the esophagus will be a key future question to address that is relevant for epithelial biology at large.
We have identified heterogeneity along the esophageal axis, both in terms of progenitor (Troy+ and Troy-) and stromal cell composition. In addition, we find that this cellular heterogeneity corresponds to gradients of signaling pathway mediators, suggesting that a) epithelial homeostasis is regionally regulated and b) specific esophageal regions are more prone to develop disease. To understand this cellular and signaling landscape will lead to understanding of mechanisms of disease initiation.
Defining progenitor cell heterogeneity in the esophagus is important for understanding tissue maintenance. Without understanding mechanisms in place to maintain normal stem/progenitor cell function, we are likely to fail treatment directed at targeting dysfunctional stem and progenitor cells in cancer. Work in my group has identified heterogeneity within the esophageal progenitor pool, based on which we aim to transform the management of squamous cell carcinoma.
Understanding how stem cell fate is regulated is of considerable importance in cancer. Oncogenic lesions acquired by cells that are undergoing terminal differentiation have relatively little impact on a tissue because the cells are rapidly lost. In contrast, stem cells are permanent tissue residents and therefor have the potential to acquire further deleterious changes and form a tumor. Progenitor cells in the esophagus are suggested to be the cell-of-origin in squamous cell carcinomas, indicating that regulation of stem and cancer stem cell fates are closely linked.
Until now, we have identified and characterized Troy+ progenitor cells in the esophageal epithelium, and find that Troy+ progenitor cells are symmetrically fated. Our findings challenge the current model for how the esophageal epithelium is maintained. This is a major finding which is likely to have implications for esophageal disease and regeneration. While Troy marks symmetrically fated progenitor cells, Troy protein itself does not mediate symmetric fate. Understanding fate choices in the esophagus will be a key future question to address that is relevant for epithelial biology at large.
We have identified heterogeneity along the esophageal axis, both in terms of progenitor (Troy+ and Troy-) and stromal cell composition. In addition, we find that this cellular heterogeneity corresponds to gradients of signaling pathway mediators, suggesting that a) epithelial homeostasis is regionally regulated and b) specific esophageal regions are more prone to develop disease. To understand this cellular and signaling landscape will lead to understanding of mechanisms of disease initiation.
Defining progenitor cell heterogeneity in the esophagus is important for understanding tissue maintenance. Without understanding mechanisms in place to maintain normal stem/progenitor cell function, we are likely to fail treatment directed at targeting dysfunctional stem and progenitor cells in cancer. Work in my group has identified heterogeneity within the esophageal progenitor pool, based on which we aim to transform the management of squamous cell carcinoma.
Work performed during period:
During the first year of TroyCAN, we have initiated work in Objective 1,2 and 4. Functional heterogeneity within the esophageal progenitor pool has been explored during homeostasis and during tissue stress. We find that during homeostasis, Troy+ progenitors are less likely to undergo division than Troy- progenitors, although neutrally competing (Objective 1). In contrast, tissue stress favors activation and proliferation of Troy+ progenitors (Objective 2). Furthermore, we have characterized the esophageal stroma niche during homeostasis and define subpopulations of fibroblasts with distinct molecular profiles. Organoid co-cultures reveal distinct functional roles for subsets of fibroblasts during organoid formation (Objective 4).
During the first year of TroyCAN, we have initiated work in Objective 1,2 and 4. Functional heterogeneity within the esophageal progenitor pool has been explored during homeostasis and during tissue stress. We find that during homeostasis, Troy+ progenitors are less likely to undergo division than Troy- progenitors, although neutrally competing (Objective 1). In contrast, tissue stress favors activation and proliferation of Troy+ progenitors (Objective 2). Furthermore, we have characterized the esophageal stroma niche during homeostasis and define subpopulations of fibroblasts with distinct molecular profiles. Organoid co-cultures reveal distinct functional roles for subsets of fibroblasts during organoid formation (Objective 4).
Expected results at end of project:
We expect to have a better understanding on how the esophagus is maintained during homeostasis, with regards to progenitor heterogeneity as well as stem cell niche components. Furthermore, we are exploring tumor models to map out specific cellular requirements in tumor initiation and expansion. We aim to develop a human organoid model that can be exploited for identification of druggable targets in human squamous cell carcinoma of the esophagus.
We expect to have a better understanding on how the esophagus is maintained during homeostasis, with regards to progenitor heterogeneity as well as stem cell niche components. Furthermore, we are exploring tumor models to map out specific cellular requirements in tumor initiation and expansion. We aim to develop a human organoid model that can be exploited for identification of druggable targets in human squamous cell carcinoma of the esophagus.