Juliette
Gaytan
52 Harvard Stem Cell Institute Internship Program Retinoic Acid Receptor Inhibition Promotes Hillock Stem Cell Expansion
Abstract profile. Full document pending author claim.
Authors:
Juliette Gaytan, Viral S. Shah, Jayaraj Rajagopal
Date Created:
2025-01-01
Course Title:
Professor:
Not specified
About Paper:
The airway is constantly exposed to environmental insults that can from hillocks and non-hillock regions. Cultures were categorized cause damage to the airway surface. After injury, the airway must as hillock-enriched, ciliated, or mixed populations, and epithelial be able to regenerate the epithelial surface in order to maintain itsmorphology and lineage distribution were monitored over time. critical functions. Recently, the Rajagopal lab identified a new High-dose Agn treatment promoted widespread expansion of stem cell reservoir, called the hillock, which is the primary cellularillock cells, leading to a loss of defined single-cell architecture source of airway regeneration after injury. Hillocks are stratified and dominant stratified squamous morphology, suggesting a cell- epithelial structures lacking ciliated cells, and containing a distincttrinsic responsiveness to RA inhibition. However, hillock population of highly proliferative, injury-resistant basal stem cellsexpansion occurred at the expense of the development of ciliated found in mouse and human large airways. However, there is no cells. Lowerconcentrationsallowedpartialreemergenceofciliated established in vitro model to study hillocks. When hillock basal cell differentiation. These results are consistent with enrichment cells are cultured they no longer demonstrate the aforementioned of RA anabolic genes found in hillock basal cells, demonstrating properties of hillocks. Thus, the primary objective of this study a functional response to RA inhibition. This study identifies RA was to develop an approach to culture hillocks in vitro so that signaling as a pivotal regulator of hillock expansion and epithelial theymaintaintheiruniqueproperties. Unliketheirpseudostratified regeneration. Future work may be able to capitalize on this counterparts, hillock stem cells exhibit a distinct transcriptional understanding by enhancing hillock expansion in order to make signature characterized by enhanced retinoic acid (RA) anabolism. the airways more resilient to environmental injuries. However, I hypothesize that modulating retinoic acid metabolism could the potential deleterious implications of hillock expansion and the be critical for the successful in vitro culture hillock epithelia. physiologic consequences of the relative absence of ciliated cells To test this hypothesis, a six-point dose gradient (0-10µM) of must be defined before we are able to truly bring this work towards Agn193109, a pan-retinoic acid receptor antagonist, was applied novel treatments and therapies. to murine and human in vitro airway basal cell culture isolated Decoding Vorasidenib Response in IDH-Mutant Gliomas Through Spatial Transcriptomics Blake Hammond, Ester Calvo Fernández, Mario Suvà Columbia University | Molecular and Cellular Biology | 2027 Approximately 12,000 new cases of glioma are diagnosed of patient exhibits intrinsic or acquired resistance, highlighting the annually in the United States. Somatic mutations in isocitrate need to better understand the molecular determinant of therapeutic dehydrogenase (IDH) 1 and 2 are prevalent in the majority of response and failure. The Suvà Lab is investigating the cellular low-grade gliomas and secondary high-grade gliomas. These and spatial effects of Vorasidenib in IDH-mutant gliomas using neomorphic mutations lead to the aberrant production of the spatial transcriptomics. To this end, FFPE-embedded tumor oncometabolite D-2-hydroxyglutarate (2HG), which contributes samples from patients pre- and on-treatment with IDH inhibitors to tumorigenesis through widespread epigenetic reprogramming. are profiled to characterize tumor cell states across spatial contexts In the phase III INDIGO trial, treatment of patients with and assess treatment-induced alterations. Prior single-cell RNA WHO grade II IDH-mutant gliomas found that administering sequencing studies from the lab demonstrated that Vorasidenib Vorasidenib, a drug that inhibits mutant IDH1 and IDH2 enzymes, promoted differentiation of stem-like tumor cells into more to patients with grade 2 IDH-mutant gliomas using Vorasidenib— mature, astrocytic-like states. This study aims to define the a brain-penetrant dual IDH1/2 inhibitor—significantly prolonged spatial dynamics of therapeutic response and resistance, ultimately progression-free survival and delayed the time to subsequent guidingmoreeffectivetreatmentstrategiesforIDH-mutantglioma. therapeutic intervention. Despite these promising results, a subset
Abstract:
The airway is constantly exposed to environmental insults that can from hillocks and non-hillock regions. Cultures were categorized cause damage to the airway surface. After injury, the airway must as hillock-enriched, ciliated, or mixed populations, and epithelial be able to regenerate the epithelial surface in order to maintain itsmorphology and lineage distribution were monitored over time. critical functions. Recently, the Rajagopal lab identified a new High-dose Agn treatment promoted widespread expansion of stem cell reservoir, called the hillock, which is the primary cellularillock cells, leading to a loss of defined single-cell architecture source of airway regeneration after injury. Hillocks are stratified and dominant stratified squamous morphology, suggesting a cell- epithelial structures lacking ciliated cells, and containing a distincttrinsic responsiveness to RA inhibition. However, hillock population of highly proliferative, injury-resistant basal stem cellsexpansion occurred at the expense of the development of ciliated found in mouse and human large airways. However, there is no cells. Lowerconcentrationsallowedpartialreemergenceofciliated established in vitro model to study hillocks. When hillock basal cell differentiation. These results are consistent with enrichment cells are cultured they no longer demonstrate the aforementioned of RA anabolic genes found in hillock basal cells, demonstrating properties of hillocks. Thus, the primary objective of this study a functional response to RA inhibition. This study identifies RA was to develop an approach to culture hillocks in vitro so that signaling as a pivotal regulator of hillock expansion and epithelial theymaintaintheiruniqueproperties. Unliketheirpseudostratified regeneration. Future work may be able to capitalize on this counterparts, hillock stem cells exhibit a distinct transcriptional understanding by enhancing hillock expansion in order to make signature characterized by enhanced retinoic acid (RA) anabolism. the airways more resilient to environmental injuries. However, I hypothesize that modulating retinoic acid metabolism could the potential deleterious implications of hillock expansion and the be critical for the successful in vitro culture hillock epithelia. physiologic consequences of the relative absence of ciliated cells To test this hypothesis, a six-point dose gradient (0-10µM) of must be defined before we are able to truly bring this work towards Agn193109, a pan-retinoic acid receptor antagonist, was applied novel treatments and therapies. to murine and human in vitro airway basal cell culture isolated Decoding Vorasidenib Response in IDH-Mutant Gliomas Through Spatial Transcriptomics Blake Hammond, Ester Calvo Fernández, Mario Suvà Columbia University | Molecular and Cellular Biology | 2027 Approximately 12,000 new cases of glioma are diagnosed of patient exhibits intrinsic or acquired resistance, highlighting the annually in the United States. Somatic mutations in isocitrate need to better understand the molecular determinant of therapeutic dehydrogenase (IDH) 1 and 2 are prevalent in the majority of response and failure. The Suvà Lab is investigating the cellular low-grade gliomas and secondary high-grade gliomas. These and spatial effects of Vorasidenib in IDH-mutant gliomas using neomorphic mutations lead to the aberrant production of the spatial transcriptomics. To this end, FFPE-embedded tumor oncometabolite D-2-hydroxyglutarate (2HG), which contributes samples from patients pre- and on-treatment with IDH inhibitors to tumorigenesis through widespread epigenetic reprogramming. are profiled to characterize tumor cell states across spatial contexts In the phase III INDIGO trial, treatment of patients with and assess treatment-induced alterations. Prior single-cell RNA WHO grade II IDH-mutant gliomas found that administering sequencing studies from the lab demonstrated that Vorasidenib Vorasidenib, a drug that inhibits mutant IDH1 and IDH2 enzymes, promoted differentiation of stem-like tumor cells into more to patients with grade 2 IDH-mutant gliomas using Vorasidenib— mature, astrocytic-like states. This study aims to define the a brain-penetrant dual IDH1/2 inhibitor—significantly prolonged spatial dynamics of therapeutic response and resistance, ultimately progression-free survival and delayed the time to subsequent guidingmoreeffectivetreatmentstrategiesforIDH-mutantglioma. therapeutic intervention. Despite these promising results, a subset
Source:
Harvard / Institute Internship / 2025
Topics:
hillock, cell, airway, glioma, stem, idh, expansion, vorasidenib, spatial, acid, culture, injury
