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Targeting an RNA polymerase II-associated PHF5A transcriptional subcomplex with a KMT2A-WDR5 inhibitor impairs self-renewal, pluripotency and tumorigenicity of pancreatic cancer stem cells II

ABSTRACT: Pancreatic cancer remains one of the most aggressive and lethal cancers in humans. It is undeniably known for its notorious resistance to conventional chemotherapeutics which are often associated with a transient response to treatment but rapidly followed by drug resistance and tumor recurrence. Increasing evidence suggests that therapy failure in pancreatic cancer is largely ascribed to the residual subpopulation of undifferentiated cells, known as cancer stem cells (CSCs), which are evolutionary 'fitter' than other tumor cells to evade the cytotoxic effects of chemotherapy. Those cells are outstandingly critical for tumor relapse as they possess unique 'stem cell-like' features of self-renewal and differentiation which render them capable of regenerating the original tumor. Through the identification of key epigenetic regulators of CSCs phenotypes and functions, this project seeks to gain insight into the molecular mechanisms underlying tumor recurrence and identify novel therapeutic candidates for eliminating CSCs and achieving long-term clinical responses in pancreatic cancer patients.

ORGANISM(S): Homo sapiens

PROVIDER: GSE217330 | GEO | 2023/08/10

REPOSITORIES: GEO

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Targeting an RNA polymerase II-associated PHF5A transcriptional subcomplex with a KMT2A-WDR5 inhibitor impairs self-renewal and tumorigenicity of pancreatic cancer stem cells III

Project description:Pancreatic cancer remains one of the most aggressive and lethal cancers in humans. It is undeniably known for its notorious resistance to conventional chemotherapeutics which are often associated with a transient response to treatment but rapidly followed by drug resistance and tumor recurrence. Increasing evidence suggests that therapy failure in pancreatic cancer is largely ascribed to the residual subpopulation of undifferentiated cells, known as cancer stem cells (CSCs), which are evolutionary 'fitter' than other tumor cells to evade the cytotoxic effects of chemotherapy. Those cells are outstandingly critical for tumor relapse as they possess unique 'stem cell-like' features of self-renewal and differentiation which render them capable of regenerating the original tumor. Through the identification of key epigenetic regulators of CSCs phenotypes and functions, this project seeks to gain insight into the molecular mechanisms underlying tumor recurrence and identify novel therapeutic candidates for eliminating CSCs and achieving long-term clinical responses in pancreatic cancer patients.

2023-08-10 | GSE217331 | GEO

Targeting an RNA polymerase II-associated PHF5A transcriptional subcomplex with a KMT2A-WDR5 inhibitor impairs self-renewal and tumorigenicity of pancreatic cancer stem cells I

2023-08-10 | GSE217329 | GEO

Targeting an RNA polymerase II-associated PHF5A protein subcomplex with a KMT2A-WDR5 inhibitor impairs self-renewal and tumorigenicity of pancreatic cancer stem cells

Project description:Pancreatic cancer (PC) remains one of the most aggressive and life-threatening malignancies known for its notorious resistance to chemotherapy. This is increasingly ascribed to the subpopulation of undifferentiated cells, known as pancreatic cancer stem cells (PCSCs), which are evolutionary fitter than other tumor cells to evade the cytotoxic effects of chemotherapy. Those cells are crucial for tumor relapse as they possess ‘stem cell-like’ features of self-renewal and differentiation. However, what molecular mechanisms maintain the unique characteristics of PCSCs are poorly understood. Here, we identified an RNA polymerase II-associated PHF5A-PHF14-HMG20A-RAI1-KMT2A transcriptional subcomplex, which regulates the stemness characteristics and tumorigenicity of PCSCs through epigenetic control of gene expression. Targeting the protein subcomplex with a KMT2A-WDR5 inhibitor attenuated the self-renewal and in vivo tumorigenicity of PCSCs, thus offering a novel anti-PCSCs targeting strategy for enhancing the efficiency of chemotherapy which is likely to translate into durable clinical responses in PC patients.

2023-08-23 | PXD038378 | Pride

Abernathy2016 - glioblastoma treatment

Project description:The paper describes a model of glioblastoma. Created by COPASI 4.25 (Build 207) This model is described in the article: Modeling the Treatment of Glioblastoma Multiforme and Cancer Stem Cells with Ordinary Differential Equations Kristen Abernathy and Jeremy Burke BMC Computational and Mathematical Methods in Medicine Volume 2016, Article ID 1239861, 11 pages Abstract: Despite improvements in cancer therapy and treatments, tumor recurrence is a common event in cancer patients. One explanation of recurrence is that cancer therapy focuses on treatment of tumor cells and does not eradicate cancer stem cells (CSCs). CSCs are postulated to behave similar to normal stem cells in that their role is to maintain homeostasis. That is, when the population of tumor cells is reduced or depleted by treatment, CSCs will repopulate the tumor, causing recurrence. In this paper, we study the application of the CSC Hypothesis to the treatment of glioblastoma multiforme by immunotherapy. We extend the work of Kogan et al. (2008) to incorporate the dynamics of CSCs, prove the existence of a recurrence state, and provide an analysis of possible cancerous states and their dependence on treatment levels. To cite BioModels Database, please use: BioModels Database: An enhanced, curated and annotated resource for published quantitative kinetic models . To the extent possible under law, all copyright and related or neighbouring rights to this encoded model have been dedicated to the public domain worldwide. Please refer to CC0 Public Domain Dedication for more information.

2019-07-24 | BIOMD0000000757 | BioModels

Proteins and Molecular Pathways Relevant for Stemness Properties of Tumor-Initiating Pancreatic Cancer Stem Cells Recognized by Differential Proteome-, Gene Expression-, and Functional Analysis

Project description:Cancer stem cells (CSCs), a small subset of the tumor bulk with highly malignant properties, are deemed responsible for tumor initiation, growth, metastasis, and relapse. In order to reveal molecular markers and determinants of stemness properties, pancreatic CSCs were enriched in three-dimensional spheroid cultures of two highly metastatic pancreatic cancer cell lines (L3.6sl and L3.6pl) and compared to bulk tumor cells using differential proteomics (PTX). We identified about 400 putative target proteins with significantly different expression in pancreatic CSCs and bulk tumor cells. By combining the unbiased PTX with gene expression analysis using quantitative polymerase chain reaction (qPCR) we nominated the two calcium binding proteins S100A8 (MRP8) and S100A9 (MRP14), as well as galactin-3-binding protein LGALS3BP (MAC-2-BP) as putative determinants of pancreatic CSCs. In silico pathway analysis followed by candidate-based RNA interference mediated functional analysis revealed a critical role of S100A8, S100A9, and LGALS3BP as molecular determinants of CSC proliferation, migration and in vivo tumor initiation. Our study highlights the power of combining unbiased proteomics with focused gene expression and functional analyses for the identification of key regulators of CSCs, an approach that warrants further application to identify CSCs proteins amenable to drug targeting.

2020-06-25 | PXD018585 | Pride

Direct cell-to-cell transfer in stressed tumor microenvironment aggravates tumorigenic or metastatic potential in pancreatic cancer

Project description:Pancreatic cancer exhibits a characteristic tumor microenvironment (TME) due to enhanced fibrosis and hypoxia and is particularly resistant to conventional chemotherapy. However, the molecular mechanisms underlying TME-associated treatment resistance in pancreatic cancer are not fully understood. Here, we developed an in vitro TME mimic system comprising pancreatic cancer cells, fibroblasts and immune cells, and a stress condition, including hypoxia and gemcitabine. Cells with high viability under stress showed evidence of increased direct cell-to-cell transfer of biomolecules. The resulting derivative cells (CD44high/SLC16A1high) were similar to cancer stem cell-like-cells (CSCs) with enhanced anchorage-independent growth or invasiveness and acquired metabolic reprogramming. Furthermore, CD24 was a determinant for transition between the tumorsphere formation or invasive properties. Pancreatic cancer patients with CD44low/SLC16A1low expression exhibited better prognoses compared to other groups. Our results suggest that crosstalk via direct cell-to-cell transfer of cellular components foster chemotherapy-induced tumor evolution and that targeting of CD44 and MCT1(encoded by SLC16A1) may be useful strategy to prevent recurrence of gemcitabine-exposed pancreatic cancers.

2023-03-11 | PXD037275 | Pride

Expression data from LNCaP cells

Project description:Prostate Cancer Stem Cells (CSCs) are considered one of the main reasons the tumor recurrence after chemotherapy. Here we employed a chemoresistant xenograft prostate cancer model in NOD/SCID mice and found CD54 is a reliable new marker for prostate CSCs. Gene expression profile were utilized to analyze stemness-related genes in cancer stem cells.

2016-02-23 | GSE78196 | GEO

Changes in gene expression by SNAI2 knockdown in the spheroid derived from human pancreatic cancer

Project description:The prognosis of pancreatic cancer is still poor due to resistance to conventional therapies, and cancer stem cells (CSCs) targeted therapy is expected to be a promising therapy. Although epithelial mesenchymal transition-inducing transcription factors (EMT-TF) are known to impart the CSCs properties to some of solid tumors, it has not been clearly reported in pancreatic cancer yet. Zinc finger protein SNAI2, a member of the Snail superfamily of EMT-TF, is frequently overexpressed in pancreatic cancer cells and the poor prognosis has been reported in cases with high SNAI2 expression. we found the suppression of SNAI2 expression using RNA interference decreased the tumorigenicity in the tumor spheroid (Sph) derived from surgically resected pancreatic cancer tissues. Also, it increased the sensitivities to Gemcitabine treatment and reduced the expression of CD44, one of the pancreatic CSCs markers. Furthemore, microarray analysis suggests that the mechanism is mediated by insulin-like growth factor binding protein 2 (IGFBP2). These results indicate that SNAI2 may be a critical factor for the CSCs properties and indispensable for the homeostasis of pancreatic CSCs.

2020-07-25 | GSE155107 | GEO

miRNA Expression data from CD133+CD15+ chordoma cells (Chordoma Cance Stem Cells) and CD133-CD15- chordoma cells

Project description:Chordoma is a rare, resistant bone tumor thought to be arised from remnants of embryonic notochord. Cancer stem cells (CSCs) are associated with tumorigenesis, recurrence and resistance in cancers. Here, we used miRNA and mRNA transcriptome analysis to discover novel genes and networks in chordoma CSCs

2019-04-15 | GSE109943 | GEO

Direct cell-to-cell transfer in stressed tumor microenvironment aggravates tumorigenic or metastatic potential in pancreatic cancer

2022-05-02 | GSE201876 | GEO

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