Biology subjects

Hjelmeland, A.

Publications and source records attributed to Hjelmeland, A..

6 recordsLinked to original sources

bioRxiv2022

PKD-1 Signaling Is Required for the Maintenance of CSCs with Epithelial-mesenchymal Plasticity in Pancreatic Neuroendocrine Tumors

Pancreatic neuroendocrine tumors (pNETs) are extremely heterogeneous and highly vascularized neoplasms that arise from endocrine cells in the pancreas. pNETs harbor a subpopulation of stem cell-like cancer cells (cancer stem cells/CSCs), which contribute to intratumoral heterogeneity and promote tumor maintenance and recurrence. In this study we demonstrated that CSCs in human pNETs co-expressed PKD-1 and CD44. We further identified PKD-1 signaling as a critical pathway in the regulation of CSC maintenance in pNET cells. PKD-1 signaling regulated the expression of a CSC-related gene signature and promoted CSC self-renewal. Intriguingly, pharmacological or genetic disruption of PKD-1 signaling in human pNET cells impaired lysophosphatidic acid-induced expression of genes associated with epithelial to mesenchymal transition (EMT), specifically E-cadherin and vimentin. This study indicates that PKD-1 signaling is essential for the maintenance of a subpopulation of CSCs in pNETs at an intermediate state along the epithelial-mesenchymal spectrum, thereby leading to a CSC phenotype with plasticity and partial EMT. Inhibiting the PKD-1 pathway may facilitate the elimination of CSC subpopulations to curb pNET progression, therapeutic resistance and metastasis. Given that the signaling networks associated with CSC maintenance and EMT are complex and extend across multiple levels of gene regulation, this study provides insight into signaling regulation of partial EMT in determining CSC fate and aids in developing potential therapeutic strategies that target different subsets of CSCs in a variety of cancers.

cancer biology↗

bioRxiv2021

Fine-tuned repression of Drp1 driven mitochondrial fission primes a slow cycling stem/progenitor-like state towards accelerating neoplastic transformation of keratinocytes

The opposing processes of mitochondrial fission and fusion are emerging as crucial regulators of stemness. Gene knockout of the master regulator of mitochondrial fission, Drp1, prevents neoplastic transformation. However, stem/progenitor cells maintaining repressed mitochondrial fission are primed for self-renewal and proliferation. Here, we demonstrate that only fine-tuned repression of Drp1 establishes a stem/progenitor-like state towards supporting carcinogen driven neoplastic transformation of keratinocytes, while more complete Drp1 repression prevents it. Only fine-tuned Drp1 repression maintains small networks of fused mitochondria to sustain a unique gene-expression profile with elevated stem/progenitor cell functional markers (Krt15, Sox2 etc) and their regulators (Cyclin E). Cells with such a mitochondria-primed state are slow cycling, susceptible to transformation, and when enriched by mild carcinogen exposure sustains elevated self-renewal/proliferation to form less differentiated tumors. Therefore, our data for the first time highlights a goldilocks level of Drp1 repression that supports stem/progenitor state dependent neoplastic transformation.

cell biology↗

bioRxiv2020

Tumor edge architecture in glioblastoma is constructed by inter-cellular signals from vascular endothelial cells

One of the hallmarks of glioblastoma (GBM) is extensive neovascularization. In addition to supplying blood and nutrients, vascular endothelial (VE) cells provide trophic support to GBM cells via paracrine signaling, the precise mechanisms of which are being unraveled. Here, using patient-derived GBM and VE cells as well as orthotopic GBM mouse models, we report that Endocan (ESM1), an endothelial-secreted proteoglycan, confers enhanced proliferative, migratory, and angiogenic properties to GBM cells and regulates their spatial identity. Mechanistically, Endocan exerts at least part of its functions via direct binding and activation of the PDGFRA receptor. Subsequent downstream signaling enhances chromatin accessibility of the Myc promoter and upregulates Myc expression inducing highly stable phenotypic changes in GBM cells. Furthermore, Endocan confers a radioprotection phenotype in GBM cells, both in vitro and in vivo. Inhibition of Endocan-PDGFRA signaling with ponatinib increases survival in the Esm1 wild-type but not in the Esm1 knock-out mouse GBM model. Our findings identify Endocan and its downstream signaling axis as a potential target to subdue the recurrence of GBM and further highlight the importance of vascular to tumor cell signaling for GBM biology. Significance statementIdentification of the Endocan/PDGFRA/Myc axis demonstrates an important role of VE cells in GBM malignancy. The contribution of Endocan to the development of GBM cell populations with different phenotypes reveal an additional pathway underlying the origin of GBM intratumoral heterogeneity. Targeting Endocan-mediated crosstalk may enhance the efficacy of GBM treatment.

cancer biology↗

bioRxiv2019

Mito-SinCe2 Approach to Quantify Relationships between Mitochondrial Dynamics and Energetics status

Mitochondrial dynamics primarily refers to the opposing fission and fusion events between individual mitochondria, which maintains steady-state mitochondrial morphology in cells. The details of the bidirectional relationship between mitochondrial dynamics and energetics are unclear as the methods to integrate these mitochondrial aspects are lacking. To study the quantitative relationship between mitochondrial dynamics (fission, fusion, matrix continuity and diameter) and energetics (ATP and redox), we have developed and validated an analytical approach, mito-SinCe2. Application of this approach led to the hypothesis that mitochondria-dependent ovarian tumor initiating cells interconvert between 3 states with distinct relationships between mitochondrial energetics and dynamics. Interestingly, fusion and ATP increase linearly with each other only once a certain level of fusion is attained. Moreover, mitochondrial dynamics status changes linearly either with ATP or with redox, but not simultaneously with both. Furthermore, mito-SinCe2 analyses can potentially predict new quantitative features of the opposing fission vs. fusion relationship and classify cells into functional classes based on their mito-SinCe2 states.

cell biology↗

bioRxiv2018

HPAanalyze: An R Package that Facilitate the Retrieval and Analysis of The Human Protein Atlas Data

BackgroundThe Human Protein Atlas (HPA) aims to map human proteins via multiple technologies including imaging, proteomics and transcriptomics. Access of the HPA data is mainly via web-based interface allowing views of individual proteins, which may not be optimal for data analysis of a gene set, or automatic retrieval of original images.\n\nResultsHPAanalyze is an R package for retrieving and performing exploratory analysis of data from HPA. HPAanalyze provides functionality for importing data tables and xml files from HPA, exporting and visualizing data, as well as downloading all staining images of interest. The package is free, open source, and available via Bioconductor and Github.\n\nConclusionsHPAanalyze integrates into the R workflow via the tidyverse philosophy and data structures, and it can be used in combination with Bioconductor packages for easy analysis of HPA data.

bioinformatics↗

bioRxiv2017

Recasting the cancer stem cell hypothesis: unification using a continuum model of microenvironmental forces

Since the first evidence for cancer stem cells in leukemia, experimentalists have sought to identify tumorigenic subpopulations in solid tumors. In parallel, scientists have argued over the implications of the existence of this subpopulation. On one side, the cancer stem cell hypothesis posits that a small subset of cells within a tumor are responsible for tumorigenesis and are capable of recapitulating the entire tumor on their own. Under this hypothesis, a tumor may be conceptualized as a series of coupled compartments, representing populations of progressively differentiated cell types, starting from stem cells. The allure of this model is that it elegantly explains our therapeutic failures: we have been targeting the wrong cells. Alternatively, the stochastic model states that all cells in a tumor can have stem-like properties, and have an equally small capability of forming a tumor. As tumors are, by nature, heterogeneous, there is ample evidence to support both hypotheses. We propose a mechanistic mathematical description that integrates these two theories, settling the dissonance between the schools of thought and providing a road map for integrating disparate experimental results into a single theoretical framework. We present experimental results from clonogenic assays that demonstrate the importance of defining this novel formulation, and the clarity that is provided when interpreting these results through the lens of this formulation.

cancer biology↗