Hypoxia- and MicroRNA-Induced Metabolic Reprogramming of Tumor-Initiating Cells

in Cells (2019), 8(6),

Colorectal cancer (CRC), the second most common cause of cancer mortality in theWestern world, is a highly heterogeneous disease that is driven by a rare subpopulation of tumorigenic cells, known as ... [more ▼]

Colorectal cancer (CRC), the second most common cause of cancer mortality in theWestern world, is a highly heterogeneous disease that is driven by a rare subpopulation of tumorigenic cells, known as cancer stem cells (CSCs) or tumor-initiating cells (TICs). Over the past few years, a plethora of di erent approaches, aimed at identifying and eradicating these self-renewing TICs, have been described. A focus on the metabolic and bioenergetic di erences between TICs and less aggressive di erentiated cancer cells has thereby emerged as a promising strategy to specifically target the tumorigenic cell compartment. Extrinsic factors, such as nutrient availability or tumor hypoxia, are known to influence the metabolic state of TICs. In this review, we aim to summarize the current knowledge on environmental stress factors and how they a ect the metabolism of TICs, with a special focus on microRNA (miRNA)- and hypoxia-induced e ects on colon TICs. [less ▲]

Hypoxia-induced Autophagy Drives Colorectal Cancer Initiation and Progression by Activating the PRKC/PKC-EZR (Ezrin) Pathway

in Autophagy (2019)

In solid tumors, cancer stem cells (CSCs) or tumor-initiating cells (TICs) are often found in hypoxic niches. Nevertheless, the influence of hypoxia on TICs is poorly understood. Using previously ... [more ▼]

In solid tumors, cancer stem cells (CSCs) or tumor-initiating cells (TICs) are often found in hypoxic niches. Nevertheless, the influence of hypoxia on TICs is poorly understood. Using previously established, TIC-enriched patient-derived colorectal cancer (CRC) cultures, we show that hypoxia increases the self-renewal capacity of TICs while inducing proliferation arrest in their more differentiated counterpart cultures. Gene expression data revealed macroautophagy/autophagy as one of the major pathways induced by hypoxia in TICs. Interestingly, hypoxia-induced autophagy was found to induce phosphorylation of EZR (ezrin) at Thr567 residue, which could be reversed by knocking down ATG5, BNIP3, BNIP3L, or BECN1. Furthermore, we identified PRKCA/PKCα as a potential kinase involved in hypoxia-induced autophagy-mediated TIC self-renewal. Genetic targeting of autophagy or pharmacological inhibition of PRKC/PKC and EZR resulted in decreased tumor-initiating potential of TICs. In addition, we observed significantly reduced in vivo tumor initiation and growth after a stable knockdown of ATG5. Analysis of human CRC samples showed that p-EZR is often present in TICs located in the hypoxic and autophagic regions of the tumor. Altogether, our results establish the hypoxia-autophagy-PKC-EZR signaling axis as a novel regulatory mechanism of TIC self-renewal and CRC progression. Autophagy inhibition might thus represent a promising therapeutic strategy for cancer patients. [less ▲]

Hypoxia-responsive miR-210 promotes self-renewal capacity of colon tumor-initiating cells by repressing ISCU and by inducing lactate production

in Oncotarget (2016), 7(40), 97-114

Low oxygen concentrations (hypoxia) are known to affect the cellular metabolism and have been suggested to regulate a subpopulation of cancer cells with tumorigenic properties, the so-called tumor ... [more ▼]

Low oxygen concentrations (hypoxia) are known to affect the cellular metabolism and have been suggested to regulate a subpopulation of cancer cells with tumorigenic properties, the so-called tumor-initiating cells (TICs). To better understand the mechanism of hypoxia-induced TIC activation, we set out to study the role of hypoxia-responsive miRNAs in recently established colon cancer patientderived TICs. We were able to show that low oxygen concentrations consistently lead to the upregulation of miR-210 in different primary TIC-enriched cultures. Both stable overexpression of miR-210 and knockdown of its target gene ISCU resulted in enhanced TIC self-renewal. We could validate the tumorigenic properties of miR- 210 in in vivo experiments by showing that ectopic expression of miR-210 results in increased tumor incidence. Furthermore, enhanced miR-210 expression correlated with reduced TCA cycle activity and increased lactate levels. Importantly, by blocking lactate production via inhibition of LDHA, we could reverse the promoting effect of miR-210 on self-renewal capacity, thereby emphasizing the regulatory impact of the glycolytic phenotype on colon TIC properties. Finally, by assessing expression levels in patient tissue, we could demonstrate the clinical relevance of the miR-210/ISCU signaling axis for colorectal carcinoma. Taken together, our study highlights the importance of hypoxia-induced miR-210 in the regulation of colon cancer initiation. [less ▲]

HyWercs: A middleware for backbone- assisted mobile ad hoc networks

Doctoral thesis (2008)

H∞ filtering for stochastic time- delay systems

in The 7th World Congress on Intelligent Control and Automation (2008)

This paper presents the robust H∞ filter design for stochastic systems with time-varying delay. The aim is to design a stable linear filter assuring exponential stability in mean-square and a prescribed ... [more ▼]

This paper presents the robust H∞ filter design for stochastic systems with time-varying delay. The aim is to design a stable linear filter assuring exponential stability in mean-square and a prescribed H∞ performance level for the filtering error system. Based on the application of the descriptor model transformation and free weighting matrices, delaydependent sufficient conditions are respectively proposed in terms of linear matrix inequalities(LMIs). Numerical example demonstrates the proposed approaches are effective and are an improvement over existing ones. [less ▲]

„I always look for groups that challenge each other.“ Improvisation und kollektives Schreiben als Prinzipien interkultureller Theaterpraxis

in Bloch, Natalie; Heimböckel, Dieter (Eds.) Theater und Ethnologie. Beiträge zu einer produktiven Beziehung (2016)

"I am a worm!": Safe Spaces, Science Notebooks in a 5-year-old Multilingual Science Classroom

Presentation (2017, March)

"I am definitely manipulated, even when I am aware of it. It’s ridiculous!" - Dark Patterns from the End-User Perspective

in Proceedings of ACM DIS Conference on Designing Interactive Systems (2021)

Online services pervasively employ manipulative designs (i.e., dark patterns) to influence users to purchase goods and subscriptions, spend more time on-site, or mindlessly accept the harvesting of their ... [more ▼]

Online services pervasively employ manipulative designs (i.e., dark patterns) to influence users to purchase goods and subscriptions, spend more time on-site, or mindlessly accept the harvesting of their personal data. To protect users from the lure of such designs, we asked: are users aware of the presence of dark patterns? If so, are they able to resist them? By surveying 406 individuals, we found that they are generally aware of the influence that manipulative designs can exert on their online behaviour. However, being aware does not equip users with the ability to oppose such influence. We further find that respondents, especially younger ones, often recognise the "darkness" of certain designs, but remain unsure of the actual harm they may suffer. Finally, we discuss a set of interventions (e.g., bright patterns, design frictions, training games, applications to expedite legal enforcement) in the light of our findings. [less ▲]

"I am not that kind of...": Personal relating with social borders

in Wagoner, Brady; Chaudhary, Nandita; Hviid, Pernille (Eds.) Integrating Experiences : Body and Mind Moving Between Contexts (2015)

“I didn’t know water could be so messy”: Coteaching in elementary teacher education and the production of identity for a new teacher of science

in Cultural Studies of Science Education (2012), 7(1), 1-30

Through the examination of the experiences of a pre-service teacher participating in a field-based science methods course, we make evident the ways in which a combination of collaborative teaching ... [more ▼]

Through the examination of the experiences of a pre-service teacher participating in a field-based science methods course, we make evident the ways in which a combination of collaborative teaching experiences and reflexive dialogues allowed for the evolution and transformation of her identity. This teacher is Johaira Lara, the second author of this paper, and we have engaged in a cowriting approach that has created layers of writings over time, with the focus of providing evidence of her changing perceptions and understandings of teaching and learning science. We describe the ways coteaching and cogenerative dialogues provided the opportunity for Johaira to examine and reconsider her views on science teaching, and mediated the production and transformation of her identity. We offer an evolving analysis of her identity transformation related to specific aspects of the course that were pivotal for her emergence as an elementary teacher of science. [less ▲]