Transitions in development – an interview with Rosa Uribe

Rosa Uribe is an Assistant Professor of BioSciences at Rice University. Having established her lab in 2017, her research focusses on identifying the genetic, cellular and signalling-level mechanisms of neural crest stem cell proliferation, migration and differentiation during embryogenesis. We caught up with Rosa to find out more about her career, her opinions about mentorship and a series of virtual seminars that she co-organises.

Boosting Magnetoelectric Effect in Polymer-Based Nanocomposites

Polymer-based magnetoelectric composite materials have attracted a lot of attention due to their high potential in various types of applications as magnetic field sensors, energy harvesting, and biomedical devices. Current researches are focused on the increase in the efficiency of magnetoelectric transformation. In this work, a new strategy of arrangement of clusters of magnetic nanoparticles by an external magnetic field in PVDF and PFVD-TrFE matrixes is proposed to increase the voltage coefficient (αME) of the magnetoelectric effect. Another strategy is the use of 3-component composites through the inclusion of piezoelectric BaTiO3 particles. Developed strategies allow us to increase the αME value from ~5 mV/cm·Oe for the composite of randomly distributed CoFe2O4 nanoparticles in PVDF matrix to ~18.5 mV/cm·Oe for a composite of magnetic particles in PVDF-TrFE matrix with 5%wt of piezoelectric particles. The applicability of such materials as bioactive surface is demonstrated on neural crest stem cell cultures.

A neural crest stem cell-like state drives nongenetic resistance to targeted therapy in melanoma

The ability to predict the future behaviour of an individual cancer is crucial for precision cancer medicine and, in particular, for the development of strategies that prevent acquisition of resistance to anti-cancer drugs. Therapy resistance, which often develops from a heterogeneous pool of drug-tolerant cells known as minimal residual disease (MRD), is thought to mainly occur through acquisition of genetic alterations. Increasing evidence, however, indicates that drug resistance might also be acquired though nongenetic mechanisms. A key emerging question is therefore whether specific molecular and/or cellular features of the MRD ecosystem determine which of these two distinct resistance trajectories will eventually prevail. We show herein that, in melanoma exposed to MAPK-therapeutics, the presence of a neural crest stem cell (NCSC) subpopulation in MRD concurred with the rapid development of resistance through nongenetic mechanisms. Emergence of this drug-tolerant population in MRD relies on a GDNF-dependent autocrine and paracrine signalling cascade, which activates the AKT survival pathway in a Focal-adhesion kinase- (FAK) dependent manner. Ablation of this subpopulation through inhibition of FAK/SRC-signalling delayed relapse in patient-derived tumour xenografts. Strikingly, all tumours that eventually escaped this treatment exhibited resistance-conferring genetic alterations and increased sensitivity to ERK-inhibition. These findings firmly establish that nongenetic reprogramming events contribute to therapy resistance in melanoma and identify a clinically-compatible approach that abrogates such a trajectory. Importantly, these data demonstrate that the cellular composition of MRD deterministically imposes distinct drug resistance evolutionary paths and highlight key principles that may permit more effective pre-emptive therapeutic interventions.

Phenotypic distribution of the stem-like melanoma initiating state depends on CDKN2A status

Many cancers contain distinct tumor-initiating cell populations. However, the existence of distinct stem-like melanoma initiating cells and their contribution to tumorigenesis remains contested1–5. To identify this cell population in melanoma, we used quantitative single cell approaches linking gene expression, genotype and phenotype in melanoma cells, and observed that bidirectional interconversion between tumor-initiating and differentiated non-tumorigenic states establishes distinct phenotypic equilibria dependent on genotype. Genetic loss of the CDKN2A locus corresponds to a uniform adoption of a neural crest stem cell (NCSC) like tumor-initiating state. Exposure to a putative chemopreventative α-melanocyte stimulating hormone (αMSH) analog can substitute for CDKN2A loss and shift phenotype distribution toward the tumor-initiating state. Alarmingly, in vivo application of the analog is sufficient to induce tumorigenesis in otherwise non-tumorigenic populations. Our results demonstrate that dynamic stemness in melanoma is dependent on secondary mutation status, highlighting the need to incorporate genomic characterization when developing potential chemopreventative agents.

EMT-Inducing Transcription Factors, Drivers of Melanoma Phenotype Switching, and Resistance to Treatment

Transcription factors, extensively described for their role in epithelial–mesenchymal transition (EMT-TFs) in epithelial cells, also display essential functions in the melanocyte lineage. Recent evidence has shown specific expression patterns and functions of these EMT-TFs in neural crest-derived melanoma compared to carcinoma. Herein, we present an update of the specific roles of EMT-TFs in melanocyte differentiation and melanoma progression. As major regulators of phenotype switching between differentiated/proliferative and neural crest stem cell-like/invasive states, these factors appear as major drivers of intra-tumor heterogeneity and resistance to treatment in melanoma, which opens new avenues in terms of therapeutic targeting.