Research

Our mission

In the Mandinova lab we use the epidermis as a model system to study adult stem cells in health and disease. The questions we ask are: How is homeostatic stem cell renewal regulated and how is it balanced with commitment to differentiation to ensure tissue integrity? How does the epidermis withstand and repair frequent injuries and insults? How are genomically damaged stem cells guarded and what permits, in rare cases, aberrant clonal expansion and transformation into benign and malignant lesions? To find our answers, we focus extensively on posttranscriptional regulation of gene expression and its interplay with cellular metabolism. We reason that this approach offers realistic opportunities for therapeutic intervention and identification of “druggable” targets.

Epidermal Stem Cells in
Health and Disease

Our Approach

We combine numerous experimental approaches, including high-resolution imaging, metabolomics, single-cell or pooled RNA-seq, polysome profiling, TRAP-seq and RIP-seq, organoids, flow cytometry and primary cell culture.

Current Projects

Identification of essential early events that govern epidermal stem cells differentiation.

The epidermis, the outermost layer of the skin, relies on the regenerative capacity of stem cells to maintain a functional equilibrium between self-renewal and commitment to differentiation. Our research is focused on pivotal early events in the differentiation process of epidermal stem cells, which occur before transcriptional changes, prime them to undergo differentiation, and are crucial for their role in epidermal homeostasis.

1. Mitochondrial reprogramming during epidermal progenitor commitment to differentiation

As epidermal stem cells transition from the basal to the suprabasal layers, undergoing terminal differentiation, both mitochondrial function and morphology experience dynamic changes. Moreover, the dysregulation of mitochondrial function in keratinocytes is pivotal for the development of the skin barrier and overall skin health. Our recent study investigates the role of mitochondrial metabolism in triggering the early events of cellular differentiation.

2. Protein synthesis drives epidermal stem cell differentiation

Protein synthesis plays a critical role in either preserving stemness or driving differentiation cascades, thereby significantly influencing cell identity, lineage switching, and commitment. Currently, we are pinpointing the specific events in protein biosynthesis that regulate epidermal homeostasis and the differentiation of epidermal stem cells.

RNA-binding proteins in tumor progression

RNA-binding proteins (RBPs) undergo a dynamic spatiotemporal regulation process and play crucial roles in various biological functions. These proteins are essential for preserving the transcriptome by exerting post-transcriptional control over RNA processing and transportation. They influence key aspects such as RNA splicing, polyadenylation, mRNA stability, localization, and translation. Disruptions in any of these processes can significantly impact the RNA life cycle, resulting in the generation of abnormal protein phenotypes. Consequently, such alterations contribute to the initiation and progression of tumor development.

The role of YBX1 in the pathogenesis of keratinocyte-derived cancers

The Y-box binding protein 1 (YBX1), encoded by the YBX1 gene, is a versatile cold-shock protein that interacts with both DNA and RNA to control transcription, RNA processing, and translation. Recently, we have shown that YBX1 is a post-transcriptional regulator essential for maintaining epidermal homeostasis. While YBX1’s significant pro-oncogenic roles in promoting malignant transformation and cell invasion across a wide range of cancers are well documented, its specific mechanisms of action in cutaneous squamous cell carcinoma (cSCC) remain poorly understood. Through the application of multiple ‘omics’ approaches, we aim to elucidate the mechanisms by which YBX1 influences its targets at the post-transcriptional and translational levels.

The translational landscape of cutaneous squamous cell carcinoma

Alterations in both epithelial and stromal compartments of premalignant lesions are required for their progression to invasive and metastatic cSCC. The overall purpose of the project is to characterize the post-transcriptional and translational landscape of cutaneous squamous cell carcinoma and to understand how protein synthesis and posttranscriptional regulation are involved in cSCC. Our studies will provide a comprehensive overview of the interactions between tumor and stromal cells and highlight strategies to identify potential new targets for a therapy in cSCC.

Define the age-dependent transcriptional and posttranscriptional changes in metabolism-associated genes for homeostatic skin regeneration

Aging is accompanied by numerous physiological changes across a broad range of biological functions. These include the depletion of stem cell reserves, which is partly due to cellular senescence driven by factors such as telomere attrition, genomic instability, mitochondrial dysfunction, epigenetic alterations, altered intracellular communication, deregulated nutrient sensing, and the loss of proteostasis. Given that these molecular hallmarks of aging both affect and are affected by transcriptional and post-transcriptional changes, we plan to employ multi-level ‘omics’ approaches to gain a deeper understanding of the metabolic alterations occurring during the aging process. By studying transcriptional and post-transcriptional changes during skin aging, we aim to reveal new facets of this process and identify potential targets for novel therapies or drug repurposing.

Adopting a holistic approach to skin biology

We are in collaboration with the scientific team at Shiseido (Japan) to delve into the multifaceted aspects of skin health. This comprehensive study explores the impact of nutrition on skin health, examining how dietary choices influence skin condition and its aging process. Additionally, we are investigating the roles of neurotransmitters and hormones in aging skin, aiming to understand the complex interactions that accelerate or mitigate the aging process. Beyond biochemical factors, our research extends to traditional practices, specifically examining how ancient interventions like acupuncture affect skin biology. Through this integrative research, we aim to uncover the underlying mechanisms that influence skin health and aging, potentially leading to innovative strategies for skincare and rejuvenation.