Stem cells tightly regulate dead cell clearance to maintain tissue fitness.

Billions of cells are eliminated daily from our bodies. Although macrophages and dendritic cells are dedicated to migrating and engulfing dying cells and debris, many epithelial and mesenchymal tissue cells can digest nearby apoptotic corpses. How these non-motile, non-professional phagocytes sense and eliminate dying cells while maintaining their normal tissue functions is unclear.

The pioneer factor SOX9 competes for epigenetic factors to switch stem cell fates.

During development, progenitors simultaneously activate one lineage while silencing another, a feature highly regulated in adult stem cells but derailed in cancers. Equipped to bind cognate motifs in closed chromatin, pioneer factors operate at these crossroads, but how they perform fate switching remains elusive. Here we tackle this question with SOX9, a master regulator that diverts embryonic epidermal stem cells (EpdSCs) into becoming hair follicle stem cells.

Stem cells tightly regulate dead cell clearance to maintain tissue fitness.

Macrophages and dendritic cells have long been appreciated for their ability to migrate to and engulf dying cells and debris, including some of the billions of cells that are naturally eliminated from our body daily. However, a substantial number of these dying cells are cleared by 'non-professional phagocytes', local epithelial cells that are critical to organismal fitness. How non-professional phagocytes sense and digest nearby apoptotic corpses while still performing their normal tissue functions is unclear.

BMP signaling: at the gate between activated melanocyte stem cells and differentiation.

Through recurrent bouts synchronous with the hair cycle, quiescent melanocyte stem cells (McSCs) become activated to generate proliferative progeny that differentiate into pigment-producing melanocytes. The signaling factors orchestrating these events remain incompletely understood. Here, we use single-cell RNA sequencing with comparative gene expression analysis to elucidate the transcriptional dynamics of McSCs through quiescence, activation, and melanocyte maturation.

NFI transcription factors provide chromatin access to maintain stem cell identity while preventing unintended lineage fate choices.

Tissue homeostasis and regeneration rely on resident stem cells (SCs), whose behaviour is regulated through niche-dependent crosstalk. The mechanisms underlying SC identity are still unfolding. Here, using spatiotemporal gene ablation in murine hair follicles, we uncover a critical role for the transcription factors (TFs) nuclear factor IB (NFIB) and IX (NFIX) in maintaining SC identity.

Mahak Sharma: Weaving through traffic.

Sharma investigates vesicular trafficking to lysosomes and how pathogens hijack the endolysosomal system during infection.

Xiaochen Wang: Building up our understanding of breaking down.

Wang studies lysosomal degradation pathways using as a model system.

Beata Mierzwa: Bridging the divide between science and art.

Mierzwa studies mechanisms of cell division in different cell types and tissue contexts.

BethAnn McLaughlin: Protecting neurons and women in science.

McLaughlin studies how neurons respond to acute and chronic stress.

Dan Davis: Up close and personal with immune cells.

Davis uses microscopy and imaging approaches to study immune cell interactions.

Jerry Edward Chipuk: A powerhouse for mitochondrial biology.

Chipuk studies the interaction between mitochondrial dynamics and cell death in cancer.

Johan Auwerx: Sowing the seeds of translational research.

Auwerx studies the signaling networks that underlie mitochondrial function and metabolism.

Dual and Inhibition Demonstrates Synergy against Neuroblastoma.

Anaplastic lymphoma kinase () is the most frequently mutated oncogene in the pediatric cancer neuroblastoma. We performed an screen for synergistic drug combinations that target neuroblastomas with mutations in to determine whether drug combinations could enhance antitumor efficacy. We screened combinations of eight molecularly targeted agents against 17 comprehensively characterized human neuroblastoma-derived cell lines.

The ALK/ROS1 Inhibitor PF-06463922 Overcomes Primary Resistance to Crizotinib in ALK-Driven Neuroblastoma.

Unlabelled: Neuroblastomas harboring activating point mutations in anaplastic lymphoma kinase (ALK) are differentially sensitive to the ALK inhibitor crizotinib, with certain mutations conferring intrinsic crizotinib resistance. To overcome this clinical obstacle, our goal was to identify inhibitors with improved potency that can target intractable ALK variants such as F1174L. We find that PF-06463922 has high potency across ALK variants and inhibits ALK more effectively than crizotinib in vitro.

Crizotinib Synergizes with Chemotherapy in Preclinical Models of Neuroblastoma.

Purpose: The presence of an ALK aberration correlates with inferior survival for patients with high-risk neuroblastoma. The emergence of ALK inhibitors such as crizotinib has provided novel treatment opportunities. However, certain ALK mutations result in de novo crizotinib resistance, and a phase I trial of crizotinib showed a lack of response in patients harboring those ALK mutations.