Promoting brown adipose tissue (BAT) formation and function may reduce obesity. Recent data link retinoids to energy balance, but a specific role for retinoid metabolism in white versus brown fat is unknown. Retinaldehyde dehydrogenases (Aldhs), also known as aldehyde dehydrogenases, are rate-limiting enzymes that convert retinaldehyde (Rald) to retinoic acid. Here we show that Aldh1a1 is expressed predominately in white adipose tissue (WAT), including visceral depots in mice and humans. Deficiency of the Aldh1a1 gene induced a BAT-like transcriptional program in WAT that drove uncoupled respiration and adaptive thermogenesis. WAT-selective Aldh1a1 knockdown conferred this BAT program in obese mice, limiting weight gain and improving glucose homeostasis. Rald induced uncoupling protein-1 (Ucp1) mRNA and protein levels in white adipocytes by selectively activating the retinoic acid receptor (RAR), recruiting the coactivator PGC-1α and inducing Ucp1 promoter activity. These data establish Aldh1a1 and its substrate Rald as previously unrecognized determinants of adipocyte plasticity and adaptive thermogenesis, which may have potential therapeutic implications.

Resistance against radio(chemo)therapy-induced cell death is a major determinant of oncological treatment failure and remains a perpetual clinical challenge. The underlying mechanisms are manifold and demand for comprehensive, cancer entity- and subtype-specific examination. In the present study, resistance against radiotherapy was systematically assessed in a panel of human head-and-neck squamous cell carcinoma (HNSCC) cell lines and xenotransplants derived thereof with the overarching aim to extract master regulators and potential candidates for mechanism-based pharmacological targeting. Clonogenic survival data were integrated with molecular and functional data on DNA damage repair and different cell fate decisions. A positive correlation between radioresistance and early induction of HNSCC cell senescence accompanied by NF-κB-dependent production of distinct senescence-associated cytokines, particularly ligands of the CXCR2 chemokine receptor, was identified. Time-lapse microscopy and medium transfer experiments disclosed the non-cell autonomous, paracrine nature of these mechanisms, and pharmacological interference with senescence-associated cytokine production by the NF-κB inhibitor metformin significantly improved radiotherapeutic performance in vitro and in vivo. With regard to clinical relevance, retrospective analyses of TCGA HNSCC data and an in-house HNSCC cohort revealed that elevated expression of CXCR2 and/or its ligands are associated with impaired treatment outcome. Collectively, our study identifies radiation-induced tumor cell senescence and the NF-κB-dependent production of distinct senescence-associated cytokines as critical drivers of radioresistance in HNSCC whose therapeutic targeting in the context of multi-modality treatment approaches should be further examined and may be of particular interest for the subgroup of patients with elevated expression of the CXCR2/ligand axis.

Transforming growth factor β (TGFβ) is a major component of tumor‐derived small extracellular vesicles (TEX) in cancer patients. Mechanisms utilized by TGFβ + TEX to promote tumor growth and pro‐tumor activities in the tumor microenvironment (TME) are largely unknown. TEX produced by head and neck squamous cell carcinoma (HNSCC) cell lines carried TGFβ and angiogenesis‐promoting proteins. TGFβ + TEX stimulated macrophage chemotaxis without a notable M1/M2 phenotype shift and reprogrammed primary human macrophages to a pro‐angiogenic phenotype characterized by the upregulation of pro‐angiogenic factors and functions. In a murine basement membrane extract plug model, TGFβ + TEX promoted macrophage infiltration and vascularization ( p < 0.001), which was blocked by using the TGFβ ligand trap mRER ( p < 0.001). TGFβ + TEX injected into mice undergoing the 4‐nitroquinoline‐1‐oxide (4‐NQO)‐driven oral carcinogenesis promoted tumor angiogenesis ( p < 0.05), infiltration of M2‐like macrophages in the TME ( p < 0.05) and ultimately tumor progression ( p < 0.05). Inhibition of TGFβ signaling in TEX with mRER ameliorated these pro‐tumor activities. Silencing of TGFβ emerges as a critical step in suppressing pro‐angiogenic functions of TEX in HNSCC.

Purpose Free flaps have become the standard option in reconstructive surgery of the head and neck. Even though many authors have outlined the reliability of free transplants, there is an ongoing discussion about treatment options for patients bearing particular risks as previous irradiation treatment. In this analysis, we aim to address these patients with particular risk profiles by comparing different flap entity outcome parameters. Methods We retrospectively analyzed a cohort of 494 patients who underwent flap surgery between 2009 and 2018 in our department. Focusing on free microvascular transplants, we additionally analyzed the pectoralis major myocutaneous flap as the most frequently used vascular pedicled flap. Data analysis was performed by uni-and multivariate statistics. Results Overall flap success rate was 90%, with the radial forearm flap occurring to be most reliable (93%) in head and neck reconstruction. Previous radiation therapy (RT) and intraoperative revision of vascular anastomosis during primary surgery significantly resulted in impaired transplant outcome with a success rate of 91.8% (no RT) vs. 83.7% (RT), respectively. There was a negative linear correlation between incision to suture time and number of flaps per year (R 2 = 0.67). Conclusions Preoperative radiation therapy and intraoperative revision of anastomosis significantly impair outcome of microvascular flaps in the head and neck and oral cavity, whereas patient's age is not a predictor of flap failure. Increasing case number and experience reduces time of flap surgery as well as rate of complications and flap failure.