Oxana Dmitrieva-Posocco, Andrea C Wong, Patrick Lundgren, Aleksandra M Golos, Hélène C Descamps, Lenka Dohnalová, Zvi Cramer, Yuhua Tian, Brian Yueh, Onur Eskiocak, Gabor Egervari, Yemin Lan, Jinping Liu, Jiaxin Fan, Jihee Kim, Bhoomi Madhu, Kai Markus Schneider, Svetlana Khoziainova, Natalia Andreeva, Qiaohong Wang, Ning Li, Emma E Furth, Will Bailis, Judith R Kelsen, Kathryn E Hamilton, Klaus H Kaestner, Shelley L Berger, Jonathan A Epstein, Rajan Jain, Mingyao Li, Semir Beyaz, Christopher J Lengner, Bryson W Katona, Sergei I Grivennikov, Christoph A Thaiss, Maayan Levy <<<

Colorectal cancer (CRC) is among the most frequent forms of cancer, and new strategies for its prevention and therapy are urgently needed. Here we identify a metabolite signalling pathway that provides actionable insights towards this goal. We perform a dietary screen in autochthonous animal models of CRC and find that ketogenic diets exhibit a strong tumour-inhibitory effect. These properties of ketogenic diets are recapitulated by the ketone body β-hydroxybutyrate (BHB), which reduces the proliferation of colonic crypt cells and potently suppresses intestinal tumour growth. We find that BHB acts through the surface receptor Hcar2 and induces the transcriptional regulator Hopx, thereby altering gene expression and inhibiting cell proliferation. Cancer organoid assays and single-cell RNA sequencing of biopsies from patients with CRC provide evidence that elevated BHB levels and active HOPX are associated with reduced intestinal epithelial proliferation in humans. This study thus identifies a BHB-triggered pathway regulating intestinal tumorigenesis and indicates that oral or systemic interventions with a single metabolite may complement current prevention and treatment strategies for CRC. <<<

Robert Bentham, Kevin Litchfield, Thomas B K Watkins, Emilia L Lim, Rachel Rosenthal, Carlos Martínez-Ruiz, Crispin T Hiley, Maise Al Bakir, Roberto Salgado, David A Moore, Mariam Jamal-Hanjani, TRACERx Consortium, Charles Swanton, Nicholas McGranahan <<<

The immune microenvironment influences tumour evolution and can be both prognostic and predict response to immunotherapy. However, measurements of tumour infiltrating lymphocytes (TILs) are limited by a shortage of appropriate data. Whole-exome sequencing (WES) of DNA is frequently performed to calculate tumour mutational burden and identify actionable mutations. Here we develop T cell exome TREC tool (T cell ExTRECT), a method for estimation of T cell fraction from WES samples using a signal from T cell receptor excision circle (TREC) loss during V(D)J recombination of the T cell receptor-α gene (TCRA (also known as TRA)). TCRA T cell fraction correlates with orthogonal TIL estimates and is agnostic to sample type. Blood TCRA T cell fraction is higher in females than in males and correlates with both tumour immune infiltrate and presence of bacterial sequencing reads. Tumour TCRA T cell fraction is prognostic in lung adenocarcinoma. Using a meta-analysis of tumours treated with immunotherapy, we show that tumour TCRA T cell fraction predicts immunotherapy response, providing value beyond measuring tumour mutational burden. Applying T cell ExTRECT to a multi-sample pan-cancer cohort reveals a high diversity of the degree of immune infiltration within tumours. Subclonal loss of 12q24.31-32, encompassing SPPL3, is associated with reduced TCRA T cell fraction. T cell ExTRECT provides a cost-effective technique to characterize immune infiltrate alongside somatic changes. <<<

Rina Kim, Ayumi Hashimoto, Nune Markosyan, Vladimir A Tyurin, Yulia Y Tyurina, Gozde Kar, Shuyu Fu, Mohit Sehgal, Laura Garcia-Gerique, Andrew Kossenkov, Bereket A Gebregziabher, John W Tobias, Kristin Hicks, Rebecca A Halpin, Nevena Cvetesic, Hui Deng, Laxminarasimha Donthireddy, Andrew Greenberg, Brian Nam, Robert H Vonderheide, Yulia Nefedova, Valerian E Kagan, Dmitry I Gabrilovich <<<

Ferroptosis is a non-apoptotic form of regulated cell death that is triggered by the discoordination of regulatory redox mechanisms culminating in massive peroxidation of polyunsaturated phospholipids. Ferroptosis inducers have shown considerable effectiveness in killing tumour cells in vitro, yet there has been no obvious success in experimental animal models, with the notable exception of immunodeficient mice. This suggests that the effect of ferroptosis on immune cells remains poorly understood. Pathologically activated neutrophils (PMNs), termed myeloid-derived suppressor cells (PMN-MDSCs), are major negative regulators of anti-tumour immunity. Here we found that PMN-MDSCs in the tumour microenvironment spontaneously die by ferroptosis. Although decreasing the presence of PMN-MDSCs, ferroptosis induces the release of oxygenated lipids and limits the activity of human and mouse T cells. In immunocompetent mice, genetic and pharmacological inhibition of ferroptosis abrogates suppressive activity of PMN-MDSCs, reduces tumour progression and synergizes with immune checkpoint blockade to suppress the tumour growth. By contrast, induction of ferroptosis in immunocompetent mice promotes tumour growth. Thus, ferroptosis is a unique and targetable immunosuppressive mechanism of PMN-MDSCs in the tumour microenvironment that can be pharmacologically modulated to limit tumour progression. <<<

Long Song, Jie Liu, Beilu Cao, Bin Liu, Xiaoping Zhang, Zhaoyan Chen, Chaoqun Dong, Xiangqing Liu, Zhaoheng Zhang, Wenxi Wang, Lingling Chai, Jing Liu, Jun Zhu, Shubin Cui, Fei He, Huiru Peng, Zhaorong Hu, Zhenqi Su, Weilong Guo, Mingming Xin, Yingyin Yao, Yong Yan, Yinming Song, Guihua Bai, Qixin Sun, Zhongfu Ni <<<

Modern green revolution varieties of wheat (Triticum aestivum L.) confer semi-dwarf and lodging-resistant plant architecture owing to the Reduced height-B1b (Rht-B1b) and Rht-D1b alleles. However, both Rht-B1b and Rht-D1b are gain-of-function mutant alleles encoding gibberellin signalling repressors that stably repress plant growth and negatively affect nitrogen-use efficiency and grain filling. Therefore, the green revolution varieties of wheat harbouring Rht-B1b or Rht-D1b usually produce smaller grain and require higher nitrogen fertilizer inputs to maintain their grain yields. Here we describe a strategy to design semi-dwarf wheat varieties without the need for Rht-B1b or Rht-D1b alleles. We discovered that absence of Rht-B1 and ZnF-B (encoding a RING-type E3 ligase) through a natural deletion of a haploblock of about 500 kilobases shaped semi-dwarf plants with more compact plant architecture and substantially improved grain yield (up to 15.2%) in field trials. Further genetic analysis confirmed that the deletion of ZnF-B induced the semi-dwarf trait in the absence of the Rht-B1b and Rht-D1b alleles through attenuating brassinosteroid (BR) perception. ZnF acts as a BR signalling activator to facilitate proteasomal destruction of the BR signalling repressor BRI1 kinase inhibitor 1 (TaBKI1), and loss of ZnF stabilizes TaBKI1 to block BR signalling transduction. Our findings not only identified a pivotal BR signalling modulator but also provided a creative strategy to design high-yield semi-dwarf wheat varieties by manipulating the BR signal pathway to sustain wheat production. <<<

Pablo Gainza, Sarah Wehrle, Alexandra Van Hall-Beauvais, Anthony Marchand, Andreas Scheck, Zander Harteveld, Stephen Buckley, Dongchun Ni, Shuguang Tan, Freyr Sverrisson, Casper Goverde, Priscilla Turelli, Charlène Raclot, Alexandra Teslenko, Martin Pacesa, Stéphane Rosset, Sandrine Georgeon, Jane Marsden, Aaron Petruzzella, Kefang Liu, Zepeng Xu, Yan Chai, Pu Han, George F Gao, Elisa Oricchio, Beat Fierz, Didier Trono, Henning Stahlberg, Michael Bronstein, Bruno E Correia <<<

Physical interactions between proteins are essential for most biological processes governing life. However, the molecular determinants of such interactions have been challenging to understand, even as genomic, proteomic and structural data increase. This knowledge gap has been a major obstacle for the comprehensive understanding of cellular protein-protein interaction networks and for the de novo design of protein binders that are crucial for synthetic biology and translational applications. Here we use a geometric deep-learning framework operating on protein surfaces that generates fingerprints to describe geometric and chemical features that are critical to drive protein-protein interactions. We hypothesized that these fingerprints capture the key aspects of molecular recognition that represent a new paradigm in the computational design of novel protein interactions. As a proof of principle, we computationally designed several de novo protein binders to engage four protein targets: SARS-CoV-2 spike, PD-1, PD-L1 and CTLA-4. Several designs were experimentally optimized, whereas others were generated purely in silico, reaching nanomolar affinity with structural and mutational characterization showing highly accurate predictions. Overall, our surface-centric approach captures the physical and chemical determinants of molecular recognition, enabling an approach for the de novo design of protein interactions and, more broadly, of artificial proteins with function. <<<

Endosymbiotic bacteria have evolved intricate delivery systems that enable these organisms to interface with host biology. One example, the extracellular contractile injection systems (eCISs), are syringe-like macromolecular complexes that inject protein payloads into eukaryotic cells by driving a spike through the cellular membrane. Recently, eCISs have been found to target mouse cells, raising the possibility that these systems could be harnessed for therapeutic protein delivery. However, whether eCISs can function in human cells remains unknown, and the mechanism by which these systems recognize target cells is poorly understood. Here we show that target selection by the Photorhabdus virulence cassette (PVC)-an eCIS from the entomopathogenic bacterium Photorhabdus asymbiotica-is mediated by specific recognition of a target receptor by a distal binding element of the PVC tail fibre. Furthermore, using in silico structure-guided engineering of the tail fibre, we show that PVCs can be reprogrammed to target organisms not natively targeted by these systems-including human cells and mice-with efficiencies approaching 100%. Finally, we show that PVCs can load diverse protein payloads, including Cas9, base editors and toxins, and can functionally deliver them into human cells. Our results demonstrate that PVCs are programmable protein delivery devices with possible applications in gene therapy, cancer therapy and biocontrol. <<<

Cheng Chen, Guillaume Bornet, Marcus Bintz, Gabriel Emperauger, Lucas Leclerc, Vincent S Liu, Pascal Scholl, Daniel Barredo, Johannes Hauschild, Shubhayu Chatterjee, Michael Schuler, Andreas M Läuchli, Michael P Zaletel, Thierry Lahaye, Norman Y Yao, Antoine Browaeys <<<

Spontaneous symmetry breaking underlies much of our classification of phases of matter and their associated transitions. The nature of the underlying symmetry being broken determines many of the qualitative properties of the phase; this is illustrated by the case of discrete versus continuous symmetry breaking. Indeed, in contrast to the discrete case, the breaking of a continuous symmetry leads to the emergence of gapless Goldstone modes controlling, for instance, the thermodynamic stability of the ordered phase. Here, we realize a two-dimensional dipolar XY model that shows a continuous spin-rotational symmetry using a programmable Rydberg quantum simulator. We demonstrate the adiabatic preparation of correlated low-temperature states of both the XY ferromagnet and the XY antiferromagnet. In the ferromagnetic case, we characterize the presence of a long-range XY order, a feature prohibited in the absence of long-range dipolar interaction. Our exploration of the many-body physics of XY interactions complements recent works using the Rydberg-blockade mechanism to realize Ising-type interactions showing discrete spin rotation symmetry. <<<

Mark Schmitt, Fatih Ceteci, Jalaj Gupta, Marina Pesic, Tim W Böttger, Adele M Nicolas, Kilian B Kennel, Esther Engel, Matthias Schewe, Asude Callak Kirisözü, Valentina Petrocelli, Yasamin Dabiri, Julia Varga, Mallika Ramakrishnan, Madina Karimova, Andrea Ablasser, Toshiro Sato, Melek C Arkan, Frederic J de Sauvage, Florian R Greten <<<

Solid cancers exhibit a dynamic balance between cell death and proliferation ensuring continuous tumour maintenance and growth. Increasing evidence links enhanced cancer cell apoptosis to paracrine activation of cells in the tumour microenvironment initiating tissue repair programs that support tumour growth, yet the direct effects of dying cancer cells on neighbouring tumour epithelia and how this paracrine effect potentially contributes to therapy resistance are unclear. Here we demonstrate that chemotherapy-induced tumour cell death in patient-derived colorectal tumour organoids causes ATP release triggering P2X4 (also known as P2RX4) to mediate an mTOR-dependent pro-survival program in neighbouring cancer cells, which renders surviving tumour epithelia sensitive to mTOR inhibition. The induced mTOR addiction in persisting epithelial cells is due to elevated production of reactive oxygen species and subsequent increased DNA damage in response to the death of neighbouring cells. Accordingly, inhibition of the P2X4 receptor or direct mTOR blockade prevents induction of S6 phosphorylation and synergizes with chemotherapy to cause massive cell death induced by reactive oxygen species and marked tumour regression that is not seen when individually applied. Conversely, scavenging of reactive oxygen species prevents cancer cells from becoming reliant on mTOR activation. Collectively, our findings show that dying cancer cells establish a new dependency on anti-apoptotic programs in their surviving neighbours, thereby creating an opportunity for combination therapy in P2X4-expressing epithelial tumours. <<<

Cancer is driven by genetic change, and the advent of massively parallel sequencing has enabled systematic documentation of this variation at the whole-genome scale. Here we report the integrative analysis of 2,658 whole-cancer genomes and their matching normal tissues across 38 tumour types from the Pan-Cancer Analysis of Whole Genomes (PCAWG) Consortium of the International Cancer Genome Consortium (ICGC) and The Cancer Genome Atlas (TCGA). We describe the generation of the PCAWG resource, facilitated by international data sharing using compute clouds. On average, cancer genomes contained 4-5 driver mutations when combining coding and non-coding genomic elements; however, in around 5% of cases no drivers were identified, suggesting that cancer driver discovery is not yet complete. Chromothripsis, in which many clustered structural variants arise in a single catastrophic event, is frequently an early event in tumour evolution; in acral melanoma, for example, these events precede most somatic point mutations and affect several cancer-associated genes simultaneously. Cancers with abnormal telomere maintenance often originate from tissues with low replicative activity and show several mechanisms of preventing telomere attrition to critical levels. Common and rare germline variants affect patterns of somatic mutation, including point mutations, structural variants and somatic retrotransposition. A collection of papers from the PCAWG Consortium describes non-coding mutations that drive cancer beyond those in the TERT promoter; identifies new signatures of mutational processes that cause base substitutions, small insertions and deletions and structural variation; analyses timings and patterns of tumour evolution; describes the diverse transcriptional consequences of somatic mutation on splicing, expression levels, fusion genes and promoter activity; and evaluates a range of more-specialized features of cancer genomes. <<<

Yongcai Huang, Haihai Wang, Yidong Zhu, Xing Huang, Shuai Li, Xingguo Wu, Yao Zhao, Zhigui Bao, Li Qin, Yongbo Jin, Yahui Cui, Guangjin Ma, Qiao Xiao, Qiong Wang, Jiechen Wang, Xuerong Yang, Hongjun Liu, Xiaoduo Lu, Brian A Larkins, Wenqin Wang, Yongrui Wu <<<

Teosinte, the wild ancestor of maize (Zea mays subsp. mays), has three times the seed protein content of most modern inbreds and hybrids, but the mechanisms that are responsible for this trait are unknown. Here we use trio binning to create a contiguous haplotype DNA sequence of a teosinte (Zea mays subsp. parviglumis) and, through map-based cloning, identify a major high-protein quantitative trait locus, TEOSINTE HIGH PROTEIN 9 (THP9), on chromosome 9. THP9 encodes an asparagine synthetase 4 enzyme that is highly expressed in teosinte, but not in the B73 inbred, in which a deletion in the tenth intron of THP9-B73 causes incorrect splicing of THP9-B73 transcripts. Transgenic expression of THP9-teosinte in B73 significantly increased the seed protein content. Introgression of THP9-teosinte into modern maize inbreds and hybrids greatly enhanced the accumulation of free amino acids, especially asparagine, throughout the plant, and increased seed protein content without affecting yield. THP9-teosinte seems to increase nitrogen-use efficiency, which is important for promoting a high yield under low-nitrogen conditions. <<<

Gioele La Manno, Ruslan Soldatov, Amit Zeisel, Emelie Braun, Hannah Hochgerner, Viktor Petukhov, Katja Lidschreiber, Maria E Kastriti, Peter Lönnerberg, Alessandro Furlan, Jean Fan, Lars E Borm, Zehua Liu, David van Bruggen, Jimin Guo, Xiaoling He, Roger Barker, Erik Sundström, Gonçalo Castelo-Branco, Patrick Cramer, Igor Adameyko, Sten Linnarsson, Peter V Kharchenko <<<

RNA abundance is a powerful indicator of the state of individual cells. Single-cell RNA sequencing can reveal RNA abundance with high quantitative accuracy, sensitivity and throughput. However, this approach captures only a static snapshot at a point in time, posing a challenge for the analysis of time-resolved phenomena such as embryogenesis or tissue regeneration. Here we show that RNA velocity-the time derivative of the gene expression state-can be directly estimated by distinguishing between unspliced and spliced mRNAs in common single-cell RNA sequencing protocols. RNA velocity is a high-dimensional vector that predicts the future state of individual cells on a timescale of hours. We validate its accuracy in the neural crest lineage, demonstrate its use on multiple published datasets and technical platforms, reveal the branching lineage tree of the developing mouse hippocampus, and examine the kinetics of transcription in human embryonic brain. We expect RNA velocity to greatly aid the analysis of developmental lineages and cellular dynamics, particularly in humans. <<<

Insight denotes a mental restructuring that leads to a sudden gain of explicit knowledge allowing qualitatively changed behaviour. Anecdotal reports on scientific discovery suggest that pivotal insights can be gained through sleep. Sleep consolidates recent memories and, concomitantly, could allow insight by changing their representational structure. Here we show a facilitating role of sleep in a process of insight. Subjects performed a cognitive task requiring the learning of stimulus-response sequences, in which they improved gradually by increasing response speed across task blocks. However, they could also improve abruptly after gaining insight into a hidden abstract rule underlying all sequences. Initial training establishing a task representation was followed by 8 h of nocturnal sleep, nocturnal wakefulness, or daytime wakefulness. At subsequent retesting, more than twice as many subjects gained insight into the hidden rule after sleep as after wakefulness, regardless of time of day. Sleep did not enhance insight in the absence of initial training. A characteristic antecedent of sleep-related insight was revealed in a slowing of reaction times across sleep. We conclude that sleep, by restructuring new memory representations, facilitates extraction of explicit knowledge and insightful behaviour. <<<

Teri A Manolio, Francis S Collins, Nancy J Cox, David B Goldstein, Lucia A Hindorff, David J Hunter, Mark I McCarthy, Erin M Ramos, Lon R Cardon, Aravinda Chakravarti, Judy H Cho, Alan E Guttmacher, Augustine Kong, Leonid Kruglyak, Elaine Mardis, Charles N Rotimi, Montgomery Slatkin, David Valle, Alice S Whittemore, Michael Boehnke, Andrew G Clark, Evan E Eichler, Greg Gibson, Jonathan L Haines, Trudy F C Mackay, Steven A McCarroll, Peter M Visscher <<<

Genome-wide association studies have identified hundreds of genetic variants associated with complex human diseases and traits, and have provided valuable insights into their genetic architecture. Most variants identified so far confer relatively small increments in risk, and explain only a small proportion of familial clustering, leading many to question how the remaining, 'missing' heritability can be explained. Here we examine potential sources of missing heritability and propose research strategies, including and extending beyond current genome-wide association approaches, to illuminate the genetics of complex diseases and enhance its potential to enable effective disease prevention or treatment. <<<

Jinrong Peng , Donald E. Richards , Nigel M. Hartley , George P. Murphy , Katrien M. Devos , John E. Flintham , James Beales , Leslie J. Fish , Anthony J. Worland , Fatima Pelica , Duraialagaraja Sudhakar , Paul Christou , John W. Snape , Michael D. Gale , Nicholas P. Harberd <<<

World wheat grain yields increased substantially in the 1960s and 1970s because farmers rapidly adopted the new varieties and cultivation methods of the so-called ‘green revolution’1,2,3,4. The new varieties are shorter, increase grain yield at the expense of straw biomass, and are more resistant to damage by wind and rain3,4. These wheats are short because they respond abnormally to the plant growth hormone gibberellin. This reduced response to gibberellin is conferred by mutant dwarfing alleles at one of two Reduced height-1 (Rht-B1 and Rht-D1) loci4,5. Here we show that Rht-B1/Rht-D1 and maize dwarf-8 (d8)6,7 are orthologues of the Arabidopsis Gibberellin Insensitive (GAI) gene8,9. These genes encode proteins that resemble nuclear transcription factors and contain an SH2-like10 domain, indicating that phosphotyrosine may participate in gibberellin signalling. Six different orthologous dwarfing mutant alleles encode proteins that are altered in a conserved amino-terminal gibberellin signalling domain. Transgenic rice plants containing a mutant GAI allele give reduced responses to gibberellin and are dwarfed, indicating that mutant GAI orthologues could be used to increase yield in a wide range of crop species. <<<

The human immune system is composed of a distributed network of cells circulating throughout the body, which must dynamically form physical associations and communicate using interactions between their cell-surface proteomes1. Despite their therapeutic potential2, our map of these surface interactions remains incomplete3,4. Here, using a high-throughput surface receptor screening method, we systematically mapped the direct protein interactions across a recombinant library that encompasses most of the surface proteins that are detectable on human leukocytes. We independently validated and determined the biophysical parameters of each novel interaction, resulting in a high-confidence and quantitative view of the receptor wiring that connects human immune cells. By integrating our interactome with expression data, we identified trends in the dynamics of immune interactions and constructed a reductionist mathematical model that predicts cellular connectivity from basic principles. We also developed an interactive multi-tissue single-cell atlas that infers immune interactions throughout the body, revealing potential functional contexts for new interactions and hubs in multicellular networks. Finally, we combined targeted protein stimulation of human leukocytes with multiplex high-content microscopy to link our receptor interactions to functional roles, in terms of both modulating immune responses and maintaining normal patterns of intercellular associations. Together, our work provides a systematic perspective on the intercellular wiring of the human immune system that extends from systems-level principles of immune cell connectivity down to mechanistic characterization of individual receptors, which could offer opportunities for therapeutic intervention. <<<

Takahiro Seki, Yunlong Yang, Xiaoting Sun, Sharon Lim, Sisi Xie, Ziheng Guo, Wenjing Xiong, Masashi Kuroda, Hiroshi Sakaue, Kayoko Hosaka, Xu Jing, Masahito Yoshihara, Lili Qu, Xin Li, Yuguo Chen, Yihai Cao <<<

Glucose uptake is essential for cancer glycolysis and is involved in non-shivering thermogenesis of adipose tissues. Most cancers use glycolysis to harness energy for their infinite growth, invasion and metastasis. Activation of thermogenic metabolism in brown adipose tissue (BAT) by cold and drugs instigates blood glucose uptake in adipocytes. However, the functional effects of the global metabolic changes associated with BAT activation on tumour growth are unclear. Here we show that exposure of tumour-bearing mice to cold conditions markedly inhibits the growth of various types of solid tumours, including clinically untreatable cancers such as pancreatic cancers. Mechanistically, cold-induced BAT activation substantially decreases blood glucose and impedes the glycolysis-based metabolism in cancer cells. The removal of BAT and feeding on a high-glucose diet under cold exposure restore tumour growth, and genetic deletion of Ucp1-the key mediator for BAT-thermogenesis-ablates the cold-triggered anticancer effect. In a pilot human study, mild cold exposure activates a substantial amount of BAT in both healthy humans and a patient with cancer with mitigated glucose uptake in the tumour tissue. These findings provide a previously undescribed concept and paradigm for cancer therapy that uses a simple and effective approach. We anticipate that cold exposure and activation of BAT through any other approach, such as drugs and devices either alone or in combination with other anticancer therapeutics, will provide a general approach for the effective treatment of various cancers. <<<

Mitchell E Fane, Yash Chhabra, Gretchen M Alicea, Devon A Maranto, Stephen M Douglass, Marie R Webster, Vito W Rebecca, Gloria E Marino, Filipe Almeida, Brett L Ecker, Daniel J Zabransky, Laura Hüser, Thomas Beer, Hsin-Yao Tang, Andrew Kossenkov, Meenhard Herlyn, David W Speicher, Wei Xu, Xiaowei Xu, Elizabeth M Jaffee, Julio A Aguirre-Ghiso, Ashani T Weeraratna <<<

Disseminated cancer cells from primary tumours can seed in distal tissues, but may take several years to form overt metastases, a phenomenon that is termed tumour dormancy. Despite its importance in metastasis and residual disease, few studies have been able to successfully characterize dormancy within melanoma. Here we show that the aged lung microenvironment facilitates a permissive niche for efficient outgrowth of dormant disseminated cancer cells-in contrast to the aged skin, in which age-related changes suppress melanoma growth but drive dissemination. These microenvironmental complexities can be explained by the phenotype switching model, which argues that melanoma cells switch between a proliferative cell state and a slower-cycling, invasive state. It was previously shown that dermal fibroblasts promote phenotype switching in melanoma during ageing. We now identify WNT5A as an activator of dormancy in melanoma disseminated cancer cells within the lung, which initially enables the efficient dissemination and seeding of melanoma cells in metastatic niches. Age-induced reprogramming of lung fibroblasts increases their secretion of the soluble WNT antagonist sFRP1, which inhibits WNT5A in melanoma cells and thereby enables efficient metastatic outgrowth. We also identify the tyrosine kinase receptors AXL and MER as promoting a dormancy-to-reactivation axis within melanoma cells. Overall, we find that age-induced changes in distal metastatic microenvironments promote the efficient reactivation of dormant melanoma cells in the lung. <<<

The human immune system is composed of a distributed network of cells circulating throughout the body, which must dynamically form physical associations and communicate using interactions between their cell-surface proteomes. Despite their therapeutic potential, our map of these surface interactions remains incomplete. Here, using a high-throughput surface receptor screening method, we systematically mapped the direct protein interactions across a recombinant library that encompasses most of the surface proteins that are detectable on human leukocytes. We independently validated and determined the biophysical parameters of each novel interaction, resulting in a high-confidence and quantitative view of the receptor wiring that connects human immune cells. By integrating our interactome with expression data, we identified trends in the dynamics of immune interactions and constructed a reductionist mathematical model that predicts cellular connectivity from basic principles. We also developed an interactive multi-tissue single-cell atlas that infers immune interactions throughout the body, revealing potential functional contexts for new interactions and hubs in multicellular networks. Finally, we combined targeted protein stimulation of human leukocytes with multiplex high-content microscopy to link our receptor interactions to functional roles, in terms of both modulating immune responses and maintaining normal patterns of intercellular associations. Together, our work provides a systematic perspective on the intercellular wiring of the human immune system that extends from systems-level principles of immune cell connectivity down to mechanistic characterization of individual receptors, which could offer opportunities for therapeutic intervention. <<<

Jiyoon Lee, Cyrus C Rabbani, Hongyu Gao, Matthew R Steinhart, Benjamin M Woodruff, Zachary E Pflum, Alexander Kim, Stefan Heller, Yunlong Liu, Taha Z Shipchandler, Karl R Koehler <<<

The skin is a multilayered organ, equipped with appendages (that is, follicles and glands), that is critical for regulating body temperature and the retention of bodily fluids, guarding against external stresses and mediating the sensation of touch and pain. Reconstructing appendage-bearing skin in cultures and in bioengineered grafts is a biomedical challenge that has yet to be met. Here we report an organoid culture system that generates complex skin from human pluripotent stem cells. We use stepwise modulation of the transforming growth factor β (TGFβ) and fibroblast growth factor (FGF) signalling pathways to co-induce cranial epithelial cells and neural crest cells within a spherical cell aggregate. During an incubation period of 4-5 months, we observe the emergence of a cyst-like skin organoid composed of stratified epidermis, fat-rich dermis and pigmented hair follicles that are equipped with sebaceous glands. A network of sensory neurons and Schwann cells form nerve-like bundles that target Merkel cells in organoid hair follicles, mimicking the neural circuitry associated with human touch. Single-cell RNA sequencing and direct comparison to fetal specimens suggest that the skin organoids are equivalent to the facial skin of human fetuses in the second trimester of development. Moreover, we show that skin organoids form planar hair-bearing skin when grafted onto nude mice. Together, our results demonstrate that nearly complete skin can self-assemble in vitro and be used to reconstitute skin in vivo. We anticipate that our skin organoids will provide a foundation for future studies of human skin development, disease modelling and reconstructive surgery. <<<