EGF-SNX3-EGFR axis drives tumor progression and metastasis in triple-negative breast cancers

Epidermal growth factor receptor (EGFR) has critical roles in epithelial cell physiology. Over-expression and over-activation of EGFR have been implicated in diverse cancers, including triple-negative breast cancers (TNBCs), prompting anti‐EGFR therapies. Therefore, developing potent therapies and addressing the inevitable drug resistance mechanisms necessitates deciphering of EGFR related networks. Here, we describe Sorting Nexin 3 (SNX3), a member of the recycling retromer complex, as a critical player in the epidermal growth factor (EGF) stimulated EGFR network in TNBCs. We show that SNX3 is an immediate and sustained target of EGF stimulation initially at the protein level and later at the transcriptional level, causing increased SNX3 abundance. Using a proximity labeling approach, we observed increased interaction of SNX3 and EGFR upon EGF stimulation. We also detected colocalization of SNX3 with early endosomes and endocytosed EGF. Moreover, we show that EGFR protein levels are sensitive to SNX3 loss. Transient RNAi models of SNX3 downregulation have a temporary reduction in EGFR levels. In contrast, long-term silencing forces cells to recover and overexpress EGFR mRNA and protein, resulting in increased proliferation, colony formation, migration, invasion in TNBC cells, and increased tumor growth and metastasis in syngeneic models. Consistent with these results, low SNX3 and high EGFR mRNA levels correlate with poor relapse-free survival in breast cancer patients. Overall, our results suggest that SNX3 is a critical player in the EGFR network in TNBCs with implications for other cancers dependent on EGFR activity.

Cicek, E., Circir, A., Oyken, M. et al. EGF-SNX3-EGFR axis drives tumor progression and metastasis in triple-negative breast cancers. Oncogene (2021). https://doi.org/10.1038/s41388-021-02086-9

Article access: https://www.nature.com/articles/s41388-021-02086-9

Million-year-old DNA sheds light on the genomic history of mammoths

Temporal genomic data hold great potential for studying evolutionary processes such as speciation. However, sampling across speciation events would, in many cases, require genomic time series that stretch well back into the Early Pleistocene subepoch. Although theoretical models suggest that DNA should survive on this timescale1, the oldest genomic data recovered so far are from a horse specimen dated to 780–560 thousand years ago2. Here we report the recovery of genome-wide data from three mammoth specimens dating to the Early and Middle Pleistocene subepochs, two of which are more than one million years old. We find that two distinct mammoth lineages were present in eastern Siberia during the Early Pleistocene. One of these lineages gave rise to the woolly mammoth and the other represents a previously unrecognized lineage that was ancestral to the first mammoths to colonize North America. Our analyses reveal that the Columbian mammoth of North America traces its ancestry to a Middle Pleistocene hybridization between these two lineages, with roughly equal admixture proportions. Finally, we show that the majority of protein-coding changes associated with cold adaptation in woolly mammoths were already present one million years ago. These findings highlight the potential of deep-time palaeogenomics to expand our understanding of speciation and long-term adaptive evolution.

Tom van der Valk, Patrícia Pečnerová, David Díez-del-Molino, Anders Bergström, Jonas Oppenheimer, Stefanie Hartmann, Georgios Xenikoudakis, Jessica A. Thomas, Marianne Dehasque, Ekin Sağlıcan, Fatma Rabia Fidan, Ian Barnes, Shanlin Liu, Mehmet Somel, Peter D. Heintzman, Pavel Nikolskiy, Beth Shapiro, Pontus Skoglund, Michael Hofreiter, Adrian M. Lister, Anders Götherström & Love Dalén. Million-year-old DNA sheds light on the genomic history of mammoths. Nature 591, 265–269 (2021). https://doi.org/10.1038/s41586-021-03224-9

Article access: https://www.nature.com/articles/s41586-021-03224-9

Impacts of multiple stressors on freshwater biota across spatial scales and ecosystems

Climate and land-use change drive a suite of stressors that shape ecosystems and interact to yield complex ecological responses (that is, additive, antagonistic and synergistic effects). We know little about the spatial scales relevant for the outcomes of such interactions and little about effect sizes. These knowledge gaps need to be filled to underpin future land management decisions or climate mitigation interventions for protecting and restoring freshwater ecosystems. This study combines data across scales from 33 mesocosm experiments with those from 14 river basins and 22 cross-basin studies in Europe, producing 174 combinations of paired-stressor effects on a biological response variable. Generalized linear models showed that only one of the two stressors had a significant effect in 39% of the analysed cases, 28% of the paired-stressor combinations resulted in additive effects and 33% resulted in interactive (antagonistic, synergistic, opposing or reversal) effects. For lakes, the frequencies of additive and interactive effects were similar for all spatial scales addressed, while for rivers these frequencies increased with scale. Nutrient enrichment was the overriding stressor for lakes, with effects generally exceeding those of secondary stressors. For rivers, the effects of nutrient enrichment were dependent on the specific stressor combination and biological response variable. These results vindicate the traditional focus of lake restoration and management on nutrient stress, while highlighting that river management requires more bespoke management solutions.

Sebastian Birk, Daniel Chapman, Laurence Carvalho, Bryan M. Spears, Hans Estrup Andersen, Christine Argillier, Stefan Auer, Annette Baattrup-Pedersen, Lindsay Banin, Meryem Beklioğlu, Elisabeth Bondar-Kunze, Angel Borja, Paulo Branco, Tuba Bucak, Anthonie D. Buijse, Ana Cristina Cardoso, Raoul-Marie Couture, Fabien Cremona, Dick de Zwart, Christian K. Feld, M. Teresa Ferreira, Heidrun Feuchtmayr, Mark O. Gessner, Alexander Gieswein, Lidija Globevnik, Daniel Graeber, Wolfram Graf, Cayetano Gutiérrez-Cánovas, Jenica Hanganu, Uğur Işkın, Marko Järvinen, Erik Jeppesen, Niina Kotamäki, Marijn Kuijper, Jan U. Lemm, Shenglan Lu, Anne Lyche Solheim, Ute Mischke, S. Jannicke Moe, Peeter Nõges, Tiina Nõges, Steve J. Ormerod, Yiannis Panagopoulos, Geoff Phillips, Leo Posthuma, Sarai Pouso, Christel Prudhomme, Katri Rankinen, Jes J. Rasmussen, Jessica Richardson, Alban Sagouis, José Maria Santos, Ralf B. Schäfer, Rafaela Schinegger, Stefan Schmutz, Susanne C. Schneider, Lisa Schülting, Pedro Segurado, Kostas Stefanidis, Bernd Sures, Stephen J. Thackeray, Jarno Turunen, María C. Uyarra, Markus Venohr, Peter Carsten von der Ohe, Nigel Willby & Daniel Hering. Impacts of multiple stressors on freshwater biota across spatial scales and ecosystems. Nat Ecol Evol 4, 1060–1068 (2020). https://doi.org/10.1038/s41559-020-1216-4

Article access: https://www.nature.com/articles/s41559-020-1216-4

USP32 regulates late endosomal transport and recycling through deubiquitylation of Rab7

The endosomal system is a highly dynamic multifunctional organelle, whose complexity is regulated in part by reversible ubiquitylation. Despite the wide-ranging influence of ubiquitin in endosomal processes, relatively few enzymes utilizing ubiquitin have been described to control endosome integrity and function. Here we reveal the deubiquitylating enzyme (DUB) ubiquitin-specific protease 32 (USP32) as a powerful player in this context. Loss of USP32 inhibits late endosome (LE) transport and recycling of LE cargos, resulting in dispersion and swelling of the late compartment. Using SILAC-based ubiquitome profiling we identify the small GTPase Rab7—the logistical centerpiece of LE biology—as a substrate of USP32. Mechanistic studies reveal that LE transport effector RILP prefers ubiquitylation-deficient Rab7, while retromer-mediated LE recycling benefits from an intact cycle of Rab7 ubiquitylation. Collectively, our observations suggest that reversible ubiquitylation helps switch Rab7 between its various functions, thereby maintaining global spatiotemporal order in the endosomal system.

Aysegul Sapmaz, Ilana Berlin, Erik Bos, Ruud H. Wijdeven, Hans Janssen, Rebecca Konietzny, Jimmy J. Akkermans, Ayse E. Erson-Bensan, Roman I. Koning, Benedikt M. Kessler, Jacques Neefjes & Huib Ovaa. USP32 regulates late endosomal transport and recycling through deubiquitylation of Rab7. Nat Commun 10, 1454 (2019). https://doi.org/10.1038/s41467-019-09437-x

Article access: https://www.nature.com/articles/s41467-019-09437-x