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Metastases are initiated by disseminated tumor cells (DTCs) that colonize distant organs. Growing evidence suggests that the microenvironment of the primary tumor primes DTCs for dormant or proliferative fates. However, the manner in which this occurs remains poorly understood. Here, using the Window for High-Resolution Intravital Imaging of the Lung (WHRIL), we study the live lung longitudinally and follow the fate of individual DTCs that spontaneously disseminate from orthotopic breast tumors. We find that spontaneously DTCs have increased levels of retention, increased speed of extravasation, and greater survival after extravasation, compared to experimentally metastasized tumor cells. Detailed analysis reveals that a subset of macrophages within the primary tumor induces a pro-dissemination and pro-dormancy DTC phenotype. Our work provides insight into how specific primary tumor microenvironments prime a subpopulation of cells for expression of proteins associated with dissemination and dormancy. The understanding of the mechanisms underlying the ability of disseminated tumor cells (DTCs) to form metastasis is incomplete. Here, by using high-resolution intravital imaging of the murine lung to track the fate of breast-derived DTCs, the authors show that macrophages within the primary tumor induce a pro-dissemination and pro-dormancy phenotype in tumor cells, favouring their extravasation in the lung.

Background Autologous fat grafting (AFG), defined as the re-implant to the breast of fat tissue from different body areas, has been firstly applied to esthetic plastic surgery and then has moved to reconstructive surgery, mainly used for scar correction and opposite breast altering. Nevertheless, due to the potentially unsafe stem-like properties of adipocytes at the tumoral bed level, no clear evidence of the procedure’s oncological safety has been clearly documented at present. Patients and methods We retrospectively collected data of early breast cancer (BC) patients from 17 Italian Breast Units and assessed differences in terms of locoregional recurrence rate (LRR) and locoregional recurrence-free survival (LRFS) between patients who underwent AFG and patients who did not. Differences were analyzed in the entire cohort of invasive tumors and in different subgroups, according to prognostic biological subtypes. Results With a median follow-up time of 60 months, LRR was 5.3% ( n  = 71) in the matched population, 3.9% ( n  = 18) in the AFG group, and 6.1% ( n  = 53) in the non-AFG group, suggesting non-inferiority of AFG ( p  = 0.084). Building Kaplan–Meier curves confirmed non-inferiority of the AFG procedure for LRFS (aHR 0.73, 95% CI 0.41–1.30, p  = 0.291). The same effect, in terms of LRFS, was also documented among different biological subtypes (luminal-like group, aHR 0.76, 95% CI 0.34–1.68, p  = 0.493; HER2 enriched-like, aHR 0.89, 95% CI 0.19–4.22, p  = 0.882; and TNBC, aHR 0.61, 95% CI 0.12–2.98, p  = 0.543). Conclusions Our study confirms in a very large, multicenter cohort of early BC patients that, aside the well-known benefits on the esthetic result, AFG do not interfere negatively with cancer prognosis.

Macrophages have a key role in shaping the tumour microenvironment (TME), tumour immunity and response to immunotherapy, which makes them an important target for cancer treatment 1 , 2 . However, modulating macrophages has proved extremely difficult, as we still lack a complete understanding of the molecular and functional diversity of the tumour macrophage compartment. Macrophages arise from two distinct lineages. Tissue-resident macrophages self-renew locally, independent of adult haematopoiesis 3 – 5 , whereas short-lived monocyte-derived macrophages arise from adult haematopoietic stem cells, and accumulate mostly in inflamed lesions 1 . How these macrophage lineages contribute to the TME and cancer progression remains unclear. To explore the diversity of the macrophage compartment in human non-small cell lung carcinoma (NSCLC) lesions, here we performed single-cell RNA sequencing of tumour-associated leukocytes. We identified distinct populations of macrophages that were enriched in human and mouse lung tumours. Using lineage tracing, we discovered that these macrophage populations differ in origin and have a distinct temporal and spatial distribution in the TME. Tissue-resident macrophages accumulate close to tumour cells early during tumour formation to promote epithelial–mesenchymal transition and invasiveness in tumour cells, and they also induce a potent regulatory T cell response that protects tumour cells from adaptive immunity. Depletion of tissue-resident macrophages reduced the numbers and altered the phenotype of regulatory T cells, promoted the accumulation of CD8 + T cells and reduced tumour invasiveness and growth. During tumour growth, tissue-resident macrophages became redistributed at the periphery of the TME, which becomes dominated by monocyte-derived macrophages in both mouse and human NSCLC. This study identifies the contribution of tissue-resident macrophages to early lung cancer and establishes them as a target for the prevention and treatment of early lung cancer lesions. Single-cell RNA sequencing and imaging of macrophages in human non-small cell lung cancer and in a mouse model of lung adenocarcinoma show that tissue-resident macrophages have a key role in early tumour progression.

Increasing evidence shows that disseminated cancer cells (DCCs) can disseminate from early-evolved primary lesions much earlier than the classical metastasis models predicted and can enter a state of cellular dormancy at distant sites. The current paradigm suggests that the tissue microenvironment where DCCs lodge is a critical determinant of the timing of metastasis. However, how tissue-resident myeloid cells control this process is unclear. The lung tissue contains a resident population of homeostatic alveolar macrophages (AMs), whose function in metastatic dormancy and growth is poorly understood.Here, we reveal DCC heterogeneity and plasticity in the lung across disease evolution. We found a previously unrecognized role of mesenchymal- and pluripotency-like (M-like) programs in coordinating early cancer cell spread and a long-lived dormancy program in early DCCs. To test whether homeostatic AMs in the lung regulate the dormancy state of cancer cells in vivo, we depleted AMs in mouse models of breast cancer metastasis, using pharmacologic and genetic approaches. Following AM depletion, dormant DCCs began to proliferate and formed clusters and overt metastases. We further showed that in vitro AMs are responsible for inducing an M-like phenotype in cancer cells (of both early and late evolved cancer cells) and exclusively suppressed growth of early lesion MMTV-HER2 cells. Interestingly, AM function appears to be dependent on either the stage of the disease or the type of cancer. Our results suggest that AMs play a key role in limiting metastatic expansion of breast cancer cells via the induction of a DCC dormancy-like phenotype linked to mesenchymal programs. Our study allowed us to determine the specific contribution of the alveolar macrophage population to early DCC biology and metastatic dormancy.

Increasing evidence shows that cancer cells can disseminate from early evolved primary lesions much earlier than the classical metastasis models predicted. Here, we reveal at a single-cell resolution that mesenchymal-like (M-like) and pluripotency-like programs coordinate dissemination and a long-lived dormancy program of early disseminated cancer cells (DCCs). The transcription factor ZFP281 induces a permissive state for heterogeneous M-like transcriptional programs, which associate with a dormancy signature and phenotype in vivo. Downregulation of ZFP281 leads to a loss of an invasive, M-like dormancy phenotype and a switch to lung metastatic outgrowth. We also show that FGF2 and TWIST1 induce ZFP281 expression to induce the M-like state, which is linked to CDH1 downregulation and upregulation of CDH11. We found that ZFP281 not only controls the early dissemination of cancer cells but also locks early DCCs in a dormant state by preventing the acquisition of an epithelial-like proliferative program and consequent metastases outgrowth.

Researchers at the Precision Immunology Institute at the Icahn School of Medicine (PrIISM), New York, describe their contribution to the global research effort against COVID-19 by trying to separate signal from noise in the preprint arena.This Comment article from the Precision Immunology Institute at the Icahn School of Medicine (PrIISM), New York, describes their efforts to provide critical reviews of COVID-19 articles posted daily on the preprint servers bioRxiv and medRxiv.

Purpose. In modern breast cancer treatment, a growing role has been observed for breast reconstruction together with an increase in clinical indications for postmastectomy radiotherapy (PMRT). Choosing the optimum type of reconstructive technique is a clinical challenge. We therefore conducted a national multicenter study to analyze the impact of PMRT on breast reconstruction. Methods. We conducted a retrospective case-control multicenter study on women undergoing breast reconstruction. Data were collected from 18 Italian Breast Centres and stored in a cumulative database which included the following: autologous reconstruction, direct-to-implant (DTI), and tissue expander/immediate (TE/I). For all patients, we described complications and surgical endpoints to complications such as reconstruction failure, explant, change in type of reconstruction, and reintervention. Results. From 2001 to April 2020, 3116 patients were evaluated. The risk for any complication was significantly increased in patients receiving PMRT (aOR, 1.73; 95% CI, 1.33–2.24; p<0.001). PMRT was associated with a significant increase in the risk of capsular contracture in the DTI and TE/I groups (aOR, 2.24; 95% CI, 1.57–3.20; p<0.001). Comparing type of procedures, the risk of failure (aOR, 1.82; 95% CI, 1.06–3.12, p=0.030), explant (aOR, 3.34; 95% CI, 3.85–7.83, p<0.001), and severe complications (aOR, 2.54; 95% CI, 1.88–3.43, p<0.001) were significantly higher in the group undergoing DTI reconstruction as compared to TE/I reconstruction. Conclusion. Our study confirms that autologous reconstruction is the procedure least impacted by PMRT, while DTI appears to be the most impacted by PMRT, when compared with TE/I which shows a lower rate of explant and reconstruction failure. The trial is registered with NCT04783818, and the date of registration is 1 March, 2021, retrospectively registered.

Metastases are initiated by disseminated tumor cells (DTCs) that depart from the primary tumor and colonize target organs. Growing evidence suggests that the microenvironment of the primary tumor lesion primes DTCs to display dormant or proliferative fates in target organs. However, the manner in which events taking place in the primary tumor influence DTC fate, sometimes long after dissemination, remains poorly understood. With the advent of a novel intravital imaging technique called the Window for High-Resolution Intravital Imaging of the Lung (WHRIL), we have, for the first time, been able to study the live lung longitudinally and follow the fate of individual DTCs that spontaneously disseminate from orthotopic breast tumors. We find, across several models, a high rate of success for tumor cells to complete the initial steps of the metastatic cascade in the secondary site, including retention of DTCs in the lung vasculature, speed of extravasation, and survival after extravasation. Importantly, initiation of metastatic growth was controlled primarily by a rate-limiting step that occurred post-extravasation and at the stage of the conversion of single DTCs from a dormant to a proliferative state. Detailed analysis of these events revealed that, even before dissemination, a subset of macrophages within the primary tumor induces, in tumor cells that are about to disseminate, the expression of proteins that regulate a pro-dissemination (MenaINV) and pro-dormancy (NR2F1) phenotype. Surprisingly, if cancer cells are intravenously injected, the rate limiting stages of MenaINV-associated extravasation, dormancy, and other parameters, are lost or altered in a way that impacts how DTCs progress through the metastatic cascade. Our work provides novel insight into how specific primary tumor microenvironments prime a subpopulation of cells for dissemination and dormancy. We also propose that dissecting mechanisms of metastasis, or testing anti-metastatic therapies, may yield results of limited application if derived from models that do not follow spontaneous dissemination. Competing Interest Statement Dr. Julio Aguirre-Ghiso (a Co-author in this article) is a scientific Co-Founder of, Scientific Advisory Board Member, and equity owner in the private company, HiberCell LLC. In addition, Dr. Aguirre-Ghiso receives financial compensation as a consultant for HiberCell LLC. HiberCell LLC. is a Mount Sinai spin-out company focused on the research and development of therapeutics that prevent or delay the recurrence of cancer. Footnotes * https://www.dropbox.com/s/10jksjx2ijjy1hg/Movie%201%20Intravascular%20Tumor%20Cell.avi?dl=0 * https://www.dropbox.com/s/w66acc0mxv5ysqu/Movie%202%20Extravascular%20Tumor%20Cell.avi?dl=0

This study addresses the urgent need for effective methods to monitor and conserve Araucaria angustifolia, a critically endangered species of immense ecological and cultural significance in southern Brazil. Using high-resolution satellite images from Google Earth, we apply the YOLOv7x deep learning model to detect this species in two distinct urban contexts in Curitiba, Paraná: isolated trees across the urban landscape and A. angustifolia individuals within forest remnants. Data augmentation techniques, including image rotation, hue and saturation adjustments, and mosaic augmentation, were employed to increase the model’s accuracy and robustness. Through a 5-fold cross-validation, the model achieved a mean Average Precision (AP) of 90.79% and an F1-score of 88.68%. Results show higher detection accuracy in forest remnants, where the homogeneous background of natural landscapes facilitated the identification of trees, compared to urban areas where complex visual elements like building shadows presented challenges. To reduce false positives, especially misclassifications involving palm species, additional annotations were introduced, significantly enhancing performance in urban environments. These findings highlight the potential of integrating remote sensing with deep learning to automate large-scale forest inventories. Furthermore, the study highlights the broader applicability of the YOLOv7x model for urban forestry planning, offering a cost-effective solution for biodiversity monitoring. The integration of predictive data with urban forest maps reveals a spatial correlation between A. angustifolia density and the presence of forest fragments, suggesting that the preservation of these areas is vital for the species’ sustainability. The model’s scalability also opens the door for future applications in ecological monitoring across larger urban areas. As urban environments continue to expand, understanding and conserving key species like A. angustifolia is critical for enhancing biodiversity, resilience, and addressing climate change.