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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.

Tumor-associated macrophages (TAMs) are a phenotypically diverse, highly plastic population of cells in the tumor microenvironment (TME) that have long been known to promote cancer progression. In this review, we summarize TAM ontogeny and polarization, and then explore how TAMs enhance tumor cell migration through the TME, thus facilitating metastasis. We also discuss how chemotherapy and host factors including diet, obesity, and race, impact TAM phenotype and cancer progression. In brief, TAMs induce epithelial-mesenchymal transition (EMT) in tumor cells, giving them a migratory phenotype. They promote extracellular matrix (ECM) remodeling, allowing tumor cells to migrate more easily. TAMs also provide chemotactic signals that promote tumor cell directional migration towards blood vessels, and then participate in the signaling cascade at the blood vessel that allows tumor cells to intravasate and disseminate throughout the body. Furthermore, while chemotherapy can repolarize TAMs to induce an anti-tumor response, these cytotoxic drugs can also lead to macrophage-mediated tumor relapse and metastasis. Patient response to chemotherapy may be dependent on patient-specific factors such as diet, obesity, and race, as these factors have been shown to alter macrophage phenotype and affect cancer-related outcomes. More research on how chemotherapy and patient-specific factors impact TAMs and cancer progression is needed to refine treatment strategies for cancer patients.

Correspondence to Dr Daniel C Chung, Massachusetts General Hospital, Boston, MA 02114, USA; chung.daniel@mgh.harvard.edu Lynch syndrome is the most common cause of hereditary colon cancer but is also associated with gastric cancer.1 Interestingly, gastric cancer was a distinguishing feature of the original Lynch pedigree described in 1913.2 Currently, the standardised incidence ratio (SIR) for gastric cancer in Lynch syndrome is estimated to be 3.4.3 Among 255 gene-positive patients with Lynch followed prospectively in our Hereditary Gastrointestinal Cancer programme, 7 (2.7%, 95% CI 1.3% to 5.7%) were diagnosed with gastric cancer at a median age of 55 years. Patients with Lynch syndrome, defined by a germline mutation in a DNA mismatch repair gene, were first identified in a REDCap-based Hereditary GI Cancer registry of individuals followed longitudinally at an academic centre, and clinical and endoscopic features were reviewed in those with a new diagnosis of gastric cancer. Table 1 Clinicopathological features of patients with Lynch with gastric cancer Sex Age at GC dx Gene mutation GC histology Location TNM stage Treatment Indication for EGD at GC dx Histology of gastric mucosa Previous cancers 1 F 77 MSH2 (704delAA) Adenoca (intestinal type) Fundus Stage III ypT2N0Mx Chemo, TG D AIG Colon, uterine, non-melanoma skin 2 F 48 MSH2 (229delAG) Adenoca Fundus Stage IB cT1N1 Chemo, TG D AIG Uterine 3 F 57 MSH2 (704delAA) TA-HGD* Cardia Stage 0 Tis Polypectomy S AIG Melanoma, non-melanoma skin 4 F 41 MSH2 (del exon 16) Adenoca (intestinal type) Antrum Stage IA pT1bN0 Partial gastrectomy S LG None 5 M 67 MSH2 (del exons 3–6) Adenoca (intestinal type) GJ anast Stage IB T2N0Mx Chemorad, partial gastrectomy S CAG Colon, pancreatic 6 F 43 MSH2 (NOS) Adenoca (papillary and undifferentiated) Fundus/GEJ Stage IB T2N0Mx Chemorad, partial gastrectomy D NOS None 7 M 55 MLH1 (c.298C>T)† Adenoca Body Stage IA Intramucosal carcinoma Polypectomy S Prolapse-type changes Colon, kidney *This patient also had gastric villous adenoma in a prior exam. †This patient also had an MSH6 variant of unknown significance. [...]a case of lymphocytic gastritis with infiltration of the gastric surface epithelium and glands by numerous T-lymphocytes was seen.

Metastasis is the leading cause of breast cancer death, and tumor cells must migrate and invade to metastasize. Breast cancer cells that express the pro-metastatic actin regulatory protein MenaINV have an enhanced ability to migrate and intravasate within the primary tumor and extravasate at secondary sites. Though chemotherapy improves patient survival, treatment with paclitaxel leads to upregulation of MenaINV and an increase in metastasis in mice. MenaINV expression can be induced in breast cancer cells through cooperative NF-κB/ Notch1 signaling with macrophages, which are often increased in tumors in response to chemotherapy. MenaINV-expressing cells are also resistant to paclitaxel, raising the question of whether paclitaxel increases MenaINV by induction or by selectively killing non-MenaINV-expressing cells. We hypothesized that paclitaxel causes MenaINV induction by increasing macrophage-tumor cell NF-κB/ Notch1 signaling. Understanding this pro-metastatic effect of chemotherapy is crucial to refining treatment strategies. In this study, we demonstrate that paclitaxel increases MenaINV expression by induction. Mechanistically, paclitaxel induces MenaINV by repolarizing tumor-associated macrophages towards a pro-inflammatory phenotype. These pro-inflammatory macrophages then participate in enhanced NF-κB/ Notch1 signaling with tumor cells, which leads to MenaINV induction in the tumor cells. These results lay the groundwork for novel microenvironment-based therapies to alleviate the pro-metastatic effects of chemotherapy in breast cancer.

(If you haven't heard, Puerto Rico is facing a fiscal crisis of epic proportions, with a public debt of more than $70 billion.) If you are a Puerto Rican living stateside — and there are more than 5.3 million of us, according to the Center for Puerto Rican Studies at Hunter College — you surely saw this story. No matter what the Miami Herald, Billboard, the Daily Mail, a CBS Radio affiliate in Sacramento, popular-culture blogs such as UPROXX and Remezcla, and even Newsweek all tell you. A long time ago, my father, a retired reporter who covered the island for decades and witnessed all its beautiful chaos and contradictions, gave me some great advice as I was starting out as a journalist: While its executive director, José Izquierdo, confirmed that the number of searches for Puerto Rico is up on online travel sites, he offered no hard figures on...

Pancreatic ductal adenocarcinoma is poorly immunogenic, and immune suppression prevents T cell activation. We developed a microbial-based immunotherapeutic concept for selective delivery of immunogenic tetanus toxoid (TT856-1313) antigen into tumor cells by attenuated Listeria monocytogenes, and reactivation of TT-specific memory T cells to kill infected tumor cells. Treatment of KPC mice with Listeria-TT resulted in TT accumulation inside tumor cells, and attraction of TT-specific CD4 and CD8 T cells. Lymph node-like structures were frequently observed in contact with pancreatic tumors of treated mice, and exhibited CD4 and CD8 T cells producing IFNgamma. Gemcitabine combined with Listeria-TT significantly improved migration of CD4 T cells into tumors, and enhanced perforin and granzyme B production. The combination treatment also significantly reduced pancreatic tumors and metastases in Panc-02 and KPC mouse models, with minimal side effects, turning cold tumors into hot tumors. This study provides insight into mechanisms for improving immunotherapy for pancreatic cancer. Competing Interest Statement The authors have no competing interest, except Gravekamp. A patent of the Listeria-recall antigen concept is licensed to Loki Therapeutics Footnotes * We have added data survival, CD4 and CD8 T cell depletion, colonization of Listeria in human tumors, infecting and killing human tumors, expressing TT in tumors, RNAscope, RNAseq

Chronic social stress has adverse behavioral consequences and can result in the development of depression in humans. Using a rodent social stress model, we report increased synaptic connectivity between the thalamus and striatum in susceptible mice that controls behavioral coping mechanisms relevant to depression. Postsynaptic remodeling of glutamatergic synapses on ventral striatum (vSTR) medium spiny neurons (MSNs) is critical for shaping stress responses. However, it is unclear which presynaptic inputs are involved. Susceptible mice exhibited increased synaptic strength at intralaminar thalamus (ILT), but not prefrontal cortex (PFC), inputs to vSTR MSNs following chronic social stress. Modulation of ILT-vSTR versus PFC-vSTR neuronal activity differentially regulated dendritic spine plasticity and social avoidance.