Explore the vast range of titles available.

Mathilda (Tilly), fourteen, and Ruth Anne (Roo), sixteen, are sisters and best friends in Connecticut. After Roo crashes her car while texting she's confined to a hospital bed with \"locked-in syndrome\"--aware of her surroundings, but apparently comatose--and Tilly must find a way to communicate with her sister, while dealing with her own sense of guilt.

Patients with microsatellite instability‐high (MSI‐H) colorectal cancer (CRC) have high tumor mutation burden and tumor immunogenicity, exhibiting a higher response rate to immunotherapy and better survival. However, a portion of MSI‐H CRC patients still experience adverse disease outcomes. We aimed to identify the tumor‐autonomous regulators determining these heterogeneous clinical outcomes. The Cancer Genome Atlas (TCGA) dataset was used to identify regulators in MSI‐H CRC patients with unfavorable outcomes. Stable CRC tumor clones expressing targeted regulators were established to evaluate migratory and stemness properties, immune cell vulnerability, and cell‐in‐cell (CIC) structure formation. RNA‐sequencing (RNA‐seq) was used to identify enriched biological pathways in stable CRC tumor clones. Clinicopathological characterization of formalin‐fixed paraffin‐embedded (FFPE) MSI‐H CRC specimens was performed to explore the underlying mechanisms involved. We showed that cancer/testis antigen family 45 member A1 (CT45A1) expression was upregulated in MSI‐H CRC patients with poor survival outcomes. CT45A1‐expressing microsatellite stable (MSS) CRC cells showed enhanced migratory ability. However, CT45A1‐expressing MSI‐H CRC cells, but not MSS CRC cells, showed higher resistance to natural killer (NK) cell cytotoxicity and served as outer cells in homotypic CIC structures, preventing exogenous or therapeutic antibody access to inner CRC cells. Inactivating RHO‐ROCK/MLCK‐MLC2 signaling with small‐molecule inhibitors or short‐hairpin RNAs (shRNAs) targeting myosin light chain kinase (MYLK) abolished NK cell resistance and reduced the outer cell fate of CT45A1‐expressing MSI‐H CRC cells. In MSI‐H CRC patients, CT45A1‐positive tumors exhibited increased MLC2 phosphorylation, increased outer cell fate, and decreased survival. We demonstrated that CT45A1 potentiates the advanced progression of MSI‐H CRC, and targeting MLC2 phosphorylation may enhance immunotherapy efficacy in CT45A1‐positive MSI‐H CRC patients. CT45A1, a vital driver of the RHO‐ROCK/MLCK‐MLC2 signaling, is found to enhance cancer cell resistance to natural killer (NK) cell killing and generate a protective cell‐in‐cell (CIC) structure in microsatellite instability‐high (MSI‐H) colorectal cancer (CRC) cells. This structure shields the inner CT45A1 (Low) cancer cells from targeted antibody therapy and potentially subsequent antitumor immunity, thereby driving aggressive MSI‐H CRC outcomes.

Entosis—a homotypic insertion of one cell into another, resulting in a death of the invading cell—has been described in many reports, but crucial aspects of its molecular mechanisms and clinical significance still remain controversial. While actomyosin contractility of the invading cell is very well established as a driving force in the initial phase, and autophagy induced in the outer cell is determined as the main mechanism of degradation of the inner cell, many details remain unresolved. The multitude of triggering factors and crisscrossing molecular pathways described in entosis regulation make interpretations difficult. The question of the physiological role of entosis also remains unanswered. In this review, we summarize the knowledge of molecular mechanisms and clinical data concerning entosis accumulated so far, highlighting both coherent explanations and controversies.

Despite the remarkable successes of cancer immunotherapies, the majority of patients will experience only partial response followed by relapse of resistant tumors. While treatment resistance has frequently been attributed to clonal selection and immunoediting, comparisons of paired primary and relapsed tumors in melanoma and breast cancers indicate that they share the majority of clones. Here, we demonstrate in both mouse models and clinical human samples that tumor cells evade immunotherapy by generating unique transient cell-in-cell structures, which are resistant to killing by T cells and chemotherapies. While the outer cells in this cell-in-cell formation are often killed by reactive T cells, the inner cells remain intact and disseminate into single tumor cells once T cells are no longer present. This formation is mediated predominantly by IFNγ-activated T cells, which subsequently induce phosphorylation of the transcription factors signal transducer and activator of transcription 3 (STAT3) and early growth response-1 (EGR-1) in tumor cells. Indeed, inhibiting these factors prior to immunotherapy significantly improves its therapeutic efficacy. Overall, this work highlights a currently insurmountable limitation of immunotherapy and reveals a previously unknown resistance mechanism which enables tumor cells to survive immune-mediated killing without altering their immunogenicity. Cancer immunotherapies use the body’s own immune system to fight off cancer. But, despite some remarkable success stories, many patients only see a temporary improvement before the immunotherapy stops being effective and the tumours regrow. It is unclear why this occurs, but it may have to do with how the immune system attacks cancer cells. Immunotherapies aim to activate a special group of cells known as killer T-cells, which are responsible for the immune response to tumours. These cells can identify cancer cells and inject toxic granules through their membranes, killing them. However, killer T-cells are not always effective. This is because cancer cells are naturally good at avoiding detection, and during treatment, their genes can mutate, giving them new ways to evade the immune system. Interestingly, when scientists analysed the genes of tumour cells before and after immunotherapy, they found that many of the genes that code for proteins recognized by T-cells do not change significantly. This suggests that tumours’ resistance to immune attack may be physical, rather than genetic. To investigate this hypothesis, Gutwillig et al. developed several mouse tumour models that stop responding to immunotherapy after initial treatment. Examining cells from these tumours revealed that when the immune system attacks, they reorganise by getting inside one another. This allows some cancer cells to hide under many layers of cell membrane. At this point killer T-cells can identify and inject the outer cell with toxic granules, but it cannot reach the cells inside. This ability of cancer cells to hide within one another relies on them recognising when the immune system is attacking. This happens because the cancer cells can detect certain signals released by the killer T-cells, allowing them to hide. Gutwillig et al. identified some of these signals, and showed that blocking them stopped cancer cells from hiding inside each other, making immunotherapy more effective. This new explanation for how cancer cells escape the immune system could guide future research and lead to new cancer treatments, or approaches to boost existing treatments. Understanding the process in more detail could allow scientists to prevent it from happening, by revealing which signals to block, and when, for best results.

The purpose of this study was to investigate how human umbilical cord mesenchymal stem cells (HUMSCs) affect breast cancer tumourigenesis. To observe the influence of HUMSCs on tumourigenesis in vitro, we performed a co‐culture of MDA MB‐231 breast cancer cells with HUMSCs, and a result of HUMSCs on tumourigenesis in vivo was achieved by injection of HUMSCs into nonobese diabetic/severe combined immunodeficient mice following tumour establishment with MDA‐MB231. During the co‐culture, apoptosis of MDA‐MB231 was noted, which was driven either by binding with HUMSC through direct cell–cell contact or by formation of a novel cell‐in‐cell phenomenon after internalization of HUMSC. Also, treatment with HUMSC injection was efficacious in both in situ and metastatic breast cancers in the animal models. Since HUMSCs were proved to efficaciously suppress breast cancer tumourigenesis both in vitro and in vivo, it is our expectation that treatment with HUMSCs can be a viable therapy for breast cancer in the near future. In addition, we share a new point of view on the role of HUMSCs in foetal development during pregnancy.

Multiple mechanisms have emerged where the engulfment of whole live cells, leading to the formation of what are called ‘cell-in-cell’ structures, induces cell death. Entosis is one such mechanism that drives cell-in-cell formation during carcinogenesis and development. Curiously, entotic cells participate actively in their own engulfment, by invading into their hosts, and are then killed non-cell-autonomously. Here we review the mechanisms of entosis and entotic cell death and the consequences of entosis on cell populations.

Background A population of regulatory T cells (Treg), which reside within thymic nurse cell complexes, express adiponectin and abrogate breast cancer development in transgenic mice. In this study, we examined whether adiponectin‐expressing Treg could impair triple‐negative breast cancer, which is defined by a lack of estrogen receptors, progesterone receptors, and human epidermal growth factor receptor‐2. Methods CD4‐ and CD25‐positive cells were sorted from cultured T lymphocytes of a previously characterized experimental thymic tumor model composed of thymic nurse cells and abundant lymphoid stroma. These sorted cells were examined for FOXP3 and adiponectin immunoreactivity and subsequently exposed to triple‐negative breast cancer MDA‐MB‐157 and ‐231 cells. Results Adiponectin‐expressing Treg were obtained by CD4‐ and CD25‐positive sorting and cell death was induced in triple‐negative breast cancer cells through the cell‐in‐cell phenomenon. Conclusions Adiponectin‐expressing Treg may be candidates for adoptive cell therapy against triple‐negative breast cancer. Adiponectin‐expressing Treg induced cell death of triple‐negative breast cancer cells through the cell‐in‐cell phenomenon. Triple‐negative breast cancer cells were occulted with adiponectin‐expressing Treg. The cytoplasm of cancer cells was stained red, engulfed adiponectin‐expressing Treg stained green. Horizontal and vertical cell‐in‐cell images are shown in the upper left and lower left, respectively. Numerous adiponectin‐expressing Treg attached and integrated into cancer cells (upper right) subsequently destroyed cancer cells (lower right).

BackgroundIn our previous study, we identified a population of adiponectin expressing regulatory T cells (Tregs) residing within thymic nurse cell complexes, which were capable of inhibiting the development of breast cancer in vitro. Triple-negative breast cancer (TNBC) with no proper treatment at present is characterized by the absence of estrogen receptor, progesterone receptor, and human epidermal growth factor receptor-2. In this study, we aimed to investigate the potential of a cultured T cell fraction comprising adiponectin-expressing Tregs, referred to as A-TregTF (adiponectin-expressing Treg-containing T cell fraction), in inhibiting the progression of TNBC in vivo.MethodsThe efficacy of a spontaneously expanding T cell fraction comprising adiponectin-expressing Treg in inhibiting tumor growth was analyzed in a murine orthotopic 4 T1-Luc TNBC model.ResultsThe treatment with T cell fraction containing adiponectin-expressing Tregs significantly inhibited the growth and metastasis of orthotopically transplanted 4 T1-Luc tumor cells. Histopathological examination further revealed that the adiponectin-expressing Tregs infiltrated the tumor tissue via a cell-in-cell mechanism and were found to be specifically localized around the necrotic areas.ConclusionsBased on our findings, the T cell fraction comprising adiponectin-expressing Tregs, represents a potential candidate for adoptive cell therapy against TNBC.

Cell-in-cell (CIC) structures are commonly seen in tumours. Their biological significance remains unclear, although they have been associated with more aggressive tumours. Here we report that mutant p53 promotes CIC via live cell engulfment. Engulfed cells physically interfere in cell divisions of host cells and for cells without p53 this leads to host cell death. In contrast, mutant p53 host cells survive, display aberrant divisions, multinucleation and tripolar mitoses. In xenograft studies, CIC-rich p53 mutant/null co-cultures show enhanced tumour growth. Furthermore, our results show that CIC is common within lung adenocarcinomas, is an independent predictor of poor outcome and disease recurrence, is associated with mutant p53 expression and correlated to measures of heterogeneity and genomic instability. These findings suggest that pro-tumorigenic entotic engulfment activity is associated with mutant p53 expression, and the two combined are a key factor in genomic instability. Cell-in-cell (CIC) structures are frequently observed in cancers; however, it is unclear how their formation contributes to tumorigenesis. Here, the authors show that the high frequency of CIC is linked to mutant p53 status and CIC containing p53 mutant cancer cells are pro-tumorigenic due to enhanced genomic instability.

Entosis is a phenomenon, in which one cell enters a second one. New clinico-histopathological studies of entosis prompted us to summarize its significance in cancer. It appears that entosis might be a novel, independent prognostic predictor factor in cancer histopathology. We briefly discuss the biological basis of entosis, followed by a summary of published clinico-histopathological studies on entosis significance in cancer prognosis. The correlation of entosis with cancer prognosis in head and neck squamous cell carcinoma, anal carcinoma, lung adenocarcinoma, pancreatic ductal carcinoma and breast ductal carcinoma, is shown. Numerous entotic figures are associated with a more malignant cancer phenotype and poor prognosis in many cancers. We also showed that some anticancer drugs could induce entosis in cell culture, even as an escape mechanism. Thus, entosis is likely beneficial for survival of malignant cells, i.e., an entotic cell can hide from unfavourable factors in another cell and subsequently leave the host cell remaining intact, leading to failure in therapy or cancer recurrence. Finally, we highlight the potential relationship of cell adhesion with entosis in vitro, based on the model of the BxPc3 cells cultured in full adhesive conditions, comparing them to a commonly used MCF7 semiadhesive model of entosis.