Impact of the corona pandemic on cancer research

“It is absolutely not acceptable for cancer patients to become collateral damage from this crisis” Helen Rippon (CEO, Worldwide Cancer Research)

The SARS-CoV2 pandemic has had a wide ranging impact on all areas of our lives. Lab-based scientific research has taken a big hit in most countries, and this has affected most projects extremely negatively. STV recently ran an item interviewing cancer research scientists from three different countries to discuss their experiences. Not only has the lockdown halted research progress, the funding of cancer research has already been hard hit.

Click on photo to watch the video and look out for appearances by some familiar faces.

In coronavirus chaos – all is not lost

PhD student Sonia Aristin is working to understand the the tumor-immune niche in colorectal cancer and how tumors can repress immune responses. She has been lucky to able to perform some limited lab work during the current corona-lockdown. Sonia’s research is funded by Worldwide Cancer Research. They recently interviewed her to learn a little more of her experience as a cancer researcher in these challenging times. Read the interview by clicking the link below.

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C/EBPα: a novel epithelial gatekeeper preventing EMT and metastasis

Extracellular signals such as TGF-β can induce epithelial-to-mesenchymal transition (EMT) in cancers of epithelial origin, promoting molecular and phenotypical changes resulting in prometastatic characteristics. We identified C/EBPα as one of the most TGF-β-mediated downregulated transcription factors in human mammary epithelial cells. C/EBPα expression prevents TGF-β-driven EMT by inhibiting expression of known EMT factors. Depletion of C/EBPα is sufficient to induce mesenchymal-like morphology and molecular features, while cells that had undergone TGF-β-induced EMT reverted to an epithelial-like state upon C/EBPα re-expression. In vivo, mice injected with C/EBPα-expressing breast tumor organoids display a dramatic reduction of metastatic lesions. Collectively, our results show that C/EBPα is required for maintaining epithelial homeostasis by repressing the expression of key mesenchymal markers, thereby preventing EMT-mediated tumorigenesis. These data suggest that C/EBPα is a master epithelial “gatekeeper” whose expression is required to prevent unwarranted mesenchymal transition, supporting an important role for EMT in mediating breast cancer metastasis.

This work is a collaborative effort between our group and Jacco van Rheenen (Netherlands Cancer Institute). Part of a long-term research line aimed to understand the molecular pathways underlying tumour metastasis. You can read more about this work here in Nature Communications.

This work was supported by funding from the FCT and Dutch Cancer Society

Welcome new PhD student Ed Corrigan

Ed Corrigan graduated from University of Maastricht before completing a Masters in Cancer, Stem Cells & Developmental Biology from Utrecht University. He has recently joined the Coffer Lab to work on a project focusing on understanding the biology and function of CD4+ effector T (Teff) cells in Juvenile Idiopathic Arthritis.

Juvenile idiopathic arthritis (JIA) is a chronic autoimmune disease affecting up to 1/1000 children in Western countries. Like many autoimmune diseases, it is caused by a loss of tolerance whereby inappropriately active T lymphocytes (T cells) in the joint help to generate a perpetuating inflammatory environment. One critical control mechanism that ensures that peripheral T cells avoid inappropriate activation is the induction of anergy. Anergy is defined as a state of unresponsiveness induced by suboptimal T cell stimulation from engagement of the T cell receptor (TCR) in the absence of co-stimulation. TCR activation without co-stimulation leads to a hyporesponsive state termed anergy, where cells not proliferate or produce cytokines, and are resistant to subsequent stimulation. Recent studies have expanded our understanding of the complex set of inputs that T cells integrate to determine their fate and engage in effector functions or become anergic. Interestingly, we have found that T cells isolated from the synovial fluid of JIA patients are resistant to anergy. In collaboration with the Macian Lab (Albert Einstein, NYC) we are the first to show a connection between autophagy and anergy. Whereas T cells that are allowed to induce autophagy become activated and primed to respond to subsequent stimulations, cells where activation-induced autophagy is prevented become anergic and show markedly reduced responses to re-stimulation. Importantly, inhibition of autophagy during T cell activation can lead to an ‘anergy-like’ long-lasting state of hyporesponsiveness.

In this project Ed will be examining the link between resistance to anergy and autophagy in JIA T cells, and evaluating relevance for disease pathogenesis and therapeutic intervention.

This work is supported by a grant from the Dutch Arthritis Foundation.

Welcome new postdoc Nader Atlasy

Nader Atlasy has recently finished a PhD in Henk Stunnenberg’s lab at Radboud MC.. He has joined the Coffer Lab to work on a collaborative project together with Onno Kranenburg and Genmab bv focusing on understanding the biology and function of regulatory T (Treg) cells in colorectal cancer (CRC).

The immune compartment of the tumor microenvironment has recently attracted extensive interest due to its importance both in the understanding of basic tumor biology and implications for clinical applications. Importantly, the Immune Score (IS) that assesses immune infiltrate, has been shown to provide high prognostic value for certain cancer types. For example, when compared to other clinical criteria, the IS of both primary tumors and metastases was shown to be a better predictor of disease recurrence and survival in colorectal cancer patients following surgery. From a functional perspective, one of the key features of the tumor-immune contexture is its immunosuppressive environment, which underlies the basis for tumor escape from host immune destruction. While both tumor-intrinsic and -extrinsic mechanisms have been explored, it is now generally accepted that FOXP3+ T regulatory (Treg) cells, a small subpopulation of CD4+ T cells endowed with potent suppressive capacity, can play a pivotal role in inducing tumor-specific immune tolerance. Colorectal cancer (CRC) is diagnosed over 1.5 million worldwide each year and is the third most common cause of cancer-related mortality (700,000 CRC-related deaths per year). Mortality is almost invariably due to the development of distant metastases and the factors that determine whether or not a tumor will metastasize are poorly understood and an area of intense investigation. Sonia will be exploring the identity of CRC tumor-associated immune cells and the functional consequences of interactions between Treg cells and CRC tumors using a variety of state-of-the-art in vitro and in vivo tumor-organoid models.

Welcome new PhD student Sonia Arístin

Sonia Arístin graduated from Universidad de Alcalá (Madrid, Spain) before completing a Masters in Biomedical Sciences (Oncology track) from University of Amsterdam (UvA). She has recently joined the Coffer Lab to work on a collaborative project together with Onno Kranenburg focusing on understanding the biology and function of regulatory T (Treg) cells in colorectal cancer (CRC).

The immune compartment of the tumor microenvironment has recently attracted extensive interest due to its importance both in the understanding of basic tumor biology and implications for clinical applications.  Importantly, the Immune Score (IS) that assesses immune infiltrate, has been shown to provide high prognostic value for certain cancer types.  For example, when compared to other clinical criteria, the IS of both primary tumors and metastases was shown to be a better predictor of disease recurrence and survival in colorectal cancer patients following surgery. From a functional perspective, one of the key features of the tumor-immune contexture is its immunosuppressive environment, which underlies the basis for tumor escape from host immune destruction. While both tumor-intrinsic and -extrinsic mechanisms have been explored, it is now generally accepted that FOXP3+ T regulatory (Treg) cells, a small subpopulation of CD4+ T cells endowed with potent suppressive capacity, can play a pivotal role in inducing tumor-specific immune tolerance. Colorectal cancer (CRC) is diagnosed over 1.5 million worldwide each year and is the third most common cause of cancer-related mortality (700,000 CRC-related deaths per year). Mortality is almost invariably due to the development of distant metastases and the factors that determine whether or not a tumor will metastasize are poorly understood and an area of intense investigation. Sonia will be exploring the functional consequences of interactions between Treg cells and CRC tumors using a variety of state-of-the-art in vitro and in vivo tumor-organoid models.

This work is supported by a grant from World Wide Cancer Research.

A druggable Foxp3 stability circuit that can fine-tune immune homeostasis

The Foxp3 transcription factor is a crucial determinant of both regulatory T (Treg) cell development and their functional maintenance. Appropriate modulation of tolerogenic immune responses therefore requires the tight regulation of Foxp3 transcriptional output, and this involves both transcriptional and post-translational regulation. Here, we show that during T cell activation, phosphorylation of Foxp3 in Treg cells can be regulated by a TGF-β activated kinase 1 (TAK1)-Nemo-like kinase (NLK) signaling pathway. NLK interacts and phosphorylates Foxp3 in Treg cells, resulting in the stabilization of protein levels by preventing association with the STUB1 E3-ubiquitin protein ligase. Conditional Treg cell NLK-knockout (NLKΔTreg) results in decreased Treg cell-mediated immunosuppression in vivo, and NLK-deficient Treg cell animals develop more severe experimental autoimmune encephalomyelitis. Our data suggest a molecular mechanism, in which stimulation of TCR-mediated signaling can induce a TAK1-NLK pathway to sustain Foxp3 transcriptional activity through the stabilisation of protein levels, thereby maintaining TREG cell suppressive function. This work is a collaborative effort between our group and Dietmar Zaiss and has been driven by Veerle Fleskens (UMCU) and Carlos Minutti (University of Edinburgh) together with many important international partners. Part of a long-term research line we have identified a druggable Foxp3 stability circuit that could be used to modulate Treg cell activity in a variety of pathological situations. You can read more about this work here in Cell Reports.

Welcome to new PhD student Alessandro Cutilli

Alessandro Cutilli recently graduated from University of Padua (Italy) and has joined the Coffer Lab to work on a collaborative project together with Caroline Lindeman’s group focusing on CD4+ T cells in graft-versus-host-disease. Graft-versus-Host-Disease is the most life-threatening complication following allogeneic hematopoietic stem cell transplantation (HSCT) where patients are transplanted with a combination of donor hematopoietic stem cells and lymphocytes. Despite treatment and prevention strategies GvHD with intestinal and liver involvement still has around a 30% mortality rate and forms a large urgent unmet medical need. Transferred alloreactive T cells respond in a complex manner, and the reasons for induction of GvHD, while involving inappropriately targeted CD4+ T cell activation, remain largely unclear and difficult to predict. Devising strategies to transiently "inactivate" T cells that mediate unwanted immune responses will have important implications for the control GvHD after bone marrow transplantation. Existing therapies, such as steroid-treatment, tend to broadly suppress undesirable immune responses, are often ineffective, and can trigger a variety of unwanted side effects. This is particularly dangerous in transplant patients who are extremely susceptible to infection. One critical control mechanism that ensures peripheral T cells avoid inappropriate activation is the induction of anergy, a hyporesponsive-state where cells don’t proliferate or produce cytokines and are more resistant to subsequent stimulation. Our recent preliminary data has shown for the first time that it is possible to induce anergy in CD4+ T cell populations by inhibiting (macro)autophagy, even in hyperactivated cells. Alessandro will be further investigating this using complex in vitro 3D cell culture systems as part of the EU COFUND RESCUE consortium.