查看更多>>摘要：This month, Nature Reviews Cancer launches ‘Tools of the Trade’ articles. These articles were first developed by Nature Reviews Earth & Environment and are intended to be a place where scientists who we term ‘early career researchers’ (ECRs) — graduate students, postdoctoral fellows and scientists who are just starting their independent research career — can discuss the methods or tools that they use to conduct their research. We know that a large proportion of this journal’s readers are ECRs and as such wanted to give ECRs a bigger voice in the journal’s content. Although ECRs are often the first authors of our Review and Perspective articles, and contribute substantially to our pages in this way, they do not always have the opportunity to voice their own opinions, or discuss what is important to them in these articles. Tools of the Trade articles are intended to fill a bit of that gap and give the scientists in the lab doing the research day-in and day-out a chance to talk about the tools that were essential for them to make their scientific discoveries.
查看更多>>摘要：mRNA vaccines have proven safe and effective in preventing serious illness and death during the COVID-19 pandemic. These technologies offer a novel and intriguing approach towards personalizing immune-based treatments for patients with cancer—regardless of cancer type — with the potential for immune activation beyond commonly utilized immunotherapies.
查看更多>>摘要：How tumour cells in pancreatic ductal adenocarcinoma (PDAC) evade digestion by secreted pancreatic enzymes remains unclear. Lv and colleagues show that in PDAC cells, the pore forming protein gasdermin E (GSDME) promotes the production of mucin 1 (MUC1) and mucin 13 (MUC13) (key components of the protective mucous layer of pancreatic epithelia) by transporting the transcription factor YBX1 to the nucleus, revealing that GSDME protects PDAC from digestion. As GSDME expression levels are high in human PDAC cell lines, the authors knocked down GSDME with single guide RNAs (GSDME-SG) in human PDAC cells; GSDME-SG cells were sensitized to the cytotoxic action of the pancreatic enzymes trypsin and chymotrypsin, indicating that GSDME is required for PDAC cells to resist digestion. In addition, the expression of MUC1 and MUC13 was reduced in GSDME-SG cells, which led to impaired resistance to digestive enzymes in vitro and delayed tumour growth in orthotopic transplants of GSDME-SG cells in mice. Expression of exogenous MUC1 and MUC13 in GSDME-SG cells rescued both phenotypes. Thus, GSDME seems to promote resistance to digestion by inducing MUC1 and MUC13 expression.
查看更多>>摘要：Androgens are known to dampen production of IFNγ, a cytokine that enhances the clinical response to immune checkpoint blockade therapy (for example, with an anti-PDl agent). However, the role of an drogens in immunotherapy resistance in metastatic castration-resistant prostate cancer (mCRPC) has been unclear. Now, a paper in Nature shows that the androgen receptor (AR) represses Ifng transcription in T cells. AR blockade restores the ability of CD8+ T cells to produce effector cytokines (including IFNγ), and AR blockade combined with androgen deprivation therapy (ADT) increases T cell response to PD1 inhibition and prolongs survival in mouse models of prostate cancer and sarcoma. Guan et al. analysed cells isolated from biopsy samples from eight individuals with mCRPC who were enrolled in a clinical trial of combined AR blockade (with enzalutamide) and PD1 blockade (three of the individuals responded to treatment with the PD1 inhibitor pembrolizumab during the trial, and five did not).
查看更多>>摘要：The extracellular matrix (ECM) is a vast, enormously complex structure made of proteins and glycans that shapes and supports all organs while enforcing cell behaviour. As cancer develops, a warped ECM, resulting from tumour-driven remodelling, promotes cancer cell invasion and metastasis. Understanding the tumour microenvironment (TME) requires a precise representation of the ECM; however, the three-dimensional arrangement of ECM components across healthy tissues and tumours is a poorly explored field. Native ECM, used as a biomaterial for cancer bioengineering, can yield invaluable information about its role during key steps of cancer progression. However, one obstacle impeding ECM mapping is its exquisite sensitivity to chemical denaturation: fixatives and clearing methods can alter ECM structure and result in single-cell resolution imaging, which is insufficient for detailed ECM exploration. I developed in situ decellularization to address both tumour deconstruction and reassembly. Tumours have an irregular vasculature, but it is possible to shunt vascular flow towards the area containing the lesion and perfuse decellularizing reagents to isolate ECM scaffolds that conserve their spatial integrity.
查看更多>>摘要：Many cancer cells contain numerous copies of small DNA circles that are not part of the chromosomes. This unusual ‘extrachromosomal DNA’ (ecDNA) carries cancer-promoting genes and has been associated with tumour drug resistance and poor patient outcome. The presence and amount of ecDNA, as well as the specific gene sequences each circle contains, vary substantially from one cancer cell to the next even within the same patient and are important factors that can influence tumour growth. However, the lack of a method for directly observing the behaviour of ecDNA in living cells has limited our ability to understand how it contributes to cancer progression.
查看更多>>摘要：Despite many significant advances in cancer therapies, resistance still remains a critical problem preventing durable responses and complete cures. While it is important to dissect the molecular mechanisms of therapy resistance, understanding how resistance evolves can unveil additional therapeutic opportunities. A key question is if resistance is pre-existing in a rare sub-fraction of cancer cell clones or obtained by some cancer cell clones only upon treatment. This knowledge could dictate which therapeutic strategy to pursue: specifically targeting the pre-existing relevant subfraction with a second drug in a combination treatment or targeting the relevant mechanism that allows adaptation to the primary treatment. To assess if a resistant clone was inherently resistant or adapted under treatment, the treatment-naive condition needs to be investigated. However, these clones can be particularly rare, and finding them in a complex cancer cell population is challenging. Classical sequencing approaches lack the necessary resolution, and conventional DNA barcoding experiments only allow indirect conclusions.
Marilyne LabrieJoan S. BruggeGordon B. Millsloannis K. Zervantonakis...
17页
查看更多>>摘要：Normal cells explore multiple states to survive stresses encountered during development and self-renewal as well as environmental stresses such as starvation, DNA damage, toxins or infection. Cancer cells co-opt normal stress mitigation pathways to survive stresses that accompany tumour initiation, progression, metastasis and immune evasion. Cancer therapies accentuate cancer cell stresses and invoke rapid non-genomic stress mitigation processes that maintain cell viability and thus represent key targetable resistance mechanisms. In this Review, we describe mechanisms by which tumour ecosystems, including cancer cells, immune cells and stroma, adapt to therapeutic stresses and describe three different approaches to exploit stress mitigation processes: (1) interdict stress mitigation to induce cell death; (2) increase stress to induce cellular catastrophe; and (3) exploit emergent vulnerabilities in cancer cells and cells of the tumour microenvironment. We review challenges associated with tumour heterogeneity, prioritizing actionable adaptive responses for optimal therapeutic outcomes, and development of an integrative framework to identify and target vulnerabilities that arise from adaptive responses and engagement of stress mitigation pathways. Finally, we discuss the need to monitor adaptive responses across multiple scales and translation of combination therapies designed to take advantage of adaptive responses and stress mitigation pathways to the clinic.
查看更多>>摘要：Senescence is a cellular response to a variety of stress signals that is characterized by a stable withdrawal from the cell cycle and major changes in cell morphology and physiology. While most research on senescence has been performed on non-cancer cells, it is evident that cancer cells can also mount a senescence response. In this Review, we discuss how senescence can be induced in cancer cells. We describe the distinctive features of senescent cancer cells and how these changes in cellular physiology might be exploited for the selective eradication of these cells (senolysis). We discuss activation of the host immune system as a particularly attractive way to clear senescent cancer cells. Finally, we consider the challenges and opportunities provided by a ‘one-two punch’ sequential treatment of cancer with pro-senescence therapy followed by senolytic therapy.
查看更多>>摘要：Cyclin-dependent kinase 4 (CDK4) and CDK6 are critical mediators of cellular transition into S phase and are important for the initiation, growth and survival of many cancer types. Pharmacological inhibitors of CDK4/6 have rapidly become a new standard of care for patients with advanced hormone receptor-positive breast cancer. As expected, CDK4/6 inhibitors arrest sensitive tumour cells in the G1 phase of the cell cycle. However, the effects of CDK4/6 inhibition are far more wide-reaching. New insights into their mechanisms of action have triggered identification of new therapeutic opportunities, including the development of novel combination regimens, expanded application to a broader range of cancers and use as supportive care to ameliorate the toxic effects of other therapies. Exploring these new opportunities in the clinic is an urgent priority, which in many cases has not been adequately addressed. Here, we provide a framework for conceptualizing the activity of CDK4/6 inhibitors in cancer and explain how this framework might shape the future clinical development of these agents. We also discuss the biological underpinnings of CDK4/6 inhibitor resistance, an increasingly common challenge in clinical oncology.
NSTL