The adventures of a rogue cell.

Abstract

Data! Data! Data! I can’t make bricks without clay. Sherlock Holmes [1Doyle A.C. The adventure of the copper beeches.The Adventures of Sherlock Holmes. George Newnes Ltd, 1892Google Scholar]One of the most popular crime-solving legends, Sherlock Holmes, has the uncanny ability to solve mysteries through the deduction of simple observations. Though not solving crime, basic scientists embrace a similar rigorous method of formulating questions to investigate the many ‘cases’ still left unsolved, among which remains the cure for cancer. To some, taking time to understand the fundamentals of cancer biology means delays in treating the disease, but the recent progress in cancer therapy today has been shaped largely by basic scientists doing just that. Basic scientists have gathered a wealth of information that has allowed for the design of new drugs that are based on a deep understanding of how cancer cells work. Given their recent success, perhaps we’d be well advised to take a few notes from the pages of Arthur Conan Doyle's creation and basic scientists alike when finding ways to solve the case of cancer. In appreciation of these rapid advances, this special issue of Trends in Cell Biology takes a closer look at the fundamental, cellular mechanisms regulating cancer progression and resistance in an effort to once and for all close the case on cancer. We hope this issue shows our commitment towards providing our readers with continuing coverage of the advances in cancer cell biology. The articles found in this special issue are just a highlight of the many articles to come this year. You can find more cancer-related topics on a Collection page, which will be updated throughout the year, located on our website (http://www.cell.com/trends/cell-biology/home).In true Sherlock Holmes’ fashion, our issue starts with a mystery that has confounded researchers since the discovery of cancer – the undruggable oncogenes. The proto-oncogene Ras is a small GTPase that is responsible for transmitting signals from receptor tyrosine kinases on the plasma membrane to downstream modulators of cell growth. Frequent mutations of Ras in a number of cancers have prompted efforts in developing Ras inhibitors; however, no effective inhibitors have reached the clinic. Philippe Bastiaens and colleagues discuss the biophysical mechanisms of Ras trafficking that are tightly linked to its oncogenic potential and propose that targeting Ras localization may lead to improved therapeutic strategies. Moreover, the Myc family of proto-oncogenes, which encode transcription factors that play pivotal roles in cellular proliferation and survival, are overexpressed in almost half of human cancers. However, the consequences of Myc amplification have prevented researchers from understanding its mechanistic function. David Levens and colleagues synthesize recent studies on Myc amplification and provide a framework for understanding its transcriptional function. In addition to transcription factors and regulatory GTPases, aberrant fibroblast growth factor (FGF) signaling can function in a cell-autonomous fashion, or through modulating tumor–stroma interactions, and activate different downstream pathways depending on cellular context. Richard Grose and colleagues discuss how FGF signaling regulates development and how FGF receptor aberrations promote tumorigenesis.Since tumors do not exist in isolation, the role of the tumor microenvironment has received growing attention. The tumor microenvironment consists of various cells, soluble factors, signaling molecules, and extracellular matrix that can promote tumor initiation, support tumor growth and invasion, and foster therapeutic resistance. Several reviews tackle the complexity of these interactions. Zena Werb and colleagues discuss the duality of the immune system in cancer development and suggest that innate immune cells can tune the inflammatory response to regulate cancer-related inflammation and the fate of tumor development. As the primary receptors involved in cell–matrix adhesion, integrins can influence cancer stemness, metastasis, and therapeutic resistance. David Cheresh and colleagues review how integrin expression can influence the survival and growth of cancer cells in hopes of developing new approaches to target tumors. Florian Klemm and Johanna Joyce reveal the intrinsic and acquired responses of the tumor microenvironment following therapeutic insult and offer possible ways to overcome this resistance.It is clear from the reviews in this issue that fundamental basic research is providing translational researchers with new approaches for targeting cancer. Although many of the complexities of the cell remain unknown, there is an alarming decrease in the number of recent grant applications focused on basic research. Stefano Bertuzzi and Don Cleveland discuss the recent drop in basic science funding and urge scientists to continue pursuing basic research as a way to foster new avenues of drug development. When thinking about how best to eradicate cancer, we can turn to the advice Holmes once gave, ‘… our duty is to unravel it, and isolate it, and expose every inch of it’ [2Doyle A.C. A Study in Scarlet. Ward, Lock & Co, 1887Google Scholar].I thank all of the authors and reviewers for their contributions to this issue, and I thank you for reading it. I also send a special thank you to Stefano Bertuzzi, whose cover design and article helped to inspire the Sherlock Holmes theme. Your comments and ideas are always welcome; you can contact us with feedback or questions at [email protected] or @TrendsCellBio. Data! Data! Data! I can’t make bricks without clay. Sherlock Holmes [1Doyle A.C. The adventure of the copper beeches.The Adventures of Sherlock Holmes. George Newnes Ltd, 1892Google Scholar] One of the most popular crime-solving legends, Sherlock Holmes, has the uncanny ability to solve mysteries through the deduction of simple observations. Though not solving crime, basic scientists embrace a similar rigorous method of formulating questions to investigate the many ‘cases’ still left unsolved, among which remains the cure for cancer. To some, taking time to understand the fundamentals of cancer biology means delays in treating the disease, but the recent progress in cancer therapy today has been shaped largely by basic scientists doing just that. Basic scientists have gathered a wealth of information that has allowed for the design of new drugs that are based on a deep understanding of how cancer cells work. Given their recent success, perhaps we’d be well advised to take a few notes from the pages of Arthur Conan Doyle's creation and basic scientists alike when finding ways to solve the case of cancer. In appreciation of these rapid advances, this special issue of Trends in Cell Biology takes a closer look at the fundamental, cellular mechanisms regulating cancer progression and resistance in an effort to once and for all close the case on cancer. We hope this issue shows our commitment towards providing our readers with continuing coverage of the advances in cancer cell biology. The articles found in this special issue are just a highlight of the many articles to come this year. You can find more cancer-related topics on a Collection page, which will be updated throughout the year, located on our website (http://www.cell.com/trends/cell-biology/home). In true Sherlock Holmes’ fashion, our issue starts with a mystery that has confounded researchers since the discovery of cancer – the undruggable oncogenes. The proto-oncogene Ras is a small GTPase that is responsible for transmitting signals from receptor tyrosine kinases on the plasma membrane to downstream modulators of cell growth. Frequent mutations of Ras in a number of cancers have prompted efforts in developing Ras inhibitors; however, no effective inhibitors have reached the clinic. Philippe Bastiaens and colleagues discuss the biophysical mechanisms of Ras trafficking that are tightly linked to its oncogenic potential and propose that targeting Ras localization may lead to improved therapeutic strategies. Moreover, the Myc family of proto-oncogenes, which encode transcription factors that play pivotal roles in cellular proliferation and survival, are overexpressed in almost half of human cancers. However, the consequences of Myc amplification have prevented researchers from understanding its mechanistic function. David Levens and colleagues synthesize recent studies on Myc amplification and provide a framework for understanding its transcriptional function. In addition to transcription factors and regulatory GTPases, aberrant fibroblast growth factor (FGF) signaling can function in a cell-autonomous fashion, or through modulating tumor–stroma interactions, and activate different downstream pathways depending on cellular context. Richard Grose and colleagues discuss how FGF signaling regulates development and how FGF receptor aberrations promote tumorigenesis. Since tumors do not exist in isolation, the role of the tumor microenvironment has received growing attention. The tumor microenvironment consists of various cells, soluble factors, signaling molecules, and extracellular matrix that can promote tumor initiation, support tumor growth and invasion, and foster therapeutic resistance. Several reviews tackle the complexity of these interactions. Zena Werb and colleagues discuss the duality of the immune system in cancer development and suggest that innate immune cells can tune the inflammatory response to regulate cancer-related inflammation and the fate of tumor development. As the primary receptors involved in cell–matrix adhesion, integrins can influence cancer stemness, metastasis, and therapeutic resistance. David Cheresh and colleagues review how integrin expression can influence the survival and growth of cancer cells in hopes of developing new approaches to target tumors. Florian Klemm and Johanna Joyce reveal the intrinsic and acquired responses of the tumor microenvironment following therapeutic insult and offer possible ways to overcome this resistance. It is clear from the reviews in this issue that fundamental basic research is providing translational researchers with new approaches for targeting cancer. Although many of the complexities of the cell remain unknown, there is an alarming decrease in the number of recent grant applications focused on basic research. Stefano Bertuzzi and Don Cleveland discuss the recent drop in basic science funding and urge scientists to continue pursuing basic research as a way to foster new avenues of drug development. When thinking about how best to eradicate cancer, we can turn to the advice Holmes once gave, ‘… our duty is to unravel it, and isolate it, and expose every inch of it’ [2Doyle A.C. A Study in Scarlet. Ward, Lock & Co, 1887Google Scholar]. I thank all of the authors and reviewers for their contributions to this issue, and I thank you for reading it. I also send a special thank you to Stefano Bertuzzi, whose cover design and article helped to inspire the Sherlock Holmes theme. Your comments and ideas are always welcome; you can contact us with feedback or questions at [email protected] or @TrendsCellBio.