||Introduction to the course
||First, we will get to know each other! Then we will go over the syllabus, including expectations and goals of the class, an overview of the course, and an introduction to the first two papers. We will also discuss strategies for reading primary scientific papers.
||Uncontrolled proliferation: Sonic hedgehog signaling in the developing brain and brain tumors
||Out-of-control cell growth, or proliferation, is a unifying characteristic of cancer. Sonic hedgehog (Shh) is a secreted protein that drives proliferation of a certain class of neurons in the developing cerebellum called granule neurons. Importantly, if the Shh pathway is not controlled, granule neurons can over-proliferate and generate brain tumors. Mutations in the Shh pathway are common in a childhood brain tumor, medulloblastoma, as well as a number of other cancers. Shh is important in the normal development of the limbs, teeth, lungs, pancreas, nervous system and other organs.
||Proto-oncogenes at the root of developmental disorders and cancer: the example of K-ras
||Proto-oncogenes are genes that when mutated or amplified acquire a tumorigenic potential and thus become frank oncogenes. Oncogenic mutations in Kras are prevalent in a large number of solid tumors, including those of pancreas, lung, colon and ovaries. In most cases, Kras mutations occur during the early stages of cancer development and contribute directly to cancer initiation and progression. Strikingly, several mutations in Kras can result in inheritable developmental disorders.
||To live or to die: the general principles of apoptosis
||Apoptosis –the most natural way by which cells die, is a tightly controlled process required for embryonic development and adult tissue homeostasis. Apoptosis deregulation is a hallmark of multiple diseases, including cancer, in which cells that should die instead survive and proliferate. We will discuss the general features of apoptosis, the main constituents of the apoptotic machinery and their conservation across species. Tumor cells can adopt various strategies to block this process.
||Liver apoptosis: the case of NF-kappaB
||We will discuss NF-kappaB signaling and how this pathway prevents apoptosis of the developing liver. In the adult liver, this pathway also bears anti-apoptotic roles. However, NF-kappaB inhibition surprisingly leads to liver inflammation and the development of liver cancer. We will discuss why.
||Stem cells and self-renewal
||Self-renewal is defined as the ability of a cell to proliferate without differentiation, yet maintain the ability to differentiate into multiple cell types. Self-renewal is an important property of stem cells and is also a common property of tumors. Tumors proliferate indefinitely, without terminally differentiating, and yet often express markers of multiple differentiated cell types. It has been demonstrated in animal models that cancers can arise from normal stem cells. Tumors may contain "cancer stem cells," (i.e. tumor cells within a heterogeneous population of cells that have the unique capacity to regenerate the tumor and all of its various cell types within the tumor). The Wnt pathway has been shown to be involved in normal stem cell self-renewal and is often dysregulated in cancer.
||Angiogenesis: the formation of new blood vessels and the role of VEGF
||For tumors to grow beyond a certain size, they require access to nutrients. This sustenance is provided by the development of new blood vessels in a process called angiogenesis. A signaling pathway involving vascular epithelial growth factor (VEGF) has been shown to be critical for this process in normal development and tumorigenesis. Importantly, this pathway has been the target of an active area of drug discovery and development.
||Metastasis, the lethal spread of cancer
||Most cancer deaths are ultimately caused by metastasis—the lethal spread of a primary tumor to local and distant sites. A number of transcription factors that govern early morphological changes, including Twist, Snail, Slug, and Zeb1/2, have also been implicated in cancer, particularly for their role in a process called the epithelial-mesenchymal transition (EMT). EMT is a process by which cells with epithelial characteristics take on properties of mesenchymal cells, including loss of epithelial cell junctions, expression of particular markers, and increased motility and invasion.
||Metastasis part II: the case of TGF-Beta
||The transforming growth factor-beta (TGF-beta) signaling pathway is critical during morphogenesis. TGF-Beta (also called decapentapolegic (dpp) in Drosophila) governs dorsal/ventral polarity. Interestingly, TGF-Beta has been shown to play a dual role in tumorigenesis, acting both as a tumor suppressor (by inducing cell cycle arrest or apoptosis) and as a tumor promoter (by promoting EMT or metastasis).
||Growth factor signaling: from normal function to clinical treatment
||Growth factors represent large families of proteins, which regulate the division, proliferation and differentiation of cells. The functions of one such protein, the epidermal growth factor (EGF), will be discussed. Over-expression or mutation of its receptor, EGFR, occurs in certain types of cancer, notably in lung cancers and gliomas. Importantly, mutant EGFR has been very recently targeted with success for the treatment of a subset of lung cancers.
||MicroRNAs in development and cancer
||MicroRNAs are recently defined RNAs that are not translated into proteins. MicroRNAs recognize and bind to target RNAs to inhibit their translation. Scientific interest in the biology of microRNAs has exploded in recent years, and new functions attributed to microRNAs are discovered every day. During this class, we will study the role of the microRNA cluster miR-17-92 in the development of B cells and B-cell lymphomas.
||In addition to the oral presentations, we will discuss an overview of what has been learned about the connections between development and cancer throughout the semester.