The Cancer Cell Biology Branch (CCBB) supports and directs a comprehensive research program that defines the biological basis for the differences between normal cells and cancer cells, with a major emphasis on studies that reveal processes and molecular targets where there is potential for therapeutic or preventive intervention. Of high priority in the CCBB's portfolio are studies to reveal the basic mechanisms that drive the development and behavior of cancer cells, identify solid tumor stem cells, discover how events associated with transformation disrupt the normal biological programs of cell proliferation and death, and examine the functional effects of genetic alterations that underlie tumorigenesis. Characteristic features of the cancer cell phenotype include, but are not limited to, expanded replicative potential, resistance to metabolic and oxidative stress, ability to evade programmed cell death, reduced dependence on growth factor signals, insensitivity to growth inhibitory signals, genomic plasticity and resistance to chemotherapeutic intervention. Studies of normal biology are also supported if the goal is to elucidate dysregulated processes critical for the progression of normal cells to cancer cells. Various in vivo and in vitro systems are utilized including tumor-bearing animals, human and animal tumor tissues and cells, non-mammalian organisms and biochemical approaches.
Cancer Cell Physiology: Cancer Cell Metabolism
This program area supports studies on the altered cellular metabolism seen in cancer cells, including but not limited to the metabolism of sugars, proteins, nucleic acids and fatty acids, mechanisms of metabolic fuel homeostasis (the Warburg Effect, glycolysis, and oxidative phosphorylation), insulin regulatory processes, the link between protein translation, ribosome biogenesis, and cellular metabolism, and tumor metabolite profiling and characterization. Studies of autophagy relevant to nutrient stress and recycling of damaged organelle and protein components as well as dysregulated organelle biogenesis and function (e.g., mitochondria, endoplasmic reticulum, Golgi, vesicles) in the cancer cell are also supported in this portfolio. Emerging research areas relevant to this portfolio include understanding the molecular link between organismal physiology and cancer cell biology, the role circadian rhythm plays in metabolism and cancer biology, and the molecular switches at the cellular level that lead to cancer associated cachexia.
Cancer Cell Physiology: Response to Stress
This program area supports research on cellular stress responses that influence cancer cell physiology, tumor growth, apoptosis, epigenetic changes and genomic stability. Examples of stresses studied include, but are not limited to, oxidative stress, the unfolded protein response (UPR), ER stress, hypoxia, and inflammation. Studies on the regulation of cell death that when dysregulated lead to enhanced cell survival or resistance to cancer therapy, such as apoptosis, necrosis, autophagic cell death, anoikis and other forms of programmed or non-programmed cell death, are also included in this portfolio. Additional areas of interest in this portfolio include processing and trafficking of intracellular membranes and proteins, protein maturation, endosome sorting and recycling, nuclear and cytoplasmic transport and intracellular signaling and processing of growth factors and their associated receptors in the context of cancer cell growth.
Cancer Cell Cycle Control
Altered cell cycle regulation and examination of how this mechanistically contributes to oncogenic transformation are the focus of this portfolio. Supported studies include characterization of factors that regulate the cell cycle, mitosis, cytokinesis, centrosome duplication, and DNA replication in cancer cells and tumor tissues. Proteasome induced degradation and associated mechanisms that lead to alterations in protein stability and function in relationship to oncogenic transformation, including protein modifications by ubiquitylation, sumoylation, or other mechanisms are also supported in this portfolio. An emerging area of interest in this portfolio is the link between circadian rhythm and cell cycle control and what role its dysregulation mechanistically plays in cancer cell biology.
Post-transcriptional Gene Regulation and Cancer
This program area supports studies on post-transcriptional gene expression regulation influencing the cancer phenotype, including RNA stability, splicing, transport, and translation and the role of microRNAs in the regulation of splicing, translation or mRNA stability. Alterations in protein function influencing the cancer cell phenotype due to changes in protein maturation, post-translational modifications, sorting, and abnormal degradation are also included in this portfolio.
Basis Mechanisms of Cellular Transformation
This program area supports research on the basic mechanisms of cellular transformation and the identification of cells of origin for solid tumors. Included in this portfolio are studies on oncogene and tumor suppressor expression and function that drive oncogenic transformation; the role of microRNAs as tumor suppressors and oncogenes; and the biology of progenitor cells that may be the target of oncogenic transformation in solid tumors. Mechanisms of overcoming senescence in the context of oncogenesis and mechanisms of cellular immortalization as a prerequisite for oncogenic transformation are also included in this portfolio. Another focus of this portfolio is the role of developmental genes and the effect of perturbations in cellular differentiation in cancer and the relationship between cellular aging and cancer.
Signal Transduction in Cellular Transformation
Alterations in signal transduction pathways that may modulate or lead to oncogenic transformation are the focus of studies supported by this program area. Such studies include the functional and molecular characterization of signal transduction pathways/networks related to transformation; signaling by cell surface receptors, cytokines, protein kinases, phosphatases, lipids or other molecules in cancer cells and tumor tissues; analyses of the composition, formation, and functioning of signaling complexes and mediators involved in cellular transformation; and the role of cytokines and associated inflammatory signaling cascades in oncogenic transformation and promoting cell survival, for example the activation of the NFkB cascade, through the TNF receptor super family or Toll-like receptors.
Biospecimen Resources to Support Studies in Cancer Biology
This program supports resources that collect, store, process, and disseminate human biological specimens, including nucleic acids and tissue arrays, and associated data to investigators who study human cancer biology, particularly early events in oncogenic transformation. Development of processes to improve best practices for biospecimen research use is also supported.