Basic scientific research in the UMass Cancer Center is predominantly organized on the basis of molecular and cellular processes important for both normal and cancer cell function, as well as the complex cell-cell interactions that drive tumor progression, rather than organized around specific disease sites - as is the case for Clinical Care. With this in mind, the goal of basic cancer research at UMass is to gain a better understanding of the defects underlying the initiation, progression and outcome of clinical malignancies and to leverage that understanding to improve diagnosis and treatment for cancer patients. Within that context, many basic scientists have also aligned their laboratory research efforts around common cancers such as breast and colon cancer, or liquid tumors such as leukemia and lymphomas, and others have focused their research on particularly difficult clinical tumors such pancreatic adenocarcinoma and central nervous system tumors. A primary goal of the UMass Cancer Center is to create and support multidisciplinary teams of basic researchers and clinicians who synergize to understand the complex biology of many common and rare cancers. This effort is supported by multidisciplinary conferences, three Cancer Center Scientific Cores (Tumor Bank, Small Animal Imaging and Veterinary Pathology), the development of highly specialized NSG mouse models with patient-derived xenografts for biomarker development and preclinical testing of novel therapeutics (Avatar Institute), a cancer research match-making web service to promote translational collaborations between cancer clinicians and researchers as well as between scientists and researchers of all types, collaborations with the Tumor Registry, Conquering Diseases Biorepository, Cancer Clinical Trials Office and the UMass Center for Clinical and Translational Science.
Cellular/Molecular information altered in cancer
A cell stores information in the form of DNA, which must be converted into RNA, protein and other functional molecules to make use of that information. Underlying many cancers are DNA mutations as well as alterations that disturb information processing - how information from DNA is read by cells. In this category there are three general areas of active investigation by multiple laboratories in each:
Most cancers arise from genetic mutations that are incurred sporadically during a patient’s lifetime. These mutations in DNA can be acquired incidentally or through insults such as environmental carcinogens, infectious agents or a chronic inflammatory environment. Cells are constantly bombarded with insults resulting in DNA damage. The cell is adept at correcting and repairing damaged DNA; however, inherent limitations in the DNA repair mechanisms of cells result in the accumulation of DNA damage over the life of an organism. In addition, there are at least 34 inherited human DNA repair gene mutations that increase cancer risk.
Inherited mutations can also predispose individuals to cancer. Some mutations are associated with early onset of common cancers – breast and colorectal, for example – whereas other mutations cause cancer-associated syndromes in children.
Epigenetic alterations change the way information from DNA is read and processed without changing the DNA sequence as mutations do. Epigenetic alterations include CpG island methylation and other chemical modifications to DNA, chemical modifications to DNA-associated histone proteins and changes that regulate accessibility of DNA. Nucleic acid metabolism occurs primarily in the cell nucleus. As components of the nucleus, DNA, RNA and nuclear envelope are interconnected and spatially organized to allow DNA replication, RNA transcription, RNA processing and other processes. Changes in the structure, function or relationship between these components can also be epigenetic drivers of disease. Dysregulation of epigenetic alterations can contribute to cancer through various mechanisms including aberrant activation of oncogenes or inappropriate silencing of tumor suppressor genes.
Cellular processes altered in cancer
Once information is read, cells and tissues respond to this information by invoking a variety of cellular processes. These processes control whether cells divide, migrate, live or die, or interface with the immune system. The dysregulation of these processes underlies many diseases, and is a crucial determinant of tumor initiation, progression and metastasis. A major goal is to understand the mechanisms by which components of various pathways act normally in normal cells and abnormally in cancer cells. In this category there are five general areas of active investigation.
Signal transduction pathways govern communication both within and between cells. Precise regulation of these communication networks is essential for all stages of cellular, organ and organismal development. Such communication is important because cells must sense and appropriately respond to the microenvironment, surrounding cells, and to environmental cues in order to maintain normal tissue homeostasis, proceed with ordered and effective development and tissue repair, and interface with the immune system. Perturbations in information processing can mimic normal signals such as those governing cell growth and division or disrupt normal signals that are key to keeping malignant cells under control. Many cancer genes are components of signal transduction pathways, and their dysfunction in cancers cause cells to inappropriately proliferate and evade controls that keep abnormal cells in check.
Cancers are driven by excessive proliferation as well as the failure to eliminate abnormal cells. Cancer genes, in a variety of ways, can stimulate the cell cycle, the steps that comprise the process of cell division. Modulation of the cell cycle can lead to cellular stress, for example, by depleting cellular resources or causing chromosomal damage. Cells respond to stress conditions by invoking several mechanisms. Stressors may permanently arrest the cell cycle (termed cellular senescence) or trigger autophagy, in which cellular components are degraded and recycled. Apoptosis, also known as programmed cell death, may also result, eliminating cells that have incurred genomic or other types of damage. Cancer cells must overcome these protective measures in order to survive; thus, restoring susceptibility to cellular arrest and death programs is a cornerstone of anti-cancer treatments.
The epithelial to mesenchymal transition (EMT) is a process by which epithelial cells lose their cell-cell adhesion and cell polarity, reverting to a more mesenchymal or connective tissue phenotype. This allows cells to migrate and invade. EMT is essential for many developmental processes including the formation of mesoderm and the neural tube during development, and EMT facilitates cell migration during wound healing. Pathologically, EMT contributes to organ fibrosis and underlies cancer cell invasion and metastasis.
The cytoskeleton is a network of cellular protein filaments and tubules that give three-dimensional structure, support and mobility to cells. Motor proteins working along with the structural components allow for intracellular transport, shape changes and movement. Cytoskeletal alterations underlie numerous disorders including cancer invasion and metastasis. Research focuses on the structure, function and assembly of the cytoskeleton in different cell types, and its role in cell motility processes.
Abnormal activation of the immune system, causing conditions such as autoimmunity, continued antigenic stimulation or chronic inflammation and infection by pathogens are all risk factors for malignancy. In fact, 20% of cancers worldwide are directly attributed to infectious agents. Viruses, bacteria and parasites can cause cancer by directly integrating into the host DNA, eliciting a chronic immune response or through direct pathogen-host cell interaction. These conditions are important in the initiation of gastrointestinal, liver, gynecologic and other tumors, and are active opportunities for preventative medicine. The ability of cancer cells to evade immune surveillance is also a critical feature of tumor development and progression. Activating cancer-specific immune cells in cancer patients is a promising therapy for certain cancers, and mechanisms to enhance this type of therapy are an active area of research.
The study of embryonic development and differentiation underpins our understanding of normal and abnormal development of organs, and is also fundamental to our understanding of cancer biology. Stem cells are undifferentiated cells that can self-renew and generate differentiated cells. Both stem cells and cancer cells have the capacity to continually divide. This and other shared features suggest that stem cell biology can inform our understanding of cancer cells. There are two broad types of stem cells: embryonic stem cells, which are present in the inner cell mass of embryos, and adult stem cells, which are found in various adult tissues. Embryonic stem cells have the capacity to generate any cell type in the body. Induced pluripotent stem cells, which can be generated by reprogramming differentiated cells, mimic embryonic stem cells and provide a platform to investigate development, differentiation, tissue remodeling and disease states such as cancer. Tissue-resident adult stem cells are also important for these types of studies and are thought to be the cell of origin for many types of cancer.
The use of small RNA molecules as therapeutic agents offers the potential of specificity – RNA therapies can be designed to target only one gene – and versatility – an RNA therapeutics platform can be easily adapted to target many individual genes. The RNA Therapeutics Institute, born from the strong community of RNA researchers at UMMS, was created to advance RNA-based therapies for several diseases, including cancers.