Our research is or was fully or in part supported by the following funding bodies:
cell nucleus in M phase

Research Topics:

Cancers are classically thought to arise from single cells that have randomly acquired a number of genetic mutations which drive their carcinogenic transformation. Decades of intense investigation has centered around the elucidation of these genetic drivers of individual cancer cells. Yet, cancer is also very much a systems-level disease. Interactions of tumor cells with host differentiated and progenitor cells, or among tumors cells themselves, profoundly modulate the most fundamental aspects of cancer - growth, metastatic spread, and response to treatment. Thus, an appropriate interpretation of gene network signaling in cancer cells needs to take into account interactions at the cellular, tissue and organismal levels. A major research focus of our Center is therefore the development of an augmented carcinogenesis paradigm that incorporates not only the well-established oncogene dysregulations known to drive individual cancer cell behavior, but also identifies key population-level dynamics, including intercellular interactions that can vitally contribute to carcinogenic transformation, cancer self-renewal and tumor progression.

The Timeline Paradigm

The development of cancer over time is thought to involve four events - Initiation, Promotion, Transformation and Progression. Cells are said to be initiated when they acquire predisposing genomic alterations or mutations (e.g. in tumor suppressor genes) that heighten their chance of finally becoming cancerous. Such alterations may confer a growth advantage over normal cells such that, if initiated and normal populations compete for new space, the initiated population will assume a greater proportion. This advancement of the precancerous population is termed Promotion. Over time, additional mutational events may transform one of the initiated cells, leading to the first tumor cell. The following phase, progression, is widely regarded as a transition to inevitable lifetime cancer incidence, with views differing mostly over the duration of the time lag.

The Importance of Progression

The confirmation of dormant, asymptomatic tumors in most adults as determined by autopsy overturns conventional timeline thinking by affirming a crucial mechanistic role for progression in cancer incidence. Moreover, because the roles of the earlier events in the timeline paradigm to final cancer incidence have largely been inferred assuming a passive role for progression, these inferences are now suspect and must be revisited as well. To appropriately reconstruct this paradigm, a better understanding of the role of progression, i.e., the development of cancer after the fact, is pivotal. This is considered using an expanded view of cancer systems biology - one that recognizes not only networked interactions within cells, but emergent systems properties as one moves upward in scale from molecules cells to tissues, and finally to the complete organism.

Philosophy for Elucidating the Systems Biology of Cancer Development

Accordingly, our multidisciplinary team is engaged in iterative experimental and modeling efforts to investigate how population dynamics and intercellular-interactions modulate cancer course before and after the fact of cancer cell creation, including early tumor growth, regression, dormancy, or even oscillatory behaviors. We construct both predictive analytic and computational models of the evolutionary course of cancers, with the goal of explicitly identifying novel intercellular interactions and fundamental principles driving cancer. We strive to uncover overarching principles applicable across cancers. A current focus is the influence of essential determinants of population-level control of tumor growth including: tumor-stromal cell interactions including cell-cell fusion; cancer stem cell composition of tumors; angiogenic 'carrying capacity' (host support) and intercellular spatial constraints.

The Dormancy Phenomenon

Tumors can persist in a dormant state and remain asymptomatic unless perturbed. The principle has been confirmed in our laboratory using mouse dormancy models that undergo a switch to an aggressive phenotype after a set period of time. Radiation has been found to expedite the transition. Interpreting the results in the human setting, latent tumors may be advanced to clinical disease that might otherwise have remained non-threatening. In this way, radiation, and perhaps other insults, may be carcinogenic even after the fact of cellular disease. Under support from NASA, this prospect is under active investigation. At issue is the carcinogenesis risk posed by space radiations to astronauts during long-term space flight. More broadly, it is anticipated this NASA-funded research on carcinogenesis will also provide a sound basis for better understanding of carcinogenesis here on earth.

Mathematical research at the CCSB

embraces the principle that cancer is not just a disease of cells but is facilitated at the population and inter-tissue levels. Accordingly, a multi-level approach must be implemented to fully understand its origin and course. Initial events in carcinogenesis occur within cells at the molecular level as repair and proliferation dysfunctions, leading to genomic instability, aneuploidy and final transformation. But after cancer cell creation, the clone advances to encounter additional molding and fate-determining events defined by cell-cell interactions. The associated stroma (fibroblasts and extracellular matrix) plays a critical role in cancer progression, as does induced tumor vascularization (angiogenesis). Both act to determine whether a nascent cancer advances to become symptomatic disease. Without stromal activation and angiogenesis, tumor development is halted early. Under NASA Specialized Centers of Research (NSCOR) funding, these studies are focusing on the determination of cancer risk to astronauts who will be exposed to harmful solar particle events (SPEs) and galactic cosmic radiations (GCRs) during long-term space flight. By extension we hope to better understand the carcinogenesis process more generally, and discover new therapeutic interventions for improved cancer treatment.

The origin of cancer may be attributed to events that alter the repair machinery of the cell and destabilize its genome. Of active interest in this regard is how nucleotide-level DNA damage and repair translates into chromosome aberrations, as chromosome-level misrepair is the feature most closely identified with carcinogenic transformation. By developing a revised theory for double-strand break repair/misrepair following ionizing radiation, we have found it possible to improve upon the commonly-accepted repair models. Starting from carcinogenesis-initiating lesions to DNA, we have gone on to link this action to the first population-level bottleneck to the growth of the resultant hyperplastic clones - self-limited cell growth. The resulting deterministic model for early carcinogenesis has proven to be competitive with the current stochastic standard in explaining major epidemiological data sets on radiation-induced carcinogenesis.

A second bottleneck encountered early in carcinogenesis is nutrient availability. Without angiogenesis, a tumor cannot grow beyond approximately 1mm in size. This obstacle to tumor growth requires the development of angiogenic potential within the growing clone of tumor cells - an 'angiogenic switch'. Interestingly, it was discovered quite by accident some time ago while performing autopsies on adults who died of non-cancer causes (Black and Welch 1993), that most middle-aged people harbor dormant, non-threatening cancer lesions. Held back by the failure to initiate angiogenesis, the tumors remained harmless throughout these individuals' lifetimes. One major objective of our Center is to understand how such a stasis may be maintained, and perhaps re-established as part of a novel therapeutic approach. We have made inroads into quantitatively understanding this natural control in tumor growth, and how antiangiogenic therapy might best be applied to achieve this goal.

As the subject of upcoming publications, we are expanding on the bottleneck principle to understand other population-level sources of tumor growth limitation. We have found 'agent-based' computer modeling to be a useful means of capturing the complicated cell-cell interactions involved. This form of tumor growth simulation ascribes local 'rules' to individual cells, e.g., 'divide every so often', 'divide if space is available', 'die if replicative lifetime is achieved', and so on. By tracking the locations and fates of the agents (cells) as they interact and expand across 2D or 3D lattices, the development of the entire cancer population is simulated. We are working to complete our in silico tumor analog by including mixed populations and heterogeneous environments. The importance of this population-level extension to thinking about carcinogenesis is fundamental - intercellular crosstalk doesn't just accompany cancer; it determines whether people actually get clinical cancer.