R01CA258089

ECO-EVOLUTIONARY DRIVERS OF CLONAL DYNAMICS DURING UV-INDUCED SKIN CARCINOGENESIS (PQ3) - ABSTRACT

Cancers have readily-defined characteristics often referred to as “hallmarks”. Nevertheless, the question of how the sequence of cancer development progresses -- from normal tissue to carcinogen-damaged tissue to precancerous lesion and finally to malignant tumors – remains unanswered. Classically, these steps are attributed to the sequential acquisition of discrete genetic events such as driver mutations.

However, in humans, the clonal dynamics governing cancer development happen over years, remain largely invisible even in model systems, and have been difficult to link to specific molecular changes. This rubric fails to account for clonal dynamics in the context of tissue architecture and fails to explain the consequences of large numbers of mutations present in normal tissue.

Our long-term goal is to apply ecological and evolutionary principles to cancer initiation and development in order to test whether the hallmarks of cancer are acquired in three distinct phases each with distinct selective pressures and manifestations of cell competition and cooperation. Nowhere is this more accessible to investigation than in skin.

For skin carcinomas, the most important carcinogen is ultraviolet radiation. Cutaneous squamous cell carcinoma (CUSCC) has the most tractable and clinically well-characterized progression sequence of any human cancer, from normal tissue, to a distinct precancerous lesion (the actinic keratosis), to invasive carcinoma. Therefore, it is ideal for establishing an eco-evolutionary paradigm of cancer initiation and development with respect to modeling clonal dynamics, genetic composition, and the dynamics of molecular traits.

Our central hypothesis is that cancer initiation and development occurs in three phases, each with specific and recognizable clonal dynamics. In the first phase, tissue disruption from UV exposure provides a permissive environment where extrinsically-driven mechanisms allow for some clones to experience unusually long runs of cell division and turnover. This greatly increases the variance among clone sizes with larger clones accumulating greater heritable variation.

The second phase sees the emergence of intrinsic mechanisms where mutations that confer a competitive advantage allow for clonal selection with directed expansion of some clones at the expense of others. In the third phase, one or several clones escape local tissue control, acquire a distinct fitness function, and form tumors. Within the emerging tumor microenvironments, selection pressures will promote ecological and molecular diversification of the malignant clade (or clades).

Our approach uses novel combinations of serial in-vivo quantitative imaging, mathematical modeling, and deep single-cell molecular interrogation to discern the ecological and molecular drivers of clonal dynamics, cell-to-cell competition and cooperation, and clonal evolution, producing a fundamentally unprecedented view of cancer initiation.

H. Lee Moffitt Cancer Center And Research Institute Hospital

TO IDENTIFY CANCER RISKS AND RISK REDUCTION STRATEGIES, TO IDENTIFY FACTORS THAT CAUSE CANCER IN HUMANS, AND TO DISCOVER AND DEVELOP MECHANISMS FOR CANCER PREVENTION AND PREVENTIVE INTERVENTIONS IN HUMANS. RESEARCH PROGRAMS INCLUDE: (1) CHEMICAL, PHYSICAL AND MOLECULAR CARCINOGENESIS, (2) SCREENING, EARLY DETECTION AND RISK ASSESSMENT, INCLUDING BIOMARKER DISCOVERY, DEVELOPMENT AND VALIDATION, (3) EPIDEMIOLOGY, (4) NUTRITION AND BIOACTIVE FOOD COMPONENTS, (5) IMMUNOLOGY AND VACCINES, (6) FIELD STUDIES AND STATISTICS, (7) CANCER CHEMOPREVENTION AND INTERCEPTION, (8) PRE-CLINICAL AND CLINICAL AGENT DEVELOPMENT, (9) ORGAN SITE STUDIES AND CLINICAL TRIALS, (10) HEALTH-RELATED QUALITY OF LIFE AND PATIENT-CENTERED OUTCOMES, AND (11) SUPPORTIVE CARE AND MANAGEMENT OF SYMPTOMS AND TOXICITIES. SMALL BUSINESS INNOVATION RESEARCH (SBIR) PROGRAM: TO EXPAND AND IMPROVE THE SBIR PROGRAM, TO STIMULATE TECHNICAL INNOVATION, TO INCREASE PRIVATE SECTOR COMMERCIALIZATION OF INNOVATIONS DERIVED FROM FEDERAL RESEARCH AND DEVELOPMENT FUNDING, TO INCREASE SMALL BUSINESS PARTICIPATION IN FEDERAL RESEARCH AND DEVELOPMENT, AND TO FOSTER AND ENCOURAGE PARTICIPATION IN INNOVATION AND ENTREPRENEURSHIP BY WOMEN AND SOCIALLY/ECONOMICALLY DISADVANTAGED PERSONS. SMALL BUSINESS TECHNOLOGY TRANSFER (STTR) PROGRAM: TO STIMULATE AND FOSTER SCIENTIFIC AND TECHNOLOGICAL INNOVATION THROUGH COOPERATIVE RESEARCH AND DEVELOPMENT CARRIED OUT BETWEEN SMALL BUSINESS CONCERNS AND RESEARCH INSTITUTIONS, TO FOSTER TECHNOLOGY TRANSFER THROUGH COOPERATIVE RESEARCH AND DEVELOPMENT BETWEEN SMALL BUSINESS CONCERNS AND RESEARCH INSTITUTIONS, TO INCREASE PRIVATE SECTOR COMMERCIALIZATION OF INNOVATIONS DERIVED FROM FEDERAL RESEARCH AND DEVELOPMENT FUNDING, AND FOSTER PARTICIPATION IN INNOVATION AND ENTREPRENEURSHIP BY WOMEN AND SOCIALLY/ECONOMICALLY DISADVANTAGED PERSONS.

93.393 - Cancer Cause and Prevention Research

National Cancer Institute (NCI) [HHS - NIH]

Tampa, Florida 336129497 United States

Single Zip Code

Research Answers to National Cancer Institute's (NCI) Provocative Questions (R01 Clinical Trial Optional) (RFA-CA-20-004)

Amendment Since initial award the total obligations have increased 391% from $640,021 to $3,142,500.