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Principal Investigator: Saumya Reddy Bollam
Organization: UNIVERSITY OF CALIFORNIA, SAN FRANCISCO
Fiscal Year: 2024
Award: $38,598
Funding agency: National Cancer Institute
Project Summary
Recent investigations have revealed that oncogenic mutations are not sufficient for initial stages of tumorigenesis
and that the microenvironment plays a significant role in promoting neoplastic growth of a tumor. This
microenvironment surrounding a mutated cell can be influenced by many promotion processes, including
environmental exposures, tissue damage, and chronic inflammation. This proposal aims to investigate the
mechanisms by which promotion, or non-mutagenic processes, can influence the selection of mutant clones
which eventually populate a tumor. This project will rely on theories from cancer genetics, tumor promotion, and
evolutionary cancer biology in order to provide insight into the coordination between promotion and oncogenic
mutations present in a cell. Through the use of a well-established model of chemical carcinogenesis, this project
will address a fundamental question regarding the molecular consequences of tumor promotion. This
carcinogenic regimen can produce both Hras mutant tumors and Kras mutant tumors, merely by adjusting the
genetic background of the mouse. This provides the ideal tool for us to ask the question, what are the different
promotion mechanisms which select for tumors with different mutations? To address this question, the proposed
project aims to characterize promotion mechanisms on the backgrounds of the mice which are known to produce
tumors with different mutations. The first aim will investigate how macrophage infiltration during promotion
coordinates with oncogenic Hras signaling. This will be addressed by computationally identifying signaling axes
between macrophages and epithelial cells from skin collected at different time points after application of a
promoter. The second aim will define the active functional modules in the Kras-tumor-permissive skin, in
response to a promoter. This will be achieved by constructing gene co-expression networks from single cell RNA
sequencing of skin collected subsequent to promoter treatment in the skin. The proposed research will be
completed by a graduate student with significant experience in both cancer biology and computational biology.
It will be supervised by and conducted in the lab of Allan Balmain, an expert in the field of skin cancer genetics
and tumor promotion. This training plan takes advantage of the highly collaborative and innovative research
environment in the Helen Diller Family Comprehensive Cancer Center, which facilitates access to renowned
scientific mentors and guidance in the proposed work. At the University of California, San Francisco (UCSF), the
graduate program in Biomedical Sciences is regarded as one of the best due to its inclusion of professional
development and training resources offered, which will support this highly motivated student to develop an
independent research career. Completion of the proposed work will thus expand knowledge on a critical question
in cancer biology and is enabled by an excellent institutional environment. Understanding how oncogenic
mutations can coordinate with tumor promotion mechanisms in the mutant cell’s microenvironment will provide
novel insights towards early detection and prevention strategies for cancer.
Terms: <12-Myristoyl-13-acetylphorbol><12-O-Tetradecanoyl Phorbol 13-Acetate><12-O-tetradecanoylphorbol-13-acetate><Acetates><Address><Anthracenes><Body Tissues><California><Cancer Biology><Cancer Induction><Cancers><Candidate Disease Gene><Candidate Gene><Carcinoma><Cell Body><Cell Communication and Signaling><Cell Cycle><Cell Division Cycle><Cell Function><Cell Physiology><Cell Process><Cell Signaling><Cell surface><Cells><Cellular Function><Cellular Physiology><Cellular Process><Chemical Models><Chronic><Comprehensive Cancer Center><Computational Biology><Cutaneous Squamous Cell Carcinoma><DMBA><Data><Data Analyses><Data Analysis><Dermal><Development><Dorsal><Early Diagnosis><Environment><Environmental Exposure><Epidermoid Skin Carcinoma><Epithelial Cells><Epithelial cancer><Exhibits><Family><Gene Expression><Gene set enrichment analysis><Generalized Growth><Genes><Genetic><Genetic Alteration><Genetic Change><Genetic defect><Genotoxins><Germ Lines><Goals><Growth><Histologic><Histologically><Hour><Human><Immune infiltrates><Immunomodulation><Infiltration><Inflammation><Inflammatory><Institution><Intracellular Communication and Signaling><Investigation><KRAS driven oncogenesis><KRAS oncogenesis><KRAS-driven tumorigenesis><KRAS-mediated tumorigenesis><Knowledge><Ligands><Link><Macrophage><Malignant Epithelial Neoplasms><Malignant Epithelial Tumors><Malignant Neoplasms><Malignant Skin Neoplasm><Malignant Tumor><Measures><Mediating><Mediator><Mentors><Mice><Mice Mammals><Modeling><Modern Man><Molecular><Murine><Mus><Mutagens><Mutate><Mutation><Mφ><Neoplasms><Network Analysis><Oncogenesis><Oncogenic><PMAS><Pathway Analysis><Phorbol Myristate Acetate><Play><Population><Preventative strategy><Prevention><Prevention strategy><Preventive strategy><Process><Proliferating><Receptor Protein><Regimen><Research><Research Resources><Resolution><Resources><Role><San Francisco><Science><Signal Transduction><Signal Transduction Systems><Signaling><Skin><Skin Cancer><Students><Subcellular Process><Tetradecanoylphorbol Acetate><Therapeutic><Time><Tissue Growth><Tissues><Training><Tumor Promotion><Universities><Work><Wound Repair><biological signal transduction><cancer genetics><candidate identification><carcinogenesis><carcinogenicity><career><cell type><chemical carcinogenesis><computer biology><data interpretation><developmental><dimethylbenz(a)anthracene><dimethylbenzanthracene><early detection><epithelial carcinoma><experience><extracellular><genome mutation><genotoxic agent><global gene expression><global transcription profile><graduate student><human tissue><immune cell infiltrate><immune modulation><immune regulation><immunologic reactivity control><immunomodulatory><immunoregulation><immunoregulatory><inflammatory environment><inflammatory milieu><innovate><innovation><innovative><insight><malignancy><malignant skin tumor><mouse model><murine model><mutant><neoplasia><neoplasm/cancer><neoplastic growth><new approaches><novel><novel approaches><novel strategies><novel strategy><oncogenic KRAS><ontogeny><permissiveness><population based><pressure><programs><promoter><promotor><receptor><resolutions><response><scRNA-seq><single cell RNA-seq><single cell RNAseq><single cell expression profiling><single cell transcriptomic profiling><single-cell RNA sequencing><skin squamous cell carcinoma><social role><theories><tool><transcriptome><tumor><tumor growth><tumorigenesis><tumorigenic><wound healing><wound recovery><wound resolution>