Mutant p53 in Tumorigenesis, Invasion, and Metastasis

Abstract public domain (NIH RePORTER)

Summary Project 1 (Lowe/Sánchez-Rivera) will integrate sophisticated genome editing, functional genomics, and mouse modeling approaches with innovative transcriptomic and epigenomic technologies to systematically probe the gain-of-function potential of cancer-associated mutant p53 alleles in cancer, with a particular focus on those that influence pancreatic cancer progression and metastasis. One line of investigation will focus on massively parallel cellular and molecular phenotyping of diverse mutant p53 alleles using a series of technological innovations that have been established in our laboratories, including modular barcoded cDNA libraries, optimized CRISPR base editing, and single cell genomics coupled to transcriptional profiling in a p53 mutant-specific manner. These studies will test the hypothesis that a subset of mutant p53 alleles produce gain-of-function phenotypes, including imparting pro-metastatic abilities to cancer cells, and that these mutants can be molecularly classified into functional categories. In parallel, we will exploit combined CRISPR base editing and inducible RNA interference in vivo to functionally probe the requirement for specific mutant p53 proteins in establishing and maintaining pancreatic metastasis. Lastly, we will deploy focused CRISPR-based high-throughput functional genomics to identify and validate p53 mutant-dependent effectors of tumor progression and metastasis. These studies will test the hypothesis that p53 gain-of-function alleles drive cancer progression and metastasis through a defined set of molecular programs that could be leveraged to both classify and blunt the metastatic potential of tumors harboring specific p53 mutations. Each of our proposed Aims are synergistic and are supported by substantial preliminary data and will benefit from interactions with Projects 2-4 and Core 1. Successful completion of the proposed work will elucidate at the cellular and molecular levels how p53 suppresses tumorigenesis and metastasis in vivo and may point to more precise therapeutic opportunities relevant to a large fraction of human cancers (including pancreatic cancer).

Public health relevance public domain (NIH RePORTER)

NARRATIVE While most cancer-associated TP53 alleles disable wild type p53 function, mounting evidence suggests that some alleles can exhibit gain-of-function properties that influence cancer phenotypes beyond TP53 loss but whether, to what extent, and how TP53 mutations can have gain-of-function properties is controversial. Our proposal combines sophisticated genome editing, functional genomics, and mouse modeling approaches with innovative transcriptomic and epigenomic technologies to systematically probe the gain-of-function potential of hundreds of cancer-associated mutant p53 alleles in cancer, with a particular focus on those that influence pancreatic cancer progression and metastasis. These studies will constitute the most comprehensive foray into the investigation of the biology of TP53 mutants up to date and will serve as a roadmap for future studies of allelic variation in cancer and other diseases.