# Unbiased discovery and mechanistic interrogation of genetic drivers of malignant transformation

> **NIH NIH F31** · YALE UNIVERSITY · 2020 · $8,275

## Abstract

Project Summary
Cancer is a leading cause of death in the United States, causing hundreds of thousands of deaths each year.
For the majority of these cases, tumors develop as a result of accumulated somatic mutations, of which
thousands of clinically relevant combinations exist. To better understand this process the greater scientific and
medical community has performed large-scale molecular profiling of patient samples. Such studies have
identified a comprehensive catalog of molecular alterations in the cancer genome. However, the functional
roles of many of these cancer genes still need to be explicitly tested in controlled experimental settings.
Moreover, even fewer genes have been functionally probed for how they affect the tumor micro-environment
(TME), an area of increasing interest and importance. It is therefore imperative to systematically and
quantitatively assess the contribution of each gene on tumor progression and influence on the TME. To this
end we leveraged an unbiased genome-scale CRISPR-Cas9 screen and identified and validated drivers of
tumorigenesis in the in the context of liver hepatocellular carcinoma or (HCC). Of these drivers, Prkar1a,
demonstrated robust tumor growth in validation experiments when knocked out in non-tumorigenic hepatocytes
and transplanted into Nu/Nu mice. Additionally, Prkar1a’s role in liver cancer, or cancer more generally is not
well understood. Therefore, we chose this gene for further mechanistic interrogation. In this proposal we will
further probe the importance of Prkar1a for their role in liver tumorigenesis through two specific aims: AIM 1:
Interrogate the molecular and cellular mechanism of ECM remodeling by Prkar1a AIM2: Develop
clinically relevant models and dissect the immune landscape of Prkar1a-/- tumors. Together, these
experiments will elucidate how Prkar1a knockout alters the TME, and promotes tumorigenesis in models of
HCC. These findings will provide fundamental insights into Prkar1a-/- tumorigenesis, and assist in therapeutic
development for these tumors.

## Key facts

- **NIH application ID:** 10083636
- **Project number:** 5F31CA236453-02
- **Recipient organization:** YALE UNIVERSITY
- **Principal Investigator:** Adan H. Codina
- **Activity code:** F31 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2020
- **Award amount:** $8,275
- **Award type:** 5
- **Project period:** 2019-09-30 → 2020-12-15

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10083636

## Citation

> US National Institutes of Health, RePORTER application 10083636, Unbiased discovery and mechanistic interrogation of genetic drivers of malignant transformation (5F31CA236453-02). Retrieved via AI Analytics 2026-05-27 from https://api.ai-analytics.org/grant/nih/10083636. Licensed CC0.

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