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Investigating the role of Cdkn2a in lung adenocarcinoma metastasis

Award Number: K99CA312806
ORGANIZATION: NATIONAL CANCER INSTITUTE
OPDIV: NIH
AWARD CLASS: DISCRETIONARY
AWARD ACTIVITY TYPE: TRAINING/TRAINEESHIP
PERIOD OF PERFORMANCE START DATE: 05/15/2026
PERIOD OF PERFORMANCE END DATE: 04/30/2028

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Investigating the role of Cdkn2a in lung adenocarcinoma metastasis - Abstract Lung cancer is the most frequent cause of cancer-related deaths in the world. Metastasis is responsible for the overwhelming majority of these deaths, yet the mechanisms underlying metastasis remain poorly understood. This is due in large part to the great difficulty in modeling metastasis for high-throughput functional analyses, as well as recapitulating complex tumor genotypes observed in humans. Using CRISPR-Cas9 somatic genome editing and tumor barcoding, I have developed a novel metastasis assay in genetically engineered mice that can be used to explore functional genetic effects on metastasis and immune evasion. With this approach, I found that inactivation of Cdkn2a promotes metastatic colonization and growth of oncogenic KRAS-driven lung adenocarcinoma. Furthermore, the simultaneous inactivation of several genes along with Cdkn2a dramatically increases metastatic spread, allowing spontaneous metastasis to the liver, bone and brain. In this proposed study, I hypothesize that specific tumor genotypes involving inactivation of Cdkn2a can enable potent metastatic ability. I will explore the ability of Cdkn2a knockout to promote metastasis by profiling the metastatic cell state of Cdkn2a-deficient cells and dissecting the specific impact of deleting the constituent genes Ink4a and Arf (Aim 1). I will investigate the ability of defined, Cdkn2a-related complex genotypes to dramatically promote metastasis, and I will map metastatic phenotypes to specific gene functions (Aim 2). I will produce tumors with these complex genotypes through the use of Cas12a. I have generated a Cas12a transgenic mouse to take advantage of the unique features of the enzyme, which include the simplicity of targeting multiple loci using a single CRISPR array. Finally, I will explore the metastatic role of the Mtap/Cdkn2a/Cdkn2b locus, which is frequently deleted in its entirety, and test how targeted therapy of Mtap-deficient tumors affects metastatic spread (Aim 3). This work will uncover functional genetic mechanisms by which lung cancer can metastasize, establish critical models for relevant in vivo investigation of metastasis, and identify new therapeutic strategies for treating metastatic lung cancer.


Issue Date FY	Funding FY	Legal Entity Name	Legal Entity Address	Legal Entity City	Legal Entity State	Legal Entity Zip Code	Legal Entity COUNTY	Legal Entity COUNTRY	Assistance Listing	Award Code	Budget Year	Action Date	Action Type	Action Amount

Issue Date FY: 2026 ( Subtotal = $158,499 )
2026	2026	THE LELAND STANFORD JUNIOR UNIVERSITY	450 JANE STANFORD WAY	STANFORD	CA	94305	SANTA CLARA	USA	Cancer Research Manpower	000	1	5/18/2026	NEW	$158,499
														Subtotal = $158,499

Grand Total All Awards = $158,499

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Investigating the role of Cdkn2a in lung adenocarcinoma metastasis

Award Number: K99CA312806

ORGANIZATION: NATIONAL CANCER INSTITUTE

OPDIV: NIH

AWARD CLASS: DISCRETIONARY

AWARD ACTIVITY TYPE: TRAINING/TRAINEESHIP

PERIOD OF PERFORMANCE START DATE: 05/15/2026

PERIOD OF PERFORMANCE END DATE: 04/30/2028

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