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Elucidating the evolution of Krt8+ alveolar cells to Kras-mutant lung preneoplasia and cancer

Award Number: R01CA272863
ORGANIZATION: NATIONAL CANCER INSTITUTE
OPDIV: NIH
AWARD CLASS: DISCRETIONARY
AWARD ACTIVITY TYPE: SCIENTIFIC/HEALTH RESEARCH (INCLUDES SURVEYS)
PERIOD OF PERFORMANCE START DATE: 09/01/2022
PERIOD OF PERFORMANCE END DATE: 07/31/2027

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Elucidating the evolution of Krt8+ alveolar cells to Kras-mutant lung preneoplasia and cancer - PROJECT SUMMARY A significant fraction of lung adenocarcinomas (LUADs) in lifetime smokers harbor somatic mutations in the KRAS oncogene (KM-LUADs). Due to enhanced screening, KM-LUAD is increasingly being detected at earlier pathological stages, thus posing a growing public health burden that warrants improved early treatment. Despite this urgency, early changes that conceive KM-LUAD and that would thus likely comprise ideal targets for interception remain poorly characterized. Previously, our group and others have shown that tobacco exposure leads to a pervasive field of injury that is composed of molecular (e.g., KRAS mutations) and inflammatory changes in normal-appearing epithelium and in the lung, and that are prevalent in the LUADs themselves. We and others have also previously described molecular and immune changes, including a decrement in host immunity, that are associated with development of lung premalignant lesions (PMLs) and KM-LUAD. These earlier studies have shed light on events that are likely implicated in early lung tumor development. Yet, especially for a cancer like KM-LUAD that is causally related to smoking, the identity and properties of specific cell populations that trigger a field of injury as well as its progression to PML and KM- LUAD are not known. In our preliminary efforts, we performed single-cell RNA-sequencing of lung tissues from a human-relevant mouse model of tobacco-associated KM-LUAD. We found a population of Krt8+ alveolar cells (KACs) that was greatly increased early on in lungs exposed to tobacco carcinogen but not control saline and that were also associated with tumor cell onset. KACs displayed intriguing properties that allow us to surmise that they perhaps represent KM-LUAD progenitors: they amassed the same driver Kras mutations found in the resultant LUADs; they expressed transcriptomic programs and cell-cell interactions that are highly pertinent to KM-LUAD including augmented p53 as well as pro-inflammatory IL-1β and NF-κB signaling; and their expression profiles were highly enriched in human PMLs and LUADs. We also found that KACs were markedly increased in the human LUAD ecosystem relative to matched normal lung. Our preliminary findings motivate the hypothesis that oncogenesis of KACs in concert with pro-inflammatory signaling mediated by IL-1β/NF-κB underlie initiation and development of PML and KM-LUAD. To address our hypothesis we will 1) characterize at single-cell resolution evolution of KACs to PML and KM-LUAD, as well as determine the role of p53 signaling in this process; 2) discern the role of pro-inflammatory signaling in promoting evolution of KACs to PML and KM-LUAD; and 3) use multiple approaches including drug screening to determine whether targeting KACs will intercept PML and KM-LUAD development. At the conclusion of our studies, we will have unraveled novel paths in the phenotypic evolution of KM-LUAD as well as laid the foundation for development of new strategies that inhibit the inception of this dire malignancy.


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: 2024 ( Subtotal = $593,147 )
2024	2024	THE UNIVERISTY OF TEXAS MD ANDERSON CANCER CENTER, A COMPONENT OF THE UNIVERISTY OF TEXAS SYSTEM	1515 HOLCOMBE BLVD	HOUSTON	TX	77030	HARRIS	USA	Cancer Cause and Prevention Research	000	3	7/15/2024	NON-COMPETING CONTINUATION	$593,147
														Subtotal = $593,147

Issue Date FY: 2023 ( Subtotal = $586,157 )
2023	2023	UNIVERSITY OF TEXAS M. D. ANDERSON CANCER CENTER, THE	1515 HOLCOMBE BLVD	HOUSTON	TX	77030	HARRIS	USA	Cancer Cause and Prevention Research	000	2	8/1/2023	NON-COMPETING CONTINUATION	$586,157
														Subtotal = $586,157

Issue Date FY: 2022 ( Subtotal = $596,247 )
2022	2022	UNIVERSITY OF TEXAS M. D. ANDERSON CANCER CENTER, THE	1515 HOLCOMBE BLVD	HOUSTON	TX	77030	HARRIS	USA	Cancer Cause and Prevention Research	000	1	8/29/2022	NEW	$596,247
														Subtotal = $596,247

Grand Total All Awards = $1,775,551

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Elucidating the evolution of Krt8+ alveolar cells to Kras-mutant lung preneoplasia and cancer

Award Number: R01CA272863

ORGANIZATION: NATIONAL CANCER INSTITUTE

OPDIV: NIH

AWARD CLASS: DISCRETIONARY

AWARD ACTIVITY TYPE: SCIENTIFIC/HEALTH RESEARCH (INCLUDES SURVEYS)

PERIOD OF PERFORMANCE START DATE: 09/01/2022

PERIOD OF PERFORMANCE END DATE: 07/31/2027

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