Document text
Principal Investigator: Humam Kadara
Organization: UNIVERSITY OF TX MD ANDERSON CAN CTR
Fiscal Year: 2024
Award: $593,147
Funding agency: National Cancer Institute
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.
Terms: <4-(methylnitrosamino)-1-(3-pyridyl)-1-butanone><Ablation><Address><Air><Alveolar Cell><Antioncogene Protein p53><Beta Proprotein Interleukin 1><C-K-RAS><COPD><Cancer Causing Agents><Cancer Genes><Cancer-Promoting Gene><Cancers><Carcinogen exposure><Carcinogens><Cell Body><Cell Communication><Cell Communication and Signaling><Cell Interaction><Cell Signaling><Cell-to-Cell Interaction><Cells><Cellular Tumor Antigen P53><Chronic Obstruction Pulmonary Disease><Chronic Obstructive Lung Disease><Chronic Obstructive Pulmonary Disease><Data><Development><Disease><Disorder><Drug Screening><Drugs><Early treatment><Ecologic Systems><Ecological Systems><Ecosystem><Epithelium><Event><Evolution><Exhibits><Exposure to><Foundations><Generalized Growth><Genetic Alteration><Genetic Change><Genetic defect><Growth><Human><IL-1 beta><IL-1 β><IL-1-b><IL-1β><IL1-Beta><IL1-β><IL1B Protein><IL1F2><IL1β><Immune><Immunes><Immunity><Inflammation><Inflammatory><Inflammatory Response><Injury><Intercept><Interleukin 1beta><Interleukin-1 beta><Interleukin-1β><Intracellular Communication and Signaling><K-RAS2A><K-RAS2B><K-Ras><K-Ras 2A><K-Ras-2 Oncogene><KRAS><KRAS2><KRAS2 gene><Ki-RAS><Knowledge><Lesion><Liquid substance><Lung><Lung Adenocarcinoma><Lung Neoplasms><Lung Parenchyma><Lung Respiratory System><Lung Tissue><Lung Tumor><Macrophage><Malignant Neoplasms><Malignant Tumor><Malignant Tumor of the Lung><Malignant neoplasm of lung><Mediating><Medication><Mice><Mice Mammals><Modern Man><Molecular><Murine><Mus><Mutation><Mφ><NNK><Neoplasms><Non-typable H influenza><Non-typable H. influenza><Non-typable Haemophilus influenza><Non-typeable H influenza><Non-typeable H. influenza><Non-typeable Haemophilus influenza><Nontypable H influenza><Nontypable H. influenza><Nontypable Haemophilus influenza><Nontypeable H influenza><Nontypeable H. influenza><Nontypeable Haemophilus influenza><Normal Cell><Oncogene K-Ras><Oncogenes><Oncogenesis><Oncogenic><Oncogens><Oncoprotein p53><Organoids><P53><Pathologic><Patients><Pattern><Pharmaceutical Preparations><Phenotype><Phosphoprotein P53><Phosphoprotein pp53><Population><Preinterleukin 1 Beta><Preventative strategy><Prevention strategy><Preventive strategy><Process><Prognosis><Property><Protein TP53><Public Health><Pulmonary Cancer><Pulmonary Neoplasms><Pulmonary malignant Neoplasm><RASK2><Receptor Protein><Reporter><Research Specimen><Resolution><Rest><Risk><Role><Saline><Saline Solution><Signal Transduction><Signal Transduction Systems><Signaling><Smoker><Smoking><Somatic Mutation><Specimen><Structure of parenchyma of lung><TP53><TP53 gene><TRP53><Tissue Growth><Tobacco><Tobacco-Associated Carcinogen><Transforming Genes><Tumor Cell><Tumor Protein p53><Tumor Protein p53 Gene><Visual><biological signal transduction><biomarker identification><cancer diagnosis><cell type><check point inhibition><checkpoint inhibition><chronic obstructive pulmonary disorder><cytokine><developmental><drug/agent><early therapy><exposure to tobacco><expression subtypes><fluid><genome mutation><high-throughput drug screening><human tissue><identification of biomarkers><identification of new biomarkers><immune check point inhibition><immune checkpoint inhibition><improved><injuries><insight><liquid><lung cancer><lung development><malignancy><marker identification><molecular sub-types><molecular subsets><molecular subtypes><mouse model><multidisciplinary><murine model><mutant><neoplasia><neoplasm/cancer><neoplastic cell><neoplastic growth><new approaches><novel><novel approaches><novel strategies><novel strategy><oncogenic agent><ontogeny><p53 Antigen><p53 Genes><p53 Tumor Suppressor><precancer><precancerous><premalignant><prevent><preventing><progenitor><programs><protein p53><pulmonary><receptor><resolutions><scRNA-seq><screening><screenings><single cell RNA-seq><single cell RNAseq><single cell expression profiling><single cell transcriptomic profiling><single-cell RNA sequencing><social role><somatic variant><tobacco carcinogen><tobacco exposure><tobacco related carcinogen><tobacco specific carcinogen><transcriptomics><treatment strategy><tumor><tumor initiation><tumorigenesis><v-Ki-RAS2 Kirsten Rat Sarcoma 2 Viral Oncogene Homolog>