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Principal Investigator: Jussuf Thomas Kaifi
Organization: HARRY S. TRUMAN MEMORIAL VA HOSPITAL
Fiscal Year: 2024
Funding agency: Veterans Affairs
Non-small cell lung cancer (NSCLC) is by far the leading cancer killer in Veterans. Major reasons for death
after surgical resection are the >50% recurrence rate despite curative intent treatment due to micrometastatic
disease at the time of diagnosis. To prevent the development of metastatic recurrence, surgically treated
patients receive adjuvant chemotherapy to eradicate undetectable micrometastatic disease. However, this
therapy is only associated with a 5% survival benefit due to drug resistances of cancer cells. Identifying
personalized treatment strategies to prevent metastases remains an unmet clinical need. Alveolar epithelial
type II (AT2) cells are self-renewing epithelial stem cells in the lung that have been identified as the origin for a
majority of NSCLCs. However, it is unknown whether and how epithelial cancer cells, such as AT2 cells,
contribute to metastatic progression as the major cause of death. Novel data link AT2 cells to the development
of NSCLC metastases. A research team led by a surgeon scientist has integrated expertise in human
biobanking and translational cancer research at two VA hospitals with collaborators specialized in preclinical
cancer models, single cell sequencing, genetics, and bioinformatics. It will be investigated how AT2 and other
epithelial cancer cells contribute to NSCLC metastatic progression and drug resistances, as this will allow
better molecular targeting to improve cure rates. Micrometastatic cells, such as circulating tumor cells (CTCs),
are surrogates of the early metastatic process that can be detected by a blood draw as a liquid biopsy.
Currently available preclinical models used to study the spectrum of cancer progression from a localized
primary tumor to metastatic disease are limited. To combat this, a library of patient-derived xenograft (PDX)
mouse models using primary tumors, micrometastatic CTCs (CDX) and brain metastases was developed.
Using single cell RNA sequencing techniques, presence of an additional AT2 population was confirmed in
NSCLC patients' metastatic tissues and primary lung tumors that had metastasized already. However, AT2
cells were absent in primary lung tumors of patients that had not metastasized. Importantly, AT2-depleted
NSCLC cell lines have reduced tumorigenicity in PDX mouse models. Gene expression and culture data also
suggest a strong migratory capacity of AT2-like cancer cells. This indicates an important role of AT2 cells in
metastatic progression. For further validation of these critical leads, patient-derived organoid (PDO) pipelines
for high-throughput tumor growth and drug response testing were generated. It is innovative to expand on
metastasis-associated epithelial cancer cells, such as AT2, using patient-derived models and identify drug
targets. Based on the rationale that AT2 populations with an impact on tumorigenicity are identified in
metastases, the hypothesis is that AT2 cells promote NSCLC metastatic progression and express cancer-
relevant genes. The objective is to identify AT2 lineage-specific phenotypes to detect therapeutic targets in
NSCLC. In task 1, AT2-like and other epithelial cancer cell populations will be dissected in NSCLC primary
tumors and metastases. AT2 cells will be enriched from a library of human NSCLC cell lines for study of
tumorigenicity. Druggable pathways will be identified in NSCLC patient tissues with single cell analyses. In task
2, the impact of epithelial cancer cells, including AT2, on drug responses and patient prognosis will be
determined. PDOs from human primary and metastatic NSCLC tumors will be treated with standard-of-care
chemotherapy to associate drug responses with gene expressions of epithelial cancer cells. AT2 phenotypes
will also be identified in CTCs as liquid biopsies. The impact of AT2-CTCs on survival in surgically treated
NSCLC patients will be determined for risk stratification. Upon completion of the proposal, AT2-associated
cellular and molecular targets to prevent metastatic progression in NSCLC will be identified. Results have high
potential for clinical impact to prevent recurrences in patients undergoing curative surgery for NSCLC. Data will
lead to discovery of drug targets at a single cell level that are primed for translation into clinical trials.
Terms: <3-D><3-Dimensional><3D><3D cell culture><3D culture><Abscission><Adjuvant Chemotherapy><Adjuvant Drug Therapy><Anti-Cancer Agents><Antineoplastic Agents><Antineoplastic Drugs><Antineoplastics><Anzatax><Asotax><Assay><Bio-Informatics><Bioassay><Bioinformatics><Biological Assay><Blood><Blood Reticuloendothelial System><Body Tissues><Brain Metastasis><Bristaxol><CBDCA><Cancer Cause><Cancer Drug><Cancer Etiology><Cancer Genes><Cancer Model><Cancer Patient><Cancer cell line><Cancer-Promoting Gene><CancerModel><Cancers><Carboplatin><Carboplatino><Carcinoma><Cause of Death><Cell Body><Cell Line><CellLine><Cells><Cessation of life><Chemoresistance><Chest Surgeon><Clinical><Clinical Trials><Complex><Curative Surgery><Data><Data Set><Death><Deposit><Deposition><Development><Diagnosis><Disease><Disease Progression><Disorder><Disseminated Malignant Neoplasm><Distant><Drug Targeting><Drug resistance><Drugs><Epidermoid Cell Lung Carcinoma><Epithelial cancer><Excision><Extirpation><Gene Expression><General Population><General Public><Generalized Growth><Genes><Genetic><Growth><Hospitals><Human><Intratumoral heterogeneity><Invaded><Libraries><Link><Local Cancer><Localized Cancer><Localized Malignancy><Localized Malignant Neoplasm><Lung><Lung Adenocarcinoma><Lung Alveolar Epithelia><Lung Neoplasms><Lung Respiratory System><Lung Tumor><Malignant Cell><Malignant Epithelial Neoplasms><Malignant Epithelial Tumors><Malignant Neoplasms><Malignant Tumor><Malignant Tumor of the Lung><Malignant neoplasm of lung><Medication><Metastasis><Metastasize><Metastatic Cancer><Metastatic Lesion><Metastatic Malignant Neoplasm><Metastatic Mass><Metastatic Neoplasm><Metastatic Neoplasm to the Brain><Metastatic Tumor><Metastatic Tumor to the Brain><Metastatic malignant neoplasm to brain><Metastatic/Recurrent><Methods><Modeling><Modern Man><Molecular><Molecular Target><NSCLC><NSCLC - Non-Small Cell Lung Cancer><Neoplasm Circulating Cells><Neoplasm Metastasis><Neoplastic Disease Chemotherapeutic Agents><Non-Small Cell Lung Cancer><Non-Small-Cell Lung Carcinoma><Oncogenes><Oncogenic><Operative Procedures><Operative Surgical Procedures><Organ><Organoids><Outcome><Outcome Study><PDX model><Paclitaxel><Paclitaxel (Taxol)><Pathway interactions><Patient derived xenograft><Patients><Pattern><Pharmaceutical Preparations><Phenotype><Physicians><Population><Position><Positioning Attribute><Praxel><Pre-Clinical Model><Preclinical Models><Primary Neoplasm><Primary Tumor><Progenitor Cells><Prognosis><Proliferating><Public Domains><Publishing><Pulmonary Cancer><Pulmonary Neoplasms><Pulmonary malignant Neoplasm><Recurrence><Recurrent><Recurrent Malignant Neoplasm><Recurrent Malignant Tumor><Recurrent Neoplasm><Recurrent tumor><Removal><Reproducibility><Research><Resistance><Resistance development><Resistant development><Role><Scientist><Secondary Neoplasm><Secondary Tumor><Single cell seq><Squamous Cell Lung Carcinoma><Squamous cell lung cancer><Strains Cell Lines><Surgeon><Surgical><Surgical Interventions><Surgical Procedure><Surgical Removal><System><Taxol><Taxol A><Taxol Konzentrat><Techniques><Testing><Thoracic Surgeon><Time><Tissue Growth><Tissues><Transforming Genes><Translations><Tumor Cell><Tumor Tissue><Tumor-Specific Treatment Agents><Tumorigenicity><Type II Cell><Type II Epithelial Receptor Cell><Validation><Veterans><alveolar epithelium><anti-cancer drug><anti-cancer research><biobank><biorepository><brain micrometastasis><cancer cell><cancer drug resistance><cancer initiation><cancer metastasis><cancer progression><cancer recurrence><cancer research><cell type><cellular targeting><chemoresistant><chemotherapy><chemotherapy resistance><chemotherapy resistant><circulating neoplastic cell><circulating tumor cell><combat><cultured cell line><developing resistance><developmental><drug resistant><drug/agent><epithelial carcinoma><epithelial progenitor><epithelial progenitor cell><epithelial stem cell><experience><experiment><experimental research><experimental study><experiments><heterogeneity in tumors><high risk><human RNA sequencing><human RNA-seq><human tissue><improved><in vivo><in vivo Model><innovate><innovation><innovative><intra-tumoral heterogeneity><intratumor heterogeneity><liquid biopsy><lung cancer><lung squamous cancer><lung squamous carcinoma><lung squamous cell carcinoma><malignancy><metastatic process><migration><mouse model><murine model><neoplasm progression><neoplasm recurrence><neoplasm/cancer><neoplastic cell><neoplastic progression><new drug target><new druggable target><new pharmacotherapy target><new therapeutic target><new therapy target><novel><novel drug target><novel druggable target><novel pharmacotherapy target><novel therapeutic target><novel therapy target><ontogeny><pathway><patient derived xenograft model><patient prognosis><personalization of treatment><personalized medicine><personalized therapy><personalized treatment><pre-clinical><preclinical><prevent><preventing><pulmonary><resection><resistance to Drug><resistance to cancer drugs><resistant><resistant to Drug><resistant to cancer drugs><response><risk stratification><scRNA-seq><self renewing cell><single cell RNA-seq><single cell RNAseq><single cell analysis><single cell expression profiling><single cell next generation sequencing><single cell sequencing><single cell transcriptomic profiling><single-cell RNA sequencing><social role><squamous cell carcinoma of the lung><standard of care><stem cells><stratify risk><surgery><therapeutic target><three dimensional><three dimensional cell culture><transdifferentiation><translation><translational cancer research><treatment strategy><tumor><tumor cell metastasis><tumor growth><tumor heterogeneity><tumor initiation><tumor progression><validations>