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Principal Investigator: VIKAS DUDEJA
Organization: BIRMINGHAM VA MEDICAL CENTER
Fiscal Year: 2024
Funding agency: Veterans Affairs
Project Summary
Pancreatic cancer (PDAC) is the 3rd most common cause of cancer-related mortality in the US. Our veterans
and military personnel bear significant brunt of this disease. One of the major obstacles in devising effective
treatment strategies against PDAC is the incomplete understanding of its pathogenesis. For instance, smoking
is one of the major life style factors, which affects PDAC incidence and outcomes. However, our understanding
of the mechanism(s) by which smoking affects PDAC development is still rudimentary. Thus, to develop novel
and effective treatment strategies, we need a better understanding of the pathogenesis of PDAC.
Our recent work has demonstrated that gut microbiome modulates adaptive immune response and promotes
PDAC growth and metastases. Interestingly, few studies suggest that cigarette smoking significantly impact gut
microbiome. Whether, this modulation of gut microbiome in any way mediates the pro-tumorigenic effects of
smoking is not known. Intriguingly, our preliminary data in animal models suggest that gut microbiome is critical
for the smoking induced tumor initiation and progression. Furthermore, with respect to the mechanism, our
preliminary data suggest that smoking induced dysbiosis attenuates anti-cancer immune response. The current
study is the next logical step and clinical investigation of the findings generated from the pre-clinical
models. Based on our preliminary studies we have hypothesized that ‘the cigarette smoking alters gut
microbiome, which in turn promotes tumor initiation and progression in a immune dependent fashion.
This hypothesis will be tested through a combination of a clinical, observational, non-interventional study in
humans, and translational studies in Human Gut Microbiome Avatar Mice (AVATAR) generated using the
samples collected from humans. The study will be executed through the following three specific aims:
In Aim 1, to characterize the effect of smoking on gut metagenome and metabolome, stool samples will be
collected from smokers and non-smoker generally healthy volunteers as well as PDAC patients, and analyzed
by shotgun meta-genomics (for gut metagenome) and LC-MS (unbiased-metabolome). This analysis will help
elucidate the specific gut microbial colonies as well as metabolites, which are enriched in the gut of smokers and
might contribute to the increased incidence and worse outcomes of PDAC and other cancers in them. In Aim 2,
to directly evaluate the effect of the smoking induced dysbiosis on PDAC growth and to elucidate the mechanism
of this effect, we will leverage AVATAR model. Stool from healthy volunteers (smokers and non-smokers, in aim
1), will be transplanted into germ free genetically engineered mouse models of PDAC to yield patient specific
AVATAR mice. The tumor initiation and progression in AVATAR mice generated from the stool of smokers
(healthy volunteers/PDAC patients) will be measured, and compared with those generated from stools of non-
smokers. These studies will provide direct evidence whether gut microbiome of smokers promote tumor initiation
and/or progression, when compared to that of non-smokers. Finally, in Aim 3, we will build on our preliminary
studies which suggest that smoking induced pro-tumorigenic gut microbiome promotes cancer progression.
Specifically, we will evaluate therapeutic strategies by which the pro-tumorigenic effect of gut microbiome from
smokers can be negated.
Impact Statement: Pancreatic cancer is a leading source of morbidity and mortality in the veterans population.
Moreover, tobacco product use is alarmingly high in the military veterans, with 1 in 3 using some form of tobacco.
Our study can potentially uncover a new molecular pathway of pancreatic cancer growth in smokers, which can
be easily translated into the clinical paradigm for management of these patients
Terms: <Affect><Alcohol Drinking><Alcohol consumption><Animal Model><Animal Models and Related Studies><Antibiotic Agents><Antibiotic Drugs><Antibiotics><Armed Forces Personnel><Attenuated><COX-2><COX2><Cancer Cause><Cancer Etiology><Cancers><Causality><Cell Communication and Signaling><Cell Signaling><Clinical><Clinical Research><Clinical Study><Data><Development><Diet><Disease><Disorder><EtOH drinking><EtOH use><Etiology><Evaluation><Feces><Functional Metagenomics><Future><GEM model><GEMM model><GI microbiome><Generalized Growth><Genetically Engineered Mouse><Germ-Free><Growth><Human><Immune><Immune response><Immunes><Immunological response><Incidence><Intracellular Communication and Signaling><KRAS(G12D)><KRASG12D><Life Style><Lifestyle><Malignant Neoplasms><Malignant Pancreatic Neoplasm><Malignant Tumor><Malignant neoplasm of pancreas><Measures><Mediating><Metagenomics><Metastasis><Metastasize><Metastatic Lesion><Metastatic Mass><Metastatic Neoplasm><Metastatic Tumor><Mice><Mice Mammals><Military><Military Personnel><Miscellaneous Antibiotic><Modeling><Modern Man><Molecular><Morbidity><Morbidity - disease rate><Murine><Mus><Neoplasm Metastasis><Obesity><Outcome><PGHS-2><PHS-2><PTGS2><PTGS2 gene><Pancreas Cancer><Pancreatic Cancer><Pathogenesis><Pathway interactions><Patients><Pre-Clinical Model><Preclinical Models><Risk Reduction><Role><Sampling><Secondary Neoplasm><Secondary Tumor><Shotguns><Signal Transduction><Signal Transduction Systems><Signaling><Smoker><Smoking><Source><Testing><Therapeutic><Tissue Growth><Tobacco><Tobacco Consumption><Tobacco use><Translating><Transplantation><Tumor Promotion><Tumor-infiltrating immune cells><Veterans><Work><adaptive immune response><adiposity><alcohol ingestion><alcohol intake><alcohol product use><alcohol use><alcoholic beverage consumption><alcoholic drink intake><anti-cancer><attenuate><attenuates><biological signal transduction><cancer initiation><cancer metastasis><cancer progression><causation><cigarette smoking><cigarette use><clinical investigation><corpulence><cytokine><developmental><diets><digestive tract microbiome><disease causation><dysbacteriosis><dysbiosis><dysbiotic><effective therapy><effective treatment><enteric microbiome><ethanol consumption><ethanol drinking><ethanol ingestion><ethanol intake><ethanol product use><ethanol use><ex-smoker><fecal sample><former smoker><gastrointestinal microbiome><genetically engineered mouse model><genetically engineered murine model><gut metagenome><gut microbiome><gut-associated microbiome><hCOX-2><healthy volunteer><host response><immune cell infiltration of tumors><immune cells infiltrating the tumor><immune cells that infiltrate the tumor><immune system response><immunoresponse><infiltration of tumors by immune cells><insight><intestinal biome><intestinal microbiome><intratumoral immune cell><intratumoral immune infiltrate><life-style factor><lifestyle factors><malignancy><metabolism measurement><metabolome><metabolomics><metabonome><metabonomics><metagenome><microbial><microbial colonization><microbial imbalance><microbiome community composition><microbiome composition><microbiome species composition><microbiome structure><military population><military veteran><model of animal><mortality><mouse model><murine model><neoplasm progression><neoplasm/cancer><neoplastic progression><new therapeutic approach><new therapeutic intervention><new therapeutic strategies><new therapy approaches><new treatment approach><new treatment strategy><non-smoker><nonsmoker><novel><novel therapeutic approach><novel therapeutic intervention><novel therapeutic strategies><novel therapy approach><ontogeny><pancreas development><pancreatic cancer model><pancreatic cancer patients><pancreatic malignancy><pancreatic tumor model><pathway><patients with pancreatic cancer><reduce risk><reduce risks><reduce that risk><reduce the risk><reduce these risks><reduces risk><reduces the risk><reducing risk><reducing the risk><risk-reducing><scRNA-seq><shot gun><single cell RNA-seq><single cell RNAseq><single cell expression profiling><single cell transcriptomic profiling><single-cell RNA sequencing><social role><stool><stool sample><stool specimen><tobacco product use><translational study><transplant><treatment strategy><tumor cell metastasis><tumor immune cell><tumor immune infiltrate><tumor infiltration of immune cells><tumor initiation><tumor progression><tumorigenic><veteran population>