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Principal Investigator: Matteo Ligorio
Organization: UT SOUTHWESTERN MEDICAL CENTER
Fiscal Year: 2024
Award: $445,861
Funding agency: National Cancer Institute
Pancreatic ductal adenocarcinoma (PDAC) is one of the most chemorefractory cancers among solid tumors.
Even with the most effective chemotherapy (i.e., FOLFIRINOX), only 30% of PDAC patients respond. Therefore,
identifying novel therapies is an urgent and unmet need in the PDAC field. One of the emerging strategies for
treating these patients is targeting tumor architecture. The rationale of these therapies is to target tissue-specific
properties, either in the stroma or in the tumor compartment, to disrupt tumor tissue homeostasis during disease
progression or in response to treatment (chemotherapies). The majority of the previous studies have focused on
targeting the stroma compartment (cellular or extracellular matrix portion), leaving the tumor compartment (e.g.,
tumor tissue-specific properties) a relatively unexplored territory.
The goal of this proposal is to fill this knowledge gap by identifying tissue-specific properties in the tumor
compartment to impair disease progression and to overcome PDAC chemoresistance. The rationale and
feasibility of our proposed research studies are supported by our recent published work (Ligorio et al., Cell,
2019), in which we showed the existence of 8 different types of tumor glands, based on their internal composition
of cells, with distinct proliferation (PRO) and metastatic (EMT) capabilities. Moreover, we found that tumor glands
can be considered discrete functional “units” with distinct levels of aggressiveness and different chemorefractory
behaviors. Therefore, our overarching hypothesis is that tissue-specific properties exist that govern
tumor architecture by regulating the formation, internal structure, and evolution of tumor glands during
disease progression and under treatment.
To test this central hypothesis, we have recently developed (i) a method that allows us to characterize the cell
identity (i.e., different PRO and EMT phenotypes) while preserving architectural information within human tissue,
and (ii) an ad hoc mouse model to study tumor gland-forming ability using a time-course in vivo imaging
technique (i.e., two-photon microscopy). By integrating these two methodologies, we (a) will clarify the functional
behavior of tumor glands as a consequence of their internal structure (AIM.1), (b) will target an aggressive
subpopulation of cancer cells to impair tissue homeostasis (AIM.2), and (c) will define the role of tumor
architecture in PDAC chemoresistance and as a potential novel biomarker to predict the response to
FOLFIRINOX chemotherapy (AIM.3).
The proposed study will uncover new mechanisms (i.e., tumor tissue-specific properties) that drive tumor
progression and PDAC chemoresistance with the ultimate intent (i) to find novel therapeutic avenues for PDAC
patients, (ii) to define the role of tumor architecture in PDAC chemoresistance, and (iii) discover new
FOLFIRINOX-predictive biomarkers to improve the dismal prognosis of PDAC patients.
Terms: <2-photon microscopy><21+ years old><Adult><Adult Human><After Care><After-Treatment><Aftercare><Architecture><Autoregulation><Behavior><Biological><Biological Markers><Body Tissues><CRISPR editing screen><CRISPR screen><CRISPR-based screen><CRISPR/Cas9 screen><Cancers><Cell Body><Cell-Extracellular Matrix><Cells><Chemoresistance><Clinical Trials><Cold-Insoluble Globulins><Color><Core Biopsy><Core Needle Biopsy><Disease Progression><ECM><Engineering><Engineering / Architecture><Evolution><Extracellular Matrix><Extracellular Signal-Regulated Kinase Gene><FN1><Fibronectin 1><Fibronectins><Gland><Goals><Homeostasis><Human><Imaging Procedures><Imaging Technics><Imaging Techniques><Immune mediated therapy><Immunologically Directed Therapy><Immunotherapy><Impairment><Individual><Knowledge><LETS Proteins><Large External Transformation-Sensitive Protein><MAP Kinase Gene><MAPK><Malignant Cell><Malignant Neoplasms><Malignant Pancreatic Neoplasm><Malignant Tumor><Malignant neoplasm of pancreas><Methodology><Methods><Mice><Mice Mammals><Mitogen-Activated Protein Kinase Gene><Modern Man><Murine><Mus><Names><Opsonic Glycoprotein><Opsonic alpha(2)SB Glycoprotein><Pancreas><Pancreas Cancer><Pancreas Ductal Adenocarcinoma><Pancreatic><Pancreatic Cancer><Pancreatic Ductal Adenocarcinoma><Pathway interactions><Patients><Phenotype><Physiological Homeostasis><Prognosis><Proliferating><Property><Publishing><Refractory><Reporter><Research Support><Resolution><Role><STAT3><STAT3 gene><Shapes><Solid Neoplasm><Solid Tumor><Structure><Survival Rate><System><Testing><Time><Tissues><Tumor Tissue><Work><adulthood><alpha 2-Surface Binding Glycoprotein><bio-markers><biologic><biologic marker><biomarker><cancer cell><cancer progression><chemoresistant><chemotherapy><chemotherapy resistance><chemotherapy resistant><clustered regularly interspaced short palindromic repeats screen><genome scale><genome-wide><genomewide><human tissue><imaging in vivo><immune therapeutic approach><immune therapeutic interventions><immune therapeutic regimens><immune therapeutic strategy><immune therapy><immune-based therapies><immune-based treatments><immuno therapy><improved><in vivo imaging><in vivo two-photon imaging><innovate><innovation><innovative><insight><malignancy><mouse model><murine model><name><named><naming><neoplasm progression><neoplasm/cancer><neoplastic progression><new drug treatments><new drugs><new marker><new pharmacological therapeutic><new therapeutic approach><new therapeutic intervention><new therapeutic strategies><new therapeutics><new therapy><new therapy approaches><new treatment approach><new treatment strategy><next generation therapeutics><novel biomarker><novel drug treatments><novel drugs><novel marker><novel pharmaco-therapeutic><novel pharmacological therapeutic><novel therapeutic approach><novel therapeutic intervention><novel therapeutic strategies><novel therapeutics><novel therapy><novel therapy approach><pancreatic cancer patients><pancreatic malignancy><pathway><patients with pancreatic cancer><post treatment><pre-clinical study><preclinical study><predict responsiveness><predicting response><predictive biomarkers><predictive marker><predictive molecular biomarker><preservation><prognostic ability><prognostic power><prognostic utility><prognostic value><programs><refractory cancer><research study><resistant cancer><resolutions><response><response to therapy><response to treatment><social role><subcutaneous><subdermal><synergism><targeted drug therapy><targeted drug treatments><targeted therapeutic><targeted therapeutic agents><targeted therapy><targeted treatment><therapeutic response><therapy response><time use><treatment response><treatment responsiveness><tumor><tumor behavior><tumor progression><two photon excitation microscopy><two photon microscopy>