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.
Therapies that target tumor architecture (e.g., the stroma compartment) have proven efficacy in preclinical studies and have led to ongoing clinical trials. This is the proof-of-concept of the existence of tissue-specific properties that regulate tumor architecture during tumor progression and in response to chemotherapy. Our proposed study aims to identify the mechanisms that regulate tumor tissue homeostasis (i.e., multicellular dynamics) to find novel therapeutic strategies for patients with pancreatic cancer (PDAC), to define the role of tumor architecture in PDAC chemoresistance, and to discover new biomarkers to predict the response to multi- agent chemotherapy (i.e., FOLFIRINOX).
