# Targeting tumor architecture as a novel therapeutic strategy for pancreatic cancer

> **NIH NIH R37** · UT SOUTHWESTERN MEDICAL CENTER · 2021 · $493,658

## Abstract

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.

## Key facts

- **NIH application ID:** 10120563
- **Project number:** 1R37CA242070-01A1
- **Recipient organization:** UT SOUTHWESTERN MEDICAL CENTER
- **Principal Investigator:** Matteo Ligorio
- **Activity code:** R37 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2021
- **Award amount:** $493,658
- **Award type:** 1
- **Project period:** 2021-02-01 → 2026-01-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10120563

## Citation

> US National Institutes of Health, RePORTER application 10120563, Targeting tumor architecture as a novel therapeutic strategy for pancreatic cancer (1R37CA242070-01A1). Retrieved via AI Analytics 2026-05-23 from https://api.ai-analytics.org/grant/nih/10120563. Licensed CC0.

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