# Project 2: Cell Migration in Mechanically Complex Microenvironments

> **NIH NIH U54** · UNIVERSITY OF MINNESOTA · 2020 · $494,729

## Abstract

Cancers are complex systems commonly associated with a robust fibroinflammatory stromal response, or
desmoplastic reaction. This is highly relevant as it is now recognized that, in many solid tumors, the stromal
compartment and its local microenvironments significantly influence disease progression. Through disease
progression this desmoplastic reaction continues and often intensifies, offering critical support to malignant
cells as they progress to invasive and often fully metastastic disease while also providing drug-free sanctuaries
that limit access of small molecule therapies. Likewise, even the earliest stages of disease are associated with
a robust immune reaction that evolves with disease progression. Here tumor microenvironments appear to
form sanctuaries for immune evasion and in fact are comprised, in part, of infiltrated immune cells that have
been subverted to act as active collaborators that enable tumor progression. Interestingly, while robust
biochemical stimuli are present in tumors, they are not the only factor. These microenvironments also provide
robust physical cues that conspire to promote disease progression. For instance, in solid tumors there are
fundamental roles of extracellular matrix stiffness, composition and architecture that profoundly influence
outcome. However, to date, the molecular and physical mechanisms by which matrix stiffness and
architecture, and their relative contributions, influence tumor cell behavior are not well known. Here, we
propose specific and integrated experiments and modeling to explicitly investigate the physical and molecular
mechanisms by which the tumor microenvironment regulates disease progression as a function of the
underlying carcinoma genetics. Quantitative analysis and parameterization of data will facilitate model
development and model predictions will be tested experimentally. Specifically, we will employ a series of 2D
and 3D assays with varying stiffness and architecture of increasing complexity, and multiscale network
modeling, to parse out the relative contributions of contact guidance cues and durotactic effects in complex
microenvironments. Integration of chemical gradients will be used to parse out dominance, antagonism or
synergy between chemical and physical cues. Further, we hypothesize that physical cues in the cellular
microenvironment drive communication between different tumor cell populations and regulate immune cell
infiltration and function. Thus, we seek to identify regimes where manipulating operant physical characteristics
of a tumor reduces carcinoma cell advancement while simultaneously hampering immune evasion and
promoting the antitumor response.

## Key facts

- **NIH application ID:** 9987352
- **Project number:** 5U54CA210190-05
- **Recipient organization:** UNIVERSITY OF MINNESOTA
- **Principal Investigator:** Paolo Provenzano
- **Activity code:** U54 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2020
- **Award amount:** $494,729
- **Award type:** 5
- **Project period:** 2016-08-17 → 2023-07-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/9987352

## Citation

> US National Institutes of Health, RePORTER application 9987352, Project 2: Cell Migration in Mechanically Complex Microenvironments (5U54CA210190-05). Retrieved via AI Analytics 2026-05-23 from https://api.ai-analytics.org/grant/nih/9987352. Licensed CC0.

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