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.

Agency
National Institute of Health (NIH)
Institute
National Cancer Institute (NCI)
Type
Specialized Center--Cooperative Agreements (U54)
Project #
5U54CA210190-05
Application #
9987352
Study Section
Special Emphasis Panel (ZCA1)
Project Start
2016-08-17
Project End
2021-07-31
Budget Start
2020-08-01
Budget End
2021-07-31
Support Year
5
Fiscal Year
2020
Total Cost
Indirect Cost
Name
University of Minnesota Twin Cities
Department
Type
DUNS #
555917996
City
Minneapolis
State
MN
Country
United States
Zip Code
55455
Doak, Geneva R; Schwertfeger, Kathryn L; Wood, David K (2018) Distant Relations: Macrophage Functions in the Metastatic Niche. Trends Cancer 4:445-459
Tabdanov, Erdem D; Puram, Vikram V; Win, Zaw et al. (2018) Bimodal sensing of guidance cues in mechanically distinct microenvironments. Nat Commun 9:4891
Ray, Arja; Morford, Rachel K; Provenzano, Paolo P (2018) Cancer Stem Cell Migration in Three-Dimensional Aligned Collagen Matrices. Curr Protoc Stem Cell Biol 46:e57
Brett, Marie-Elena; Bomberger, Heather E; Doak, Geneva R et al. (2018) In vitro elucidation of the role of pericellular matrix in metastatic extravasation and invasion of breast carcinoma cells. Integr Biol (Camb) 10:242-252
Wu, Hao; de León, Marco Avila Ponce; Othmer, Hans G (2018) Getting in shape and swimming: the role of cortical forces and membrane heterogeneity in eukaryotic cells. J Math Biol 77:595-626
Shao, Qi; Liu, Feng; Chung, Connie et al. (2018) Physical and Chemical Enhancement of and Adaptive Resistance to Irreversible Electroporation of Pancreatic Cancer. Ann Biomed Eng 46:25-36
Elahi-Gedwillo, Kianna Y; Carlson, Marjorie; Zettervall, Jon et al. (2018) Antifibrotic therapy disrupts stromal barriers and modulates the immune landscape in pancreatic ductal adenocarcinoma. Cancer Res :
Tabdanov, Erdem D; Puram, Vikram; Zhovmer, Alexander et al. (2018) Microtubule-Actomyosin Mechanical Cooperation during Contact Guidance Sensing. Cell Rep 25:328-338.e5
Ray, Arja; Morford, Rachel K; Ghaderi, Nima et al. (2018) Dynamics of 3D carcinoma cell invasion into aligned collagen. Integr Biol (Camb) 10:100-112
Prahl, Louis S; Bangasser, Patrick F; Stopfer, Lauren E et al. (2018) Microtubule-Based Control of Motor-Clutch System Mechanics in Glioma Cell Migration. Cell Rep 25:2591-2604.e8

Showing the most recent 10 out of 20 publications