Dissecting the Spatially Restricted Effects of Microenvironment-Mediated Resistance on Targeted Therapy Responses
Tatiana Miti1, Bina Desai2,3, Daria Miroshnychenko2
1Department of Integrative Mathematical Oncology, H. Lee Moffitt Cancer Centre and Research Institute, Tampa, FL 33612, USA.
Abstract:
The response of tumors to anti-cancer therapies is defined not only by cell-intrinsic therapy sensitivities but also by local interactions with the tumor microenvironment. Fibroblasts that make tumor stroma have been shown to produce paracrine factors that can strongly reduce the sensitivity of tumor cells to many types of targeted therapies. Moreover, a high stroma/tumor ratio is generally associated with poor survival and reduced therapy responses. However, in contrast to advanced knowledge of the molecular mechanisms responsible for stroma-mediated resistance, its effect on the ability of tumors to escape therapeutic eradication remains poorly understood. To a large extent, this gap of knowledge reflects the challenge of accounting for the spatial aspects of microenvironmental resistance, especially over longer time frames. To address this problem, we integrated spatial inferences of proliferation-death dynamics from an experimental animal model of targeted therapy responses with spatial mathematical modeling. With this approach, we dissected the impact of tumor/stroma distribution, magnitude and distance of stromal effects. While all of the tested parameters affected the ability of tumor cells to resist elimination, spatial patterns of stroma distribution within tumor tissue had a particularly strong impact.
Insights
Tumor microenvironment interactions, particularly stroma distribution, significantly impact anti-cancer therapy effectiveness. Understanding spatial patterns is crucial for overcoming treatment resistance in cancer.
Area of Science:
- Oncology
- Cancer Biology
- Tumor Microenvironment Research
Background:
- Tumor response to anti-cancer therapies involves both cell-intrinsic factors and tumor microenvironment (TME) interactions.
- Tumor stroma, produced by fibroblasts, can secrete factors that reduce tumor cell sensitivity to targeted therapies, often correlating with poor prognosis.
- While molecular mechanisms of stroma-mediated resistance are known, its impact on tumor eradication and spatial dynamics remains unclear.
Purpose of the Study:
- To investigate the spatial aspects of tumor microenvironment-mediated resistance to anti-cancer therapies.
- To dissect the influence of tumor/stroma distribution, magnitude, and distance of stromal effects on therapy response.
- To bridge the knowledge gap regarding how spatial TME factors contribute to tumor escape from therapeutic eradication.
Main Methods:
- Integration of spatial inferences of proliferation-death dynamics from an experimental animal model.
- Application of spatial mathematical modeling to analyze therapy responses.
- Dissection of the impact of various spatial parameters, including stroma distribution, magnitude, and distance of effects.
Main Results:
- All tested parameters (distribution, magnitude, distance) influenced tumor cell resistance to elimination.
- Spatial patterns of stroma distribution within tumor tissue demonstrated a particularly strong impact on therapy resistance.
- The study provides insights into the complex interplay between spatial TME architecture and treatment efficacy.
Conclusions:
- Spatial organization of the tumor microenvironment is a critical determinant of anti-cancer therapy response.
- Targeting or understanding the spatial distribution of tumor stroma may offer new strategies to overcome therapeutic resistance.
- Further research into spatial dynamics is essential for improving cancer treatment outcomes.
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