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Updated: Oct 1, 2025
Quantifying the Brain Metastatic Tumor Micro-Environment using an Organ-On-A Chip 3D Model, Machine Learning, and Confocal Tomography
Published on: August 16, 2020
A metastasis-on-a-chip approach to explore the sympathetic modulation of breast cancer bone metastasis
Francisco Conceição1,2,3, Daniela M Sousa1,2, Joshua Loessberg-Zahl4
1Instituto de Investigação e Inovação Em Saúde (I3S), Universidade Do Porto, 4200-135, Porto, Portugal.
Abstract:
Organ-on-a-chip models have emerged as a powerful tool to model cancer metastasis and to decipher specific crosstalk between cancer cells and relevant regulators of this particular niche. Recently, the sympathetic nervous system (SNS) was proposed as an important modulator of breast cancer bone metastasis. However, epidemiological studies concerning the benefits of the SNS targeting drugs on breast cancer survival and recurrence remain controversial. Thus, the role of SNS signaling over bone metastatic cancer cellular processes still requires further clarification. Herein, we present a novel humanized organ-on-a-chip model recapitulating neuro-breast cancer crosstalk in a bone metastatic context. We developed and validated an innovative three-dimensional printing based multi-compartment microfluidic platform, allowing both selective and dynamic multicellular paracrine signaling between sympathetic neurons, bone tropic breast cancer cells and osteoclasts. The selective multicellular crosstalk in combination with biochemical, microscopic and proteomic profiling show that synergistic paracrine signaling from sympathetic neurons and osteoclasts increase breast cancer aggressiveness demonstrated by augmented levels of pro-inflammatory cytokines (e.g. interleukin-6 and macrophage inflammatory protein 1α). Overall, this work introduced a novel and versatile platform that could potentially be used to unravel new mechanisms involved in intracellular communication at the bone metastatic niche.
Insights
This study introduces a novel organ-on-a-chip model to investigate sympathetic nervous system (SNS) signaling in breast cancer bone metastasis. The model reveals how SNS and osteoclast crosstalk enhances cancer aggressiveness, offering new insights into metastatic processes.
Area of Science:
- Biomedical Engineering
- Cancer Biology
- Neuroscience
Background:
- The sympathetic nervous system (SNS) is implicated in breast cancer bone metastasis, but its precise role and the efficacy of targeting drugs remain unclear.
- Understanding the cellular crosstalk within the bone metastatic niche is crucial for developing effective therapies.
Purpose of the Study:
- To develop and validate a novel humanized organ-on-a-chip model for studying neuro-breast cancer crosstalk in bone metastasis.
- To elucidate the role of sympathetic neuron and osteoclast signaling in promoting breast cancer aggressiveness.
Main Methods:
- Development of a 3D-printed, multi-compartment microfluidic platform enabling dynamic multicellular interactions.
- Integration of sympathetic neurons, bone-tropic breast cancer cells, and osteoclasts within the chip.
- Utilized biochemical, microscopic, and proteomic analyses to assess cellular crosstalk and cancer aggressiveness.
Main Results:
- Demonstrated synergistic paracrine signaling between sympathetic neurons and osteoclasts.
- Showed increased breast cancer aggressiveness due to this crosstalk, evidenced by elevated pro-inflammatory cytokines like IL-6 and MIP-1α.
- Validated the model's capability to recapitulate key aspects of the bone metastatic niche.
Conclusions:
- The novel organ-on-a-chip platform effectively models neuro-breast cancer crosstalk in bone metastasis.
- Sympathetic neuron and osteoclast signaling significantly enhances breast cancer aggressiveness.
- This platform offers a versatile tool for uncovering novel mechanisms of intercellular communication in metastatic niches.
