02656nas a2200397   4500000000100000000000100001008004100002260001200043653002000055653001800075653002000093653002400113653004600137653004900183653002500232653002300257653003200280653001400312653003600326653003100362653002900393100002600422700002100448700002600469700002300495700001700518700001400535700001800549700001800567700002000585245010700605300001100712490000700723520151400730022001402244       2022                            d  c2022-0110aBone metastasis10aBreast cancer10aIL, interleukin10aIL-6, interleukin 610aMCP-1, monocyte chemoattractant protein 110aMIP-1α, macrophage inflammatory protein 1α10aMetastasis-on-a-chip10aNE, norepinephrine10aPDMS, poly-dimethylsiloxane10aParacrine10aSNS, Sympathetic Nervous System10aSympathetic nervous system10aTH, tyrosine hydroxylase1 aFrancisco Conceição1 aDaniela M. Sousa1 aJoshua Loessberg-Zahl1 aAnke R. Vollertsen1 aEstrela Neto1 aKent Søe1 aJoana Paredes1 aAnne Leferink1 aMeriem Lamghari00aA metastasis-on-a-chip approach to explore the sympathetic modulation of breast cancer bone metastasis  a1002190 v133 aOrgan-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.  a2590-0064