Mittal, M. | Search bioRxiv

bioRxiv2024

Dietary Fiber Modulates Macrophage Activity in a Microfluidic Model of Colonocyte-Microbiota Interactions in Colorectal Cancer

Dietary fiber has been consistently associated with a decreased risk of colorectal cancer (CRC) development. While the apoptotic effect of dietary fiber microbial fermentation products on tumor colonocytes is well established, the role of these products on other components of the tumor microenvironment remains unexplored. Tumor associated macrophages play a critical role in tumor development in the colon; however, the effect of dietary fiber fermentation by microbiota on macrophage-colonocyte interaction in colorectal cancer has been difficult to dissect due to a lack of complex in vitro models of CRC containing both immune cells and microbiota. Recently, we developed a microfluidic model that facilitates the coculture of CRC spheroids with complex microbial communities. Here, we expand our model to include macrophages and employ it to study the impact of dietary fiber on macrophage-colonocyte interaction. We optimized monocyte differentiation parameters in vitro and demonstrated the capacity of our model to recapitulate changes in microbiota composition and metabolic output associated with dietary fiber administration in vivo. Combinatorial coculture of colonocytes with microbiota and macrophages revealed that alterations in microbial production of SCFA derived from dietary fiber fermentation correlated with enhanced colonocyte death, possibly mediated by an increase in transcription of tumor pro-apoptotic signals by macrophages. Our work highlights the capacity of complex in vitro systems to study the role of microbial metabolism of dietary molecules on CRC colonocyte viability and macrophage activity.

cancer biology↗

bioRxiv2024

TrkA+ sensory neurons regulate osteosarcoma proliferation and vascularization to promote disease progression

Bone pain is a presenting feature of bone cancers such as osteosarcoma (OS), relayed by skeletal-innervating peripheral afferent neurons. Potential functions of tumor-associated sensory neurons in bone cancers beyond pain sensation are unknown. To uncover neural regulatory functions, a chemical-genetic approach in mice with a knock-in allele for TrkA was used to functionally perturb sensory nerve innervation during OS growth and disease progression. TrkA inhibition in transgenic mice led to significant reductions in sarcoma-associated sensory innervation and vascularization, tumor growth and metastasis, and prolonged overall survival. Single-cell transcriptomics revealed that sarcoma denervation was associated with phenotypic alterations in both OS tumor cells and cells within the tumor microenvironment, and with reduced calcitonin gene-related peptide (CGRP) and vascular endothelial growth factor (VEGF) signaling. Multimodal and multi-omics analyses of human OS bone samples and human dorsal root ganglia neurons further implicated peripheral innervation and neurotrophin signaling in OS tumor biology. In order to curb tumor-associated axonal ingrowth, we next leveraged FDA-approved bupivacaine liposomes leading to significant reductions in sarcoma growth, vascularity, as well as alleviation of pain. In sum, TrkA-expressing peripheral neurons positively regulate key aspects of OS progression and sensory neural inhibition appears to disrupt calcitonin receptor signaling (CALCR) and VEGF signaling within the sarcoma microenvironment leading to significantly reduced tumor growth and improved survival. These data suggest that interventions to prevent pathological innervation of osteosarcoma represent a novel adjunctive therapy to improve clinical outcomes and survival.

cancer biology↗