Cancer cells, including melanoma, often metastasize regionally through lymphatics before metastasizing systemically through the blood 1 – 4 ; however, the reason for this is unclear. Here we show that melanoma cells in lymph experience less oxidative stress and form more metastases than melanoma cells in blood. Immunocompromised mice with patient-derived melanomas and immunocompetent mice with mouse melanomas had more melanoma cells per microliter of tumor-draining lymph than tumor-draining blood. Cells metastasizing through blood, but not lymph, became dependent on the ferroptosis inhibitor GPX4. Cells pre-treated with chemical ferroptosis inhibitors formed more metastases than untreated cells after intravenous, but not intralymphatic, injection. We observed multiple differences between lymph fluid and blood plasma that may contribute to decreased oxidative stress and ferroptosis in lymph, including higher levels of glutathione and oleic acid, and less free iron, in lymph. Oleic acid protected melanoma cells from ferroptosis in an Acsl3 -dependent manner and increased their capacity to form metastatic tumors. Melanoma cells from lymph nodes were more resistant to ferroptosis and formed more metastases after intravenous injection than melanoma cells from subcutaneous tumors. Exposure to the lymphatic environment thus protects melanoma cells from ferroptosis and increases their ability to survive during subsequent metastasis through the blood.

Metastasis requires cancer cells to undergo poorly-understood metabolic changes [1][2][3] . We found that metabolic differences among melanoma cells confer differences in metastatic potential as a result of differences in Monocarboxylate Transporter 1 (MCT1) function. In vivo isotope tracing in patient-derived xenografts revealed differences in nutrient handling between efficiently and inefficiently metastasizing melanomas, with circulating lactate being a more prominent source of tumor lactate in efficient metastasizers. Efficient metastasizers had higher MCT1 levels and MCT1 inhibition reduced lactate uptake. MCT1 inhibition had little effect on primary subcutaneous tumor growth but depleted circulating melanoma cells and reduced metastatic disease burden in patientderived xenografts and in mouse melanomas. MCT1 inhibition suppressed the oxidative pentose phosphate pathway and increased ROS levels. Anti-oxidants blocked the effect of MCT1 inhibition on metastasis. MCT1 high and MCT1 −/low cells from the same melanomas had similar Users may view, print, copy, and download text and data-mine the content in such documents, for the purposes of academic research, subject always to the full Conditions of use:

Leptin Receptor + (LepR + ) stromal cells in adult bone marrow are a critical source of growth factors, including Stem Cell Factor (SCF), for the maintenance of hematopoietic stem cells (HSCs) and early restricted progenitors 1 – 6 . LepR + cells are heterogeneous, including skeletal stem cells, osteogenic, and adipogenic progenitors 7 – 12 , though few markers have been available to distinguish these subsets or to compare their functions. Here we show expression of an osteogenic growth factor, Osteolectin 13 , 14 , distinguishes peri-arteriolar LepR + cells poised to undergo osteogenesis from peri-sinusoidal LepR + cells poised to undergo adipogenesis (but retaining osteogenic potential). Peri-arteriolar LepR + Osteolectin + cells are rapidly dividing, short-lived, osteogenic progenitors that increase in number after fracture and are depleted during aging. Deletion of Scf from adult Osteolectin + cells did not affect the maintenance of HSCs or most restricted progenitors but depleted common lymphoid progenitors (CLPs), impairing lymphopoiesis, bacterial clearance, and survival after acute bacterial infection. Peri-arteriolar Osteolectin + cell maintenance required mechanical stimulation. Voluntary running increased, while hindlimb unloading decreased, the frequencies of peri-arteriolar Osteolectin + cells and CLPs. Deletion of the mechanosensitive ion channel, Piezo1 , from Osteolectin + cells depleted Osteolectin + cells and CLPs. A peri-arteriolar niche for osteogenesis and lymphopoiesis in bone marrow is maintained by mechanical stimulation and depleted during aging.

5. The conduction delays in the peripheral components of both motor and somatosensory pathways also decrease initially but then from the age of 5 years progressively increase in proportion to arm length.6. The threshold stimulus intensity for evoking muscle responses following electromagnetic stimulation of the cortex is high initially and falls progressively until the age of 16 years. A linear relationship exists between the threshold intensity and height for the height range 70-180 cm. 7. The threshold stimulus intensities for exciting peripheral motor and somatosensory nerves decrease up to the age of 5 years and then reach a plateau.8. The results support the conclusion, already reported in the literature that peripheral nerves attain maximum value for fibre diameter and conduction velocity at approximately 5 years of age.9. In contrast, it is concluded that the maximum fibre diameters in both motor and somatosensory central pathways increase in proportion to height, leading to constant central conduction delays with growth.

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