Tumor-Derived Lactic Acid Modulates Activation and Metabolic Status of Draining Lymph Node Stroma

Abstract

Communication between tumors and the stroma of tumor-draining lymph nodes (TDLN) exists before metastasis arises, altering the structure and function of the TDLN niche. Transcriptional profiling of fibroblastic reticular cells (FRC), the dominant stromal population of lymph nodes, has revealed that FRCs in TDLNs are reprogrammed. However, the tumor-derived factors driving the changes in FRCs remain to be identified. Taking an unbiased approach, we have shown herein that lactic acid (LA), a metabolite released by cancer cells, was not only secreted by B16.F10 and 4T1 tumors in high amounts, but also that it was enriched in TDLNs. LA supported an upregulation of Podoplanin (Pdpn) and Thy1 and downregulation of IL7 in FRCs of TDLNs, making them akin to activated fibroblasts found at the primary tumor site. Furthermore, we found that tumor-derived LA altered mitochondrial function of FRCs in TDLNs. Thus, our results demonstrate a mechanism by which a tumor-derived metabolite connected with a low pH environment modulates the function of fibroblasts in TDLNs. How lymph node function is perturbed to support cancer metastases remains unclear. The authors show that tumor-derived LA drains to lymph nodes where it modulates the function of lymph node stromal cells, prior to metastatic colonization.

NAMPT‐Driven M2 Polarization of Tumor‐Associated Macrophages Leads to an Immunosuppressive Microenvironment in Colorectal Cancer

“…Lactic acid is known to be enriched in the fraction (<3 kDa) of tumor‐conditioned medium. [ 25 ] Hence, we fractionated the tumor‐conditioned medium by size (<3 kDa) and found that the M2‐like TAM polarization was reduced in KO macrophages under incubation with the fraction compared to WT macrophages (<3 kDa) (Figure 3D ; Figure S3D,E , Supporting Information).…”

Identification and subsequent validation of transcriptomic signature associated with metabolic status in endometrial cancer

“…In our study, sapanisertib, PHA-793887, and ciclopirox decreased extracellular lactate concentration in Ishikawa and HEC-1B cells. Other groups have shown that lactate accumulation, and, therefore, acidic microenvironment, is a major factor in cancer cell invasiveness and lymph node metastatic colonization 73 , 74 . These observations highlight the potential benefit of targeting cancer acidity and/or lactate accumulation in EC.…”

Lymph node metastasis in cancer progression: molecular mechanisms, clinical significance and therapeutic interventions

“…FRCs can also shape the premetastatic niche through various other mechanisms. Riedel et al 84 showed that before metastatic colonization, tumor-derived lactic acid could drain to LNs, contributing to IL-7 downregulation and altered FRC mitochondrial function. IL-1 production by melanoma cells can suppress FRC contractility through JAK1/STAT3 pathway inhibition, with the consequent relaxation of the 3D FRC network, better-enabling melanoma cells to invade this niche.…”