Mechanisms of Tumor-Induced Lymphovascular Niche Formation in Draining Lymph Nodes

Commerford, Catharina D.; Dieterich, Lothar C.; He, Yuliang; Hell, Tanja; Montoya-Zegarra, Javier A.; Noerrelykke, Simon Flyvbjerg; Russo, Erica; Röcken, Martin; Detmar, Michael

doi:10.1016/j.celrep.2018.12.002

Cited by 66 publications

(84 citation statements)

References 50 publications

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“…4T1 cells have been reported to colonize tumor‐draining LNs very inefficiently . In line with this, with the exception of one mouse, we were not able to detect LN metastases in our model, neither histologically nor by bioluminescence (Supporting Information Figs.…”

Section: Resultssupporting

confidence: 79%

“…4T1 cells have been reported to colonize tumor-draining LNs very inefficiently. 16,[38][39][40][41][42] In line with this, with the exception of one mouse, we were not able to detect LN metastases in our model, neither histologically nor by bioluminescence (Supporting Information Figs. S2g and S2h), preventing us from further studying the role of lymphatic VCAM-1 in lymphogenous metastasis.…”

Section: Vcam-1 Blockade In Vivo Reduces Lymphatic Invasion Of Tumor supporting

confidence: 63%

“…Despite their implication in tumor progression and correlation with poor prognosis in many cancer types, the molecular features of primary tumor‐associated lymphatic vessels have remained largely unknown, most likely due to the technical challenge to isolate sufficient numbers of LECs from tumor tissue. The only previously reported gene expression signatures of tumor‐associated LECs were thus obtained from a VEGF‐C‐overexpressing tumor model and involved in vitro expansion of LECs (which likely affected their phenotype), concentrated on tumor‐draining lymphatic collectors, or on tumor‐draining LNs . Using FACS sorting of LECs in combination with an RNAseq protocol for ultra‐low input, we provide here the first complete and direct transcriptional characterization of primary tumor‐associated lymphatic vessels in a model of triple‐negative breast cancer (4T1).…”

Section: Discussionmentioning

confidence: 99%

“…Despite the multiple roles of the lymphatic system in cancer progression, surprisingly little is known about the molecular changes occurring in tumor‐associated lymphatic vessels that may explain their tumor‐promoting function and could reveal new targets for cancer therapy. So far, only few studies have investigated gene expression signatures of tumor‐associated lymphatic endothelium, including tumor‐derived, in vitro expanded LECs, tumor‐associated lymphatic collectors and LECs isolated from tumor‐draining LNs . Correspondingly, the mechanisms regulating lymphatic invasion of tumor cells are still not fully understood.…”

Section: Introductionmentioning

confidence: 99%

“…So far, only few studies have investigated gene expression signatures of tumor-associated lymphatic endothelium, including tumor-derived, in vitro expanded LECs, 14 tumor-associated lymphatic collectors 15 and LECs isolated from tumor-draining LNs. 16 Correspondingly, the mechanisms regulating lymphatic invasion of tumor cells are still not fully understood. It has been suggested that chemokines and adhesion molecules expressed by tumor-associated LECs are involved in this process, 14,[17][18][19] indicating that at least in some cases, cancer cells may employ similar pathways as leukocytes to enter lymphatic vessels.…”

Section: Introductionmentioning

confidence: 99%

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Transcriptional profiling of breast cancer‐associated lymphatic vessels reveals VCAM‐1 as regulator of lymphatic invasion and permeability

Kapaklikaya

Cetintas

Proulx

et al. 2019

Intl Journal of Cancer

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Tumor‐associated lymphangiogenesis and lymphatic invasion of tumor cells correlate with poor outcome in many tumor types, including breast cancer. Various explanations for this correlation have been suggested in the past, including the promotion of lymphatic metastasis and an immune‐inhibitory function of lymphatic endothelial cells (LECs). However, the molecular features of tumor‐associated lymphatic vessels and their implications for tumor progression have been poorly characterized. Here, we report the first transcriptional analysis of tumor‐associated LECs directly isolated from the primary tumor in an orthotopic mouse model of triple negative breast cancer (4T1). Gene expression analysis showed a strong upregulation of inflammation‐associated genes, including endothelial adhesion molecules such as VCAM‐1, in comparison to LECs derived from control tissue. In vitro experiments demonstrated that VCAM‐1 is not involved in the adhesion of tumor cells to LECs but unexpectedly promoted lymphatic permeability by weakening of lymphatic junctions, most likely through a mechanism triggered by interactions with integrin α4 which was also induced in tumor‐associated LECs. In line with this, in vivo blockade of VCAM‐1 reduced lymphatic invasion of 4T1 cells. Taken together, our findings suggest that disruption of lymphatic junctions and increased permeability via tumor‐induced lymphatic VCAM‐1 expression may represent a new target to block lymphatic invasion and metastasis.

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Section: Resultssupporting

confidence: 79%

Section: Vcam-1 Blockade In Vivo Reduces Lymphatic Invasion Of Tumor supporting

confidence: 63%

Section: Discussionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

See 3 more Smart Citations

Transcriptional profiling of breast cancer‐associated lymphatic vessels reveals VCAM‐1 as regulator of lymphatic invasion and permeability

Kapaklikaya

Cetintas

Proulx

et al. 2019

Intl Journal of Cancer

Self Cite

View full text Add to dashboard Cite

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Breast cancer metastasis: immune profiling of lymph nodes reveals exhaustion of effector T cells and immunosuppression

et al. 2021

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Sentinel lymph nodes are the first nodes draining the lymph from a breast and could reveal early changes in the host immune system upon dissemination of breast cancer cells. To investigate this, we performed single‐cell immune profiling of lymph nodes with and without metastatic cells. Whereas no significant changes were observed for B‐cell and natural killer (NK)‐cell subsets, metastatic lymph nodes had a significantly increased frequency of CD8 T cells and a skewing toward an effector/memory phenotype of CD4 and CD8 T cells, suggesting an ongoing immune response. Additionally, metastatic lymph nodes had an increased frequency of TIGIT (T‐cell immunoreceptor with Ig and ITIM domains)‐positive T cells with suppressed TCR signaling compared with non‐metastatic nodes, indicating exhaustion of effector T cells, and an increased frequency of regulatory T cells (Tregs) with an activated phenotype. T‐cell alterations correlated with the percentage of metastatic tumor cells, reflecting the presence of metastatic tumor cells driving T effector cells toward exhaustion and promoting immunosuppression by recruitment or increased differentiation toward Tregs. These results show that immune suppression occurs already in early stages of tumor progression.

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Melanoma‐derived extracellular vesicles mediate lymphatic remodelling and impair tumour immunity in draining lymph nodes

Leary

Walser

et al. 2022

J of Extracellular Vesicle

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Tumour-draining lymph nodes (LNs) undergo massive remodelling including expansion of the lymphatic sinuses, a process that has been linked to lymphatic metastasis by creation of a pre-metastatic niche. However, the signals leading to these changes have not been completely understood. Here, we found that extracellular vesicles (EVs) derived from melanoma cells are rapidly transported by lymphatic vessels to draining LNs, where they selectively interact with lymphatic endothelial cells (LECs) as well as medullary sinus macrophages. Interestingly, uptake of melanoma EVs by LNresident LECs was partly dependent on lymphatic VCAM-1 expression, and induced transcriptional changes as well as proliferation of those cells. Furthermore, melanoma EVs shuttled tumour antigens to LN LECs for cross-presentation on MHC-I, resulting in apoptosis induction in antigen-specific CD8 + T cells. In conclusion, our data identify EV-mediated melanoma-LN LEC communication as a new pathway involved in tumour progression and tumour immune inhibition, suggesting that EV uptake or effector mechanisms in LECs might represent a new target for melanoma therapy.

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Mechanisms of Tumor-Induced Lymphovascular Niche Formation in Draining Lymph Nodes

Cited by 66 publications

References 50 publications

Transcriptional profiling of breast cancer‐associated lymphatic vessels reveals VCAM‐1 as regulator of lymphatic invasion and permeability

Transcriptional profiling of breast cancer‐associated lymphatic vessels reveals VCAM‐1 as regulator of lymphatic invasion and permeability

Breast cancer metastasis: immune profiling of lymph nodes reveals exhaustion of effector T cells and immunosuppression

Melanoma‐derived extracellular vesicles mediate lymphatic remodelling and impair tumour immunity in draining lymph nodes

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