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2. TABLE 1 from Characterizing Neutrophil Subtypes in Cancer Using scRNA Sequencing Demonstrates the Importance of IL1β/CXCR2 Axis in Generation of Metastasis-specific Neutrophils

Author

Fetit, Rana, primary, McLaren, Alistair S., primary, White, Mark, primary, Mills, Megan L., primary, Falconer, John, primary, Cortes-Lavaud, Xabier, primary, Gilroy, Kathryn, primary, Lannagan, Tamsin R.M., primary, Ridgway, Rachel A., primary, Nixon, Colin, primary, Naiker, Varushka, primary, Njunge, Renee, primary, Clarke, Cassie J., primary, Whyte, Declan, primary, Kirschner, Kristina, primary, Jackstadt, Rene, primary, Norman, Jim, primary, Carlin, Leo M., primary, Campbell, Andrew D., primary, Sansom, Owen J., primary, and Steele, Colin W., primary

Published
2024
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3. TABLE 2 from Characterizing Neutrophil Subtypes in Cancer Using scRNA Sequencing Demonstrates the Importance of IL1β/CXCR2 Axis in Generation of Metastasis-specific Neutrophils

Author

Fetit, Rana, primary, McLaren, Alistair S., primary, White, Mark, primary, Mills, Megan L., primary, Falconer, John, primary, Cortes-Lavaud, Xabier, primary, Gilroy, Kathryn, primary, Lannagan, Tamsin R.M., primary, Ridgway, Rachel A., primary, Nixon, Colin, primary, Naiker, Varushka, primary, Njunge, Renee, primary, Clarke, Cassie J., primary, Whyte, Declan, primary, Kirschner, Kristina, primary, Jackstadt, Rene, primary, Norman, Jim, primary, Carlin, Leo M., primary, Campbell, Andrew D., primary, Sansom, Owen J., primary, and Steele, Colin W., primary

Published
2024
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4. FIGURE 4 from Characterizing Neutrophil Subtypes in Cancer Using scRNA Sequencing Demonstrates the Importance of IL1β/CXCR2 Axis in Generation of Metastasis-specific Neutrophils

Author

Fetit, Rana, primary, McLaren, Alistair S., primary, White, Mark, primary, Mills, Megan L., primary, Falconer, John, primary, Cortes-Lavaud, Xabier, primary, Gilroy, Kathryn, primary, Lannagan, Tamsin R.M., primary, Ridgway, Rachel A., primary, Nixon, Colin, primary, Naiker, Varushka, primary, Njunge, Renee, primary, Clarke, Cassie J., primary, Whyte, Declan, primary, Kirschner, Kristina, primary, Jackstadt, Rene, primary, Norman, Jim, primary, Carlin, Leo M., primary, Campbell, Andrew D., primary, Sansom, Owen J., primary, and Steele, Colin W., primary

Published
2024
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5. FIGURE 1 from Characterizing Neutrophil Subtypes in Cancer Using scRNA Sequencing Demonstrates the Importance of IL1β/CXCR2 Axis in Generation of Metastasis-specific Neutrophils

Author

Fetit, Rana, primary, McLaren, Alistair S., primary, White, Mark, primary, Mills, Megan L., primary, Falconer, John, primary, Cortes-Lavaud, Xabier, primary, Gilroy, Kathryn, primary, Lannagan, Tamsin R.M., primary, Ridgway, Rachel A., primary, Nixon, Colin, primary, Naiker, Varushka, primary, Njunge, Renee, primary, Clarke, Cassie J., primary, Whyte, Declan, primary, Kirschner, Kristina, primary, Jackstadt, Rene, primary, Norman, Jim, primary, Carlin, Leo M., primary, Campbell, Andrew D., primary, Sansom, Owen J., primary, and Steele, Colin W., primary

Published
2024
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6. TABLE 3 from Characterizing Neutrophil Subtypes in Cancer Using scRNA Sequencing Demonstrates the Importance of IL1β/CXCR2 Axis in Generation of Metastasis-specific Neutrophils

Author

Fetit, Rana, primary, McLaren, Alistair S., primary, White, Mark, primary, Mills, Megan L., primary, Falconer, John, primary, Cortes-Lavaud, Xabier, primary, Gilroy, Kathryn, primary, Lannagan, Tamsin R.M., primary, Ridgway, Rachel A., primary, Nixon, Colin, primary, Naiker, Varushka, primary, Njunge, Renee, primary, Clarke, Cassie J., primary, Whyte, Declan, primary, Kirschner, Kristina, primary, Jackstadt, Rene, primary, Norman, Jim, primary, Carlin, Leo M., primary, Campbell, Andrew D., primary, Sansom, Owen J., primary, and Steele, Colin W., primary

Published
2024
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7. FIGURE 5 from Characterizing Neutrophil Subtypes in Cancer Using scRNA Sequencing Demonstrates the Importance of IL1β/CXCR2 Axis in Generation of Metastasis-specific Neutrophils

Author

Fetit, Rana, primary, McLaren, Alistair S., primary, White, Mark, primary, Mills, Megan L., primary, Falconer, John, primary, Cortes-Lavaud, Xabier, primary, Gilroy, Kathryn, primary, Lannagan, Tamsin R.M., primary, Ridgway, Rachel A., primary, Nixon, Colin, primary, Naiker, Varushka, primary, Njunge, Renee, primary, Clarke, Cassie J., primary, Whyte, Declan, primary, Kirschner, Kristina, primary, Jackstadt, Rene, primary, Norman, Jim, primary, Carlin, Leo M., primary, Campbell, Andrew D., primary, Sansom, Owen J., primary, and Steele, Colin W., primary

Published
2024
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8. Supplementary Figure S3 from Characterizing Neutrophil Subtypes in Cancer Using scRNA Sequencing Demonstrates the Importance of IL1β/CXCR2 Axis in Generation of Metastasis-specific Neutrophils

Author

Fetit, Rana, primary, McLaren, Alistair S., primary, White, Mark, primary, Mills, Megan L., primary, Falconer, John, primary, Cortes-Lavaud, Xabier, primary, Gilroy, Kathryn, primary, Lannagan, Tamsin R.M., primary, Ridgway, Rachel A., primary, Nixon, Colin, primary, Naiker, Varushka, primary, Njunge, Renee, primary, Clarke, Cassie J., primary, Whyte, Declan, primary, Kirschner, Kristina, primary, Jackstadt, Rene, primary, Norman, Jim, primary, Carlin, Leo M., primary, Campbell, Andrew D., primary, Sansom, Owen J., primary, and Steele, Colin W., primary

Published
2024
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9. Data from Characterizing Neutrophil Subtypes in Cancer Using scRNA Sequencing Demonstrates the Importance of IL1β/CXCR2 Axis in Generation of Metastasis-specific Neutrophils

Author

Fetit, Rana, primary, McLaren, Alistair S., primary, White, Mark, primary, Mills, Megan L., primary, Falconer, John, primary, Cortes-Lavaud, Xabier, primary, Gilroy, Kathryn, primary, Lannagan, Tamsin R.M., primary, Ridgway, Rachel A., primary, Nixon, Colin, primary, Naiker, Varushka, primary, Njunge, Renee, primary, Clarke, Cassie J., primary, Whyte, Declan, primary, Kirschner, Kristina, primary, Jackstadt, Rene, primary, Norman, Jim, primary, Carlin, Leo M., primary, Campbell, Andrew D., primary, Sansom, Owen J., primary, and Steele, Colin W., primary

Published
2024
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10. Supplementary Tables from Characterizing Neutrophil Subtypes in Cancer Using scRNA Sequencing Demonstrates the Importance of IL1β/CXCR2 Axis in Generation of Metastasis-specific Neutrophils

Author

Fetit, Rana, primary, McLaren, Alistair S., primary, White, Mark, primary, Mills, Megan L., primary, Falconer, John, primary, Cortes-Lavaud, Xabier, primary, Gilroy, Kathryn, primary, Lannagan, Tamsin R.M., primary, Ridgway, Rachel A., primary, Nixon, Colin, primary, Naiker, Varushka, primary, Njunge, Renee, primary, Clarke, Cassie J., primary, Whyte, Declan, primary, Kirschner, Kristina, primary, Jackstadt, Rene, primary, Norman, Jim, primary, Carlin, Leo M., primary, Campbell, Andrew D., primary, Sansom, Owen J., primary, and Steele, Colin W., primary

Published
2024
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11. TABLE 4 from Characterizing Neutrophil Subtypes in Cancer Using scRNA Sequencing Demonstrates the Importance of IL1β/CXCR2 Axis in Generation of Metastasis-specific Neutrophils

Author

Fetit, Rana, primary, McLaren, Alistair S., primary, White, Mark, primary, Mills, Megan L., primary, Falconer, John, primary, Cortes-Lavaud, Xabier, primary, Gilroy, Kathryn, primary, Lannagan, Tamsin R.M., primary, Ridgway, Rachel A., primary, Nixon, Colin, primary, Naiker, Varushka, primary, Njunge, Renee, primary, Clarke, Cassie J., primary, Whyte, Declan, primary, Kirschner, Kristina, primary, Jackstadt, Rene, primary, Norman, Jim, primary, Carlin, Leo M., primary, Campbell, Andrew D., primary, Sansom, Owen J., primary, and Steele, Colin W., primary

Published
2024
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12. FIGURE 3 from Characterizing Neutrophil Subtypes in Cancer Using scRNA Sequencing Demonstrates the Importance of IL1β/CXCR2 Axis in Generation of Metastasis-specific Neutrophils

Author

Fetit, Rana, primary, McLaren, Alistair S., primary, White, Mark, primary, Mills, Megan L., primary, Falconer, John, primary, Cortes-Lavaud, Xabier, primary, Gilroy, Kathryn, primary, Lannagan, Tamsin R.M., primary, Ridgway, Rachel A., primary, Nixon, Colin, primary, Naiker, Varushka, primary, Njunge, Renee, primary, Clarke, Cassie J., primary, Whyte, Declan, primary, Kirschner, Kristina, primary, Jackstadt, Rene, primary, Norman, Jim, primary, Carlin, Leo M., primary, Campbell, Andrew D., primary, Sansom, Owen J., primary, and Steele, Colin W., primary

Published
2024
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13. FIGURE 2 from Characterizing Neutrophil Subtypes in Cancer Using scRNA Sequencing Demonstrates the Importance of IL1β/CXCR2 Axis in Generation of Metastasis-specific Neutrophils

Author

Fetit, Rana, primary, McLaren, Alistair S., primary, White, Mark, primary, Mills, Megan L., primary, Falconer, John, primary, Cortes-Lavaud, Xabier, primary, Gilroy, Kathryn, primary, Lannagan, Tamsin R.M., primary, Ridgway, Rachel A., primary, Nixon, Colin, primary, Naiker, Varushka, primary, Njunge, Renee, primary, Clarke, Cassie J., primary, Whyte, Declan, primary, Kirschner, Kristina, primary, Jackstadt, Rene, primary, Norman, Jim, primary, Carlin, Leo M., primary, Campbell, Andrew D., primary, Sansom, Owen J., primary, and Steele, Colin W., primary

Published
2024
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14. Characterising neutrophil subtypes in cancer using scRNA sequencing demonstrates the importance of IL-1β/CXCR2 axis in generation of metastasis specific neutrophils

Author

Fetit, Rana, primary, McLaren, Alistair, additional, White, Mark, additional, Mills, Megan L., additional, Falconer, John, additional, Cortes-Lavaud, Xabier, additional, Gilroy, Kathryn, additional, Lannagan, Tamsin RM, additional, Ridgway, Rachel A, additional, Nixon, Colin, additional, Naiker, Varushka, additional, Njunge, Renee, additional, Clarke, Cassie J, additional, Whyte, Declan, additional, Kirschner, Kristina, additional, Jackstadt, Rene, additional, Norman, Jim C, additional, Carlin, Leo M, additional, Campbell, Andrew D, additional, Sansom, Owen J., additional, and Steele, Colin W., additional

Published
2024
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15. Inhibition of ATR opposes glioblastoma invasion through disruption of cytoskeletal networks and integrin internalization via macropinocytosis

Author

Derby, Sarah J, primary, Dutton, Louise, additional, Strathdee, Karen E, additional, Stevenson, Katrina, additional, Koessinger, Anna, additional, Jackson, Mark, additional, Tian, Yuling, additional, Yu, Wenxi, additional, Mclay, Kathy, additional, Misquitta, Josette, additional, Alsharif, Sama, additional, Clarke, Cassie J, additional, Gilmour, Lesley, additional, Thomason, Peter, additional, McGhee, Ewan, additional, McGarrity-Cottrell, Connor L, additional, Vanderlinden, Aurelie, additional, Collis, Spencer J, additional, Rominyi, Ola, additional, Lemgruber, Leandro, additional, Solecki, Gergely, additional, Olson, Michael, additional, Winkler, Frank, additional, Carlin, Leo M, additional, Heiland, Dieter Henrik, additional, Inman, Gareth J, additional, Chalmers, Anthony J, additional, Norman, Jim C, additional, Carruthers, Ross, additional, and Birch, Joanna L, additional

Published
2023
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16. An investigation into the role of the initiator methionine transfer RNA in cell migration and tumour growth

Author

Clarke, Cassie J.

Subjects
616.99, Q Science (General)
Abstract

Control of cellular tRNA repertoires can drive specific programmes of translation to favour the maintenance of proliferative or differentiated phenotypes. tRNAiMet is the initiator methionine tRNA, responsible for recognising the start codon and initiating translation. We have investigated how increased expression of tRNAiMet can influence cell behaviour, using both immortalised cell lines in vitro and mouse models in vivo. Levels of tRNAiMet are increased in carcinoma-associated fibroblasts compared to normal fibroblasts. To understand the cellular effects of tRNAiMet overexpression in more detail we generated immortalised mouse embryonic fibroblasts (iMEFs) that overexpressed tRNAiMet (iMEF.tRNAiMet) or an empty vector as control (iMEF.Vector). Full characterisation of iMEF.Vector and iMEF.tRNAiMet cell lines showed that overexpression of tRNAiMet did not affect cell size, energy metabolism, cell spreading, rate of cellular protein synthesis or proliferation. Increased expression of tRNAiMet did, however, have marked effects on cell migration; with iMEF.tRNAiMet cells migrating approximately 1.5 fold faster than iMEF.Vector controls when assessing both directional and random migration. This tRNAiMet-driven increase in cell speed was dependent on the levels of phosphorylated eIF2α, indicating that fibroblast migration might be influenced by tRNAiMet in the ternary complex. Furthermore, the ability of tRNAiMet to increase cell migration depended on the ability of integrin α5β1 to bind its extracellular ligand fibronectin. However, despite the robust and reproducible role of both phospho-eIF2α and integrin α5β1 in this process, the way in which these are mechanistically linked to tRNAiMet levels is yet to be determined. To investigate whether increased stromal tRNAiMet expression may contribute to tumour progression, we utilised a mouse that expressed additional copies of the tRNAiMet gene (2+tRNAiMet mouse), and performed syngeneic allografts into these animals. Subcutaneous allograft tumours of a number of different cancer cell lines became more vascularised and grew significantly more rapidly in 2+tRNAiMet mice by comparison with tumours grown in littermate control animals. The extracellular matrix (ECM) that was deposited by fibroblasts from 2+tRNAiMet mice was found to support enhanced endothelial cell and fibroblast migration. We used SILAC mass spectrometry to compare the secretome of iMEF.Vector and iMEF.tRNAiMet cell lines and found that overexpression of tRNAiMet significantly increased synthesis and secretion of certain types of collagen, in particular collagen II. Moreover, knockdown of collagen II using siRNA and CRISPR approaches opposed the ability of tRNAiMet overexpressing fibroblasts to deposit a pro-migratory ECM. We used the prolyl hydroxylase inhibitor, ethyl-3,4-dihydroxybenzoate (DHB), to determine whether collagen synthesis contributed to the ability of tRNAiMet to drive a pro-tumorigenic stroma in vivo. Administration of DHB had no effect on the growth of syngeneic allografts in wild-type mice, but opposed the ability of 2+tRNAiMet animals to support increased angiogenesis and tumour growth. Collectively these data indicate that increased expression of tRNAiMet contributes to tumour progression by enhancing the ability of stromal fibroblasts to synthesise and secrete a collagen II-rich ECM that supports endothelial cell migration and angiogenesis. Taken together these data provide evidence that the tRNAome, and in particular cellular levels of tRNAiMet, influence both the migration of fibroblasts and the composition of their secretome in a way that promotes the generation of a microenvironment supportive of endothelial cell migration, angiogenesis and tumour growth.

Published
2015

18. Inhibition of ATR opposes glioblastoma invasion through disruption of cytoskeletal networks and integrin internalization via macropinocytosis.

Author

Derby, Sarah J, Dutton, Louise, Strathdee, Karen E, Stevenson, Katrina, Koessinger, Anna, Jackson, Mark, Tian, Yuling, Yu, Wenxi, Mclay, Kathy, Misquitta, Josette, Alsharif, Sama, Clarke, Cassie J, Gilmour, Lesley, Thomason, Peter, McGhee, Ewan, McGarrity-Cottrell, Connor L, Vanderlinden, Aurelie, Collis, Spencer J, Rominyi, Ola, and Lemgruber, Leandro

Published
2024
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20. Correction: CD93 is expressed on chronic myeloid leukemia stem cells and identifies a quiescent population which persists after tyrosine kinase inhibitor therapy

Author

Kinstrie, Ross, Horne, Gillian A., Morrison, Heather, Irvine, David, Munje, Chinmay, Castañeda, Eduardo Gómez, Moka, Hothri A., Dunn, Karen, Cassels, Jennifer E., Parry, Narissa, Clarke, Cassie J., Scott, Mary T., Clark, Richard E., Holyoake, Tessa L., Wheadon, Helen, and Copland, Mhairi

Published
2020
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21. Preclinical approaches in chronic myeloid leukemia: from cells to systems

Author

Clarke, Cassie J. and Holyoake, Tessa L.

Subjects
Cancer Research, Cell Transplantation, Drug Evaluation, Preclinical, Cell Biology, Hematology, Review, In Vitro Techniques, Xenograft Model Antitumor Assays, Animals, Genetically Modified, Disease Models, Animal, Transduction, Genetic, hemic and lymphatic diseases, Leukemia, Myelogenous, Chronic, BCR-ABL Positive, Genetics, Tumor Cells, Cultured, Animals, Humans, Transgenes, Molecular Biology, Cell Line, Transformed
Abstract

Advances in the design of targeted therapies for the treatment of chronic myeloid leukemia (CML) have transformed the prognosis for patients diagnosed with this disease. However, leukemic stem cell persistence, drug intolerance, drug resistance, and advanced-phase disease represent unmet clinical needs demanding the attention of CML investigators worldwide. The availability of appropriate preclinical models is essential to efficiently translate findings from the bench to the clinic. Here we review the current approaches taken to preclinical work in the CML field, including examples of commonly used in vivo models and recent successes from systems biology-based methodologies., Highlights • CML is a hematopoietic stem cell disorder caused by a chromosomal translocation. • TKIs have transformed CML treatment but do not eradicate LSC which maintain disease. • The current preclinical approaches applied in CML research are reviewed. • Successfully combining approaches to deliver preclinical packages is discussed.

Published
2017

22. The initiator methionine tRNA drives cell migration and invasion leading to increased metastatic potential in melanoma

Author

Birch, Joanna, primary, Clarke, Cassie J., additional, Campbell, Andrew D., additional, Campbell, Kirsteen, additional, Mitchell, Louise, additional, Liko, Dritan, additional, Kalna, Gabriela, additional, Strathdee, Douglas, additional, Sansom, Owen J., additional, Neilson, Matthew, additional, Blyth, Karen, additional, and Norman, Jim C., additional

Published
2016
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23. The Initiator Methionine tRNA Drives Secretion of Type II Collagen from Stromal Fibroblasts to Promote Tumor Growth and Angiogenesis

Author

Clarke, Cassie J., primary, Berg, Tracy J., additional, Birch, Joanna, additional, Ennis, Darren, additional, Mitchell, Louise, additional, Cloix, Catherine, additional, Campbell, Andrew, additional, Sumpton, David, additional, Nixon, Colin, additional, Campbell, Kirsteen, additional, Bridgeman, Victoria L., additional, Vermeulen, Peter B., additional, Foo, Shane, additional, Kostaras, Eleftherios, additional, Jones, J. Louise, additional, Haywood, Linda, additional, Pulleine, Ellie, additional, Yin, Huabing, additional, Strathdee, Douglas, additional, Sansom, Owen, additional, Blyth, Karen, additional, McNeish, Iain, additional, Zanivan, Sara, additional, Reynolds, Andrew R., additional, and Norman, Jim C., additional

Published
2016
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24. An investigation into the role of the initiator methionine transfer RNA in cell migration and tumour growth

Author

Clarke, Cassie J. and Clarke, Cassie J.

Abstract

Control of cellular tRNA repertoires can drive specific programmes of translation to favour the maintenance of proliferative or differentiated phenotypes. tRNAiMet is the initiator methionine tRNA, responsible for recognising the start codon and initiating translation. We have investigated how increased expression of tRNAiMet can influence cell behaviour, using both immortalised cell lines in vitro and mouse models in vivo. Levels of tRNAiMet are increased in carcinoma-associated fibroblasts compared to normal fibroblasts. To understand the cellular effects of tRNAiMet overexpression in more detail we generated immortalised mouse embryonic fibroblasts (iMEFs) that overexpressed tRNAiMet (iMEF.tRNAiMet) or an empty vector as control (iMEF.Vector). Full characterisation of iMEF.Vector and iMEF.tRNAiMet cell lines showed that overexpression of tRNAiMet did not affect cell size, energy metabolism, cell spreading, rate of cellular protein synthesis or proliferation. Increased expression of tRNAiMet did, however, have marked effects on cell migration; with iMEF.tRNAiMet cells migrating approximately 1.5 fold faster than iMEF.Vector controls when assessing both directional and random migration. This tRNAiMet-driven increase in cell speed was dependent on the levels of phosphorylated eIF2α, indicating that fibroblast migration might be influenced by tRNAiMet in the ternary complex. Furthermore, the ability of tRNAiMet to increase cell migration depended on the ability of integrin α5β1 to bind its extracellular ligand fibronectin. However, despite the robust and reproducible role of both phospho-eIF2α and integrin α5β1 in this process, the way in which these are mechanistically linked to tRNAiMet levels is yet to be determined. To investigate whether increased stromal tRNAiMet expression may contribute to tumour progression, we utilised a mouse that expressed additional copies of the tRNAiMet gene (2+tRNAiMet mouse), and performed syngeneic allografts into these animals. Sub

25. An investigation into the role of the initiator methionine transfer RNA in cell migration and tumour growth

Author

Clarke, Cassie J. and Clarke, Cassie J.

Abstract

Control of cellular tRNA repertoires can drive specific programmes of translation to favour the maintenance of proliferative or differentiated phenotypes. tRNAiMet is the initiator methionine tRNA, responsible for recognising the start codon and initiating translation. We have investigated how increased expression of tRNAiMet can influence cell behaviour, using both immortalised cell lines in vitro and mouse models in vivo. Levels of tRNAiMet are increased in carcinoma-associated fibroblasts compared to normal fibroblasts. To understand the cellular effects of tRNAiMet overexpression in more detail we generated immortalised mouse embryonic fibroblasts (iMEFs) that overexpressed tRNAiMet (iMEF.tRNAiMet) or an empty vector as control (iMEF.Vector). Full characterisation of iMEF.Vector and iMEF.tRNAiMet cell lines showed that overexpression of tRNAiMet did not affect cell size, energy metabolism, cell spreading, rate of cellular protein synthesis or proliferation. Increased expression of tRNAiMet did, however, have marked effects on cell migration; with iMEF.tRNAiMet cells migrating approximately 1.5 fold faster than iMEF.Vector controls when assessing both directional and random migration. This tRNAiMet-driven increase in cell speed was dependent on the levels of phosphorylated eIF2α, indicating that fibroblast migration might be influenced by tRNAiMet in the ternary complex. Furthermore, the ability of tRNAiMet to increase cell migration depended on the ability of integrin α5β1 to bind its extracellular ligand fibronectin. However, despite the robust and reproducible role of both phospho-eIF2α and integrin α5β1 in this process, the way in which these are mechanistically linked to tRNAiMet levels is yet to be determined. To investigate whether increased stromal tRNAiMet expression may contribute to tumour progression, we utilised a mouse that expressed additional copies of the tRNAiMet gene (2+tRNAiMet mouse), and performed syngeneic allografts into these animals. Sub

26. Characterizing Neutrophil Subtypes in Cancer Using scRNA Sequencing Demonstrates the Importance of IL1β/CXCR2 Axis in Generation of Metastasis-specific Neutrophils.

Author

Fetit R, McLaren AS, White M, Mills ML, Falconer J, Cortes-Lavaud X, Gilroy K, Lannagan TRM, Ridgway RA, Nixon C, Naiker V, Njunge R, Clarke CJ, Whyte D, Kirschner K, Jackstadt R, Norman J, Carlin LM, Campbell AD, Sansom OJ, and Steele CW

Subjects
Animals, Mice, Humans, Neoplasm Recurrence, Local metabolism, Signal Transduction genetics, Single-Cell Analysis, Neutrophils, Colorectal Neoplasms genetics
Abstract

Neutrophils are a highly heterogeneous cellular population. However, a thorough examination of the different transcriptional neutrophil states between health and malignancy has not been performed. We utilized single-cell RNA sequencing of human and murine datasets, both publicly available and independently generated, to identify neutrophil transcriptomic subtypes and developmental lineages in health and malignancy. Datasets of lung, breast, and colorectal cancer were integrated to establish and validate neutrophil gene signatures. Pseudotime analysis was used to identify genes driving neutrophil development from health to cancer. Finally, ligand-receptor interactions and signaling pathways between neutrophils and other immune cell populations in primary colorectal cancer and metastatic colorectal cancer were investigated. We define two main neutrophil subtypes in primary tumors: an activated subtype sharing the transcriptomic signatures of healthy neutrophils; and a tumor-specific subtype. This signature is conserved in murine and human cancer, across different tumor types. In colorectal cancer metastases, neutrophils are more heterogeneous, exhibiting additional transcriptomic subtypes. Pseudotime analysis implicates IL1β/CXCL8/CXCR2 axis in the progression of neutrophils from health to cancer and metastasis, with effects on T-cell effector function. Functional analysis of neutrophil-tumoroid cocultures and T-cell proliferation assays using orthotopic metastatic mouse models lacking Cxcr2 in neutrophils support our transcriptional analysis. We propose that the emergence of metastatic-specific neutrophil subtypes is driven by the IL1β/CXCL8/CXCR2 axis, with the evolution of different transcriptomic signals that impair T-cell function at the metastatic site. Thus, a better understanding of neutrophil transcriptomic programming could optimize immunotherapeutic interventions into early and late interventions, targeting different neutrophil states., Significance: We identify two recurring neutrophil populations and demonstrate their staged evolution from health to malignancy through the IL1β/CXCL8/CXCR2 axis, allowing for immunotherapeutic neutrophil-targeting approaches to counteract immunosuppressive subtypes that emerge in metastasis., (© 2024 The Authors; Published by the American Association for Cancer Research.)

Published
2024
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