Burt, Richard J. and Dey, Aditi and Akarca, Ayse and Allen, Hermione and Amerikanou, Rodothea and Atkinson, Samantha and Auty, David and Chatzigerou, Jenny and Cutler, Emily and Guerra-Assuncao, Jose Afonso and Kirschner, Kristina and Kumari, Ruchi and Manji, Jiten and Marafioti, Teresa and Ward, Juma and Fielding, Adele K. (2024) Mitochondrial dsRNA from B-ALL cells stimulates mesenchymal stromal cells to become cancer-associated fibroblasts. Blood Advances, 8 (21). pp. 5696-5709. ISSN 2473-9529
AI Summary:
Cancer-associated fibroblasts (CAFs) arising from bone marrow-derived mesenchymal stromal cells (MSCs) are prominent in B-cell precursor acute lymphoblastic leukemia (B-ALL).AI Topics:
Cancer-associated fibroblasts (CAFs) arising from bone marrow–derived mesenchymal stromal cells (MSCs) are prominent in B-cell precursor acute lymphoblastic leukemia (B-ALL). We have previously shown that CAF formation is triggered by exposure to reactive oxygen species–inducing chemotherapy and that CAFs support chemoresistance by donating mitochondria to the cancer cells through tunneling nanotubes. In the present study, we show that exposure of MSCs to ALL cell lines, patient-derived xenografts, and primary cells or their conditioned media can also trigger CAF formation. Using bulk RNA sequencing in cell lines, we show that the MSC to CAF transition is accompanied by a robust interferon pathway response, and we have validated this finding in primary cells. Using confocal microscopy and flow cytometry, we identify the uptake of leukemia cell–derived mitochondrial double-stranded RNA (dsRNA) by MSCs as a proximate trigger for the MSC to CAF transition. We demonstrate that inhibiting dsRNA formation in ALL cells by treatment with low-dose ethidium bromide or the mitochondrial transcription inhibitor IMT1, or degrading dsRNA in conditioned media by 100°C exposure eliminates the ability of the ALL conditioned media to stimulate MSC to CAF transition. Our data reveal, to our knowledge, a novel and previously undescribed mechanism by which cancer cells induce a CAF phenotype in stromal cells, showing how B-ALL cells can directly induce the previously described niche-mediated protection within the bone marrow.
Burt, Richard J.
Author
Burt, Richard J. and Dey, Aditi and Akarca, Ayse and Allen, Hermione and Amerikanou, Rodothea and Atkinson, Samantha and Auty, David and Chatzigerou, Jenny and Cutler, Emily and Guerra-Assuncao, Jose Afonso and Kirschner, Kristina and Kumari, Ruchi and Manji, Jiten and Marafioti, Teresa and Ward, Juma and Fielding, Adele K. (2024) Mitochondrial dsRNA from B-ALL cells stimulates mesenchymal stromal cells to become cancer-associated fibroblasts. Blood Advances, 8 (21). pp. 5696-5709. ISSN 2473-9529
See full publications listDey, Aditi
Author
Burt, Richard J. and Dey, Aditi and Akarca, Ayse and Allen, Hermione and Amerikanou, Rodothea and Atkinson, Samantha and Auty, David and Chatzigerou, Jenny and Cutler, Emily and Guerra-Assuncao, Jose Afonso and Kirschner, Kristina and Kumari, Ruchi and Manji, Jiten and Marafioti, Teresa and Ward, Juma and Fielding, Adele K. (2024) Mitochondrial dsRNA from B-ALL cells stimulates mesenchymal stromal cells to become cancer-associated fibroblasts. Blood Advances, 8 (21). pp. 5696-5709. ISSN 2473-9529
See full publications listAkarca, Ayse
Author
Burt, Richard J. and Dey, Aditi and Akarca, Ayse and Allen, Hermione and Amerikanou, Rodothea and Atkinson, Samantha and Auty, David and Chatzigerou, Jenny and Cutler, Emily and Guerra-Assuncao, Jose Afonso and Kirschner, Kristina and Kumari, Ruchi and Manji, Jiten and Marafioti, Teresa and Ward, Juma and Fielding, Adele K. (2024) Mitochondrial dsRNA from B-ALL cells stimulates mesenchymal stromal cells to become cancer-associated fibroblasts. Blood Advances, 8 (21). pp. 5696-5709. ISSN 2473-9529
See full publications listAllen, Hermione
Author
Burt, Richard J. and Dey, Aditi and Akarca, Ayse and Allen, Hermione and Amerikanou, Rodothea and Atkinson, Samantha and Auty, David and Chatzigerou, Jenny and Cutler, Emily and Guerra-Assuncao, Jose Afonso and Kirschner, Kristina and Kumari, Ruchi and Manji, Jiten and Marafioti, Teresa and Ward, Juma and Fielding, Adele K. (2024) Mitochondrial dsRNA from B-ALL cells stimulates mesenchymal stromal cells to become cancer-associated fibroblasts. Blood Advances, 8 (21). pp. 5696-5709. ISSN 2473-9529
See full publications listAmerikanou, Rodothea
Author
Burt, Richard J. and Dey, Aditi and Akarca, Ayse and Allen, Hermione and Amerikanou, Rodothea and Atkinson, Samantha and Auty, David and Chatzigerou, Jenny and Cutler, Emily and Guerra-Assuncao, Jose Afonso and Kirschner, Kristina and Kumari, Ruchi and Manji, Jiten and Marafioti, Teresa and Ward, Juma and Fielding, Adele K. (2024) Mitochondrial dsRNA from B-ALL cells stimulates mesenchymal stromal cells to become cancer-associated fibroblasts. Blood Advances, 8 (21). pp. 5696-5709. ISSN 2473-9529
See full publications listAtkinson, Samantha
Author
Burt, Richard J. and Dey, Aditi and Akarca, Ayse and Allen, Hermione and Amerikanou, Rodothea and Atkinson, Samantha and Auty, David and Chatzigerou, Jenny and Cutler, Emily and Guerra-Assuncao, Jose Afonso and Kirschner, Kristina and Kumari, Ruchi and Manji, Jiten and Marafioti, Teresa and Ward, Juma and Fielding, Adele K. (2024) Mitochondrial dsRNA from B-ALL cells stimulates mesenchymal stromal cells to become cancer-associated fibroblasts. Blood Advances, 8 (21). pp. 5696-5709. ISSN 2473-9529
See full publications listAuty, David
Author
Burt, Richard J. and Dey, Aditi and Akarca, Ayse and Allen, Hermione and Amerikanou, Rodothea and Atkinson, Samantha and Auty, David and Chatzigerou, Jenny and Cutler, Emily and Guerra-Assuncao, Jose Afonso and Kirschner, Kristina and Kumari, Ruchi and Manji, Jiten and Marafioti, Teresa and Ward, Juma and Fielding, Adele K. (2024) Mitochondrial dsRNA from B-ALL cells stimulates mesenchymal stromal cells to become cancer-associated fibroblasts. Blood Advances, 8 (21). pp. 5696-5709. ISSN 2473-9529
See full publications listChatzigerou, Jenny
Author
Burt, Richard J. and Dey, Aditi and Akarca, Ayse and Allen, Hermione and Amerikanou, Rodothea and Atkinson, Samantha and Auty, David and Chatzigerou, Jenny and Cutler, Emily and Guerra-Assuncao, Jose Afonso and Kirschner, Kristina and Kumari, Ruchi and Manji, Jiten and Marafioti, Teresa and Ward, Juma and Fielding, Adele K. (2024) Mitochondrial dsRNA from B-ALL cells stimulates mesenchymal stromal cells to become cancer-associated fibroblasts. Blood Advances, 8 (21). pp. 5696-5709. ISSN 2473-9529
See full publications listCutler, Emily
Author
Burt, Richard J. and Dey, Aditi and Akarca, Ayse and Allen, Hermione and Amerikanou, Rodothea and Atkinson, Samantha and Auty, David and Chatzigerou, Jenny and Cutler, Emily and Guerra-Assuncao, Jose Afonso and Kirschner, Kristina and Kumari, Ruchi and Manji, Jiten and Marafioti, Teresa and Ward, Juma and Fielding, Adele K. (2024) Mitochondrial dsRNA from B-ALL cells stimulates mesenchymal stromal cells to become cancer-associated fibroblasts. Blood Advances, 8 (21). pp. 5696-5709. ISSN 2473-9529
See full publications listGuerra-Assuncao, Jose Afonso
Author
Burt, Richard J. and Dey, Aditi and Akarca, Ayse and Allen, Hermione and Amerikanou, Rodothea and Atkinson, Samantha and Auty, David and Chatzigerou, Jenny and Cutler, Emily and Guerra-Assuncao, Jose Afonso and Kirschner, Kristina and Kumari, Ruchi and Manji, Jiten and Marafioti, Teresa and Ward, Juma and Fielding, Adele K. (2024) Mitochondrial dsRNA from B-ALL cells stimulates mesenchymal stromal cells to become cancer-associated fibroblasts. Blood Advances, 8 (21). pp. 5696-5709. ISSN 2473-9529
See full publications listKirschner, Kristina
Author
Burt, Richard J. and Dey, Aditi and Akarca, Ayse and Allen, Hermione and Amerikanou, Rodothea and Atkinson, Samantha and Auty, David and Chatzigerou, Jenny and Cutler, Emily and Guerra-Assuncao, Jose Afonso and Kirschner, Kristina and Kumari, Ruchi and Manji, Jiten and Marafioti, Teresa and Ward, Juma and Fielding, Adele K. (2024) Mitochondrial dsRNA from B-ALL cells stimulates mesenchymal stromal cells to become cancer-associated fibroblasts. Blood Advances, 8 (21). pp. 5696-5709. ISSN 2473-9529
Dawson, Amy and Zarou, Martha M. and Prasad, Bodhayan and Bittencourt-Silvestre, Joana and Zerbst, Désirée and Himonas, Ekaterini and Hsieh, Ya-Ching and van Loon, Isabel and Rodriguez Blanco, Giovanny and Ianniciello, Angela and Kerekes, Zsombor and Krishnan, Vaidehi and Agarwal, Puneet and Almasoudi, Hassan and McCluskey, Laura and Hopcroft, Lisa E.M. and Scott, Mary T. and Baquero, Pablo and Dunn, Karen and Vetrie, David and Copland, Mhairi and Bhatia, Ravi and Coffelt, Seth B. and Tiong, Ong Sin and Wheadon, Helen and Zanivan, Sara and Kirschner, Kristina and Helgason, G. Vignir (2024) Leukaemia exposure alters the transcriptional profile and function of BCR::ABL1 negative macrophages in the bone marrow niche. Nature Communications, 15: 1090. ISSN 2041-1723
Fetit, Rana and McLaren, Alistair S. and White, Mark and Mills, Megan L. and Falconer, John and Cortes-Lavaud, Xabier and Gilroy, Kathryn and Lannagan, Tamsin R.M. and Ridgway, Rachel A. and Nixon, Colin and Naiker, Varushka and Njunge, Renee and Clarke, Cassie and Whyte, Declan and Kirschner, Kristina and Jackstadt, Rene and Norman, Jim and Carlin, Leo M. and Campbell, Andrew D. and Sansom, Owen J. and Steele, Colin W. (2024) Characterising neutrophil subtypes in cancer using scRNA sequencing demonstrates the importance of IL-1β/CXCR2 axis in generation of metastasis specific neutrophils. Cancer Research Communications, 4 (2). pp. 588-606. ISSN 2767-9764
See full publications listKumari, Ruchi
Author
Burt, Richard J. and Dey, Aditi and Akarca, Ayse and Allen, Hermione and Amerikanou, Rodothea and Atkinson, Samantha and Auty, David and Chatzigerou, Jenny and Cutler, Emily and Guerra-Assuncao, Jose Afonso and Kirschner, Kristina and Kumari, Ruchi and Manji, Jiten and Marafioti, Teresa and Ward, Juma and Fielding, Adele K. (2024) Mitochondrial dsRNA from B-ALL cells stimulates mesenchymal stromal cells to become cancer-associated fibroblasts. Blood Advances, 8 (21). pp. 5696-5709. ISSN 2473-9529
See full publications listManji, Jiten
Author
Burt, Richard J. and Dey, Aditi and Akarca, Ayse and Allen, Hermione and Amerikanou, Rodothea and Atkinson, Samantha and Auty, David and Chatzigerou, Jenny and Cutler, Emily and Guerra-Assuncao, Jose Afonso and Kirschner, Kristina and Kumari, Ruchi and Manji, Jiten and Marafioti, Teresa and Ward, Juma and Fielding, Adele K. (2024) Mitochondrial dsRNA from B-ALL cells stimulates mesenchymal stromal cells to become cancer-associated fibroblasts. Blood Advances, 8 (21). pp. 5696-5709. ISSN 2473-9529
See full publications listMarafioti, Teresa
Author
Burt, Richard J. and Dey, Aditi and Akarca, Ayse and Allen, Hermione and Amerikanou, Rodothea and Atkinson, Samantha and Auty, David and Chatzigerou, Jenny and Cutler, Emily and Guerra-Assuncao, Jose Afonso and Kirschner, Kristina and Kumari, Ruchi and Manji, Jiten and Marafioti, Teresa and Ward, Juma and Fielding, Adele K. (2024) Mitochondrial dsRNA from B-ALL cells stimulates mesenchymal stromal cells to become cancer-associated fibroblasts. Blood Advances, 8 (21). pp. 5696-5709. ISSN 2473-9529
Frankell, Alexander M. and Dietzen, Michelle and Al Bakir, Maise and Lim, Emilia L. and Karasaki, Takahiro and Ward, Sophia and Veeriah, Selvaraju and Colliver, Emma and Huebner, Ariana and Bunkum, Abigail and Hill, Mark S. and Grigoriadis, Kristiana and Moore, David A. and Black, James R. M. and Liu, Wing Kin and Thol, Kerstin and Pich, Oriol and Watkins, Thomas B. K. and Naceur-Lombardelli, Cristina and Cook, Daniel E. and Salgado, Roberto and Wilson, Gareth A. and Bailey, Chris and Angelova, Mihaela and Bentham, Robert and Martínez-Ruiz, Carlos and Abbosh, Christopher and Nicholson, Andrew G. and Le Quesne, John and Biswas, Dhruva and Rosenthal, Rachel and Puttick, Clare and Hessey, Sonya and Lee, Claudia and Prymas, Paulina and Toncheva, Antonia and Smith, Jon and Xing, Wei and Nicod, Jerome and Price, Gillian and Kerr, Keith M. and Naidu, Babu and Middleton, Gary and Blyth, Kevin G. and Fennell, Dean A. and Forster, Martin D. and Lee, Siow Ming and Falzon, Mary and Hewish, Madeleine and Shackcloth, Michael J. and Lim, Eric and Benafif, Sarah and Russell, Peter and Boleti, Ekaterini and Krebs, Matthew G. and Lester, Jason F. and Papadatos-Pastos, Dionysis and Ahmad, Tanya and Thakrar, Ricky M. and Lawrence, David and Navani, Neal and Janes, Sam M. and Dive, Caroline and Blackhall, Fiona H. and Summers, Yvonne and Cave, Judith and Marafioti, Teresa and Herrero, Javier and Quezada, Sergio A. and Peggs, Karl S. and Schwarz, Roland F. and Van Loo, Peter and Miedema, Daniël M. and Birkbak, Nicolai J. and Hiley, Crispin T. and Hackshaw, Allan and Zaccaria, Simone and TRACERx Consortium and Jamal-Hanjani, Mariam and McGranahan, Nicholas and Swanton, Charles (2024) Author Correction: The evolution of lung cancer and impact of subclonal selection in TRACERx. Nature, 631 (8022): E15. ISSN 1476-4687
See full publications listWard, Juma
Author
Burt, Richard J. and Dey, Aditi and Akarca, Ayse and Allen, Hermione and Amerikanou, Rodothea and Atkinson, Samantha and Auty, David and Chatzigerou, Jenny and Cutler, Emily and Guerra-Assuncao, Jose Afonso and Kirschner, Kristina and Kumari, Ruchi and Manji, Jiten and Marafioti, Teresa and Ward, Juma and Fielding, Adele K. (2024) Mitochondrial dsRNA from B-ALL cells stimulates mesenchymal stromal cells to become cancer-associated fibroblasts. Blood Advances, 8 (21). pp. 5696-5709. ISSN 2473-9529
See full publications listFielding, Adele K.
Author
Burt, Richard J. and Dey, Aditi and Akarca, Ayse and Allen, Hermione and Amerikanou, Rodothea and Atkinson, Samantha and Auty, David and Chatzigerou, Jenny and Cutler, Emily and Guerra-Assuncao, Jose Afonso and Kirschner, Kristina and Kumari, Ruchi and Manji, Jiten and Marafioti, Teresa and Ward, Juma and Fielding, Adele K. (2024) Mitochondrial dsRNA from B-ALL cells stimulates mesenchymal stromal cells to become cancer-associated fibroblasts. Blood Advances, 8 (21). pp. 5696-5709. ISSN 2473-9529
See full publications listAvailable under License Creative Commons Attribution Non-commercial No Derivatives.
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