Cellular plasticity in the breast cancer ecosystem
Keywords:
Tumor microenvironment, tumor-initiating cells, cancer-associated fibroblasts, macrophages
Abstract
The complex interplay between genetically diverse tumor cells and their microenvironment significantly influences cancer progression and therapeutic responses. This review highlights recent findings on cellular plasticity and heterogeneity within the breast cancer ecosystem, focusing on the roles of cancer-associated fibroblasts (CAFs) and tumor-associated macrophages (TAMs). We discuss evidence suggesting that breast cancer cells exhibit phenotypic plasticity driven by both intrinsic genetic factors and external microenvironmental cues, impacting treatment responses and disease recurrence. Moreover, single-cell RNA sequencing studies reveal diverse subtypes of CAFs and TAMs, each with distinct functional gene expression programs and spatial organization within the tumor microenvironment. Understanding the hierarchical relationships and niche cues governing cellular phenotypes offers new opportunities for targeted therapeutic interventions. By elucidating the organizational principles of the tumor ecosystem, future therapies may target phenotypic states or entire cellular niches, advancing precision medicine approaches in breast cancer treatment.
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References
1. Hanahan D, Coussens LM. Accessories to the crime: functions of cells recruited to the tumor microenvironment. Cancer Cell. 2012;21:309–22. doi: 10.1016/j.ccr.2012.02.022
2. Pietras K, Ostman A. Hallmarks of cancer: interactions with the tumor stroma. Exp Cell Res. 2010;316:1324–31. doi: 10.1016/j.yexcr.2010.02.045
3. Bejarano L, Jordao MJC, Joyce JA. Therapeutic targeting of the tumor microenvironment. Cancer Discov. 2021;11:933–59. doi: 10.1158/2159-8290.CD-20-1808
4. Clara JA, Monge C, Yang Y, Takebe N. Targeting signalling pathways and the immune microenvironment of cancer stem cells – a clinical update. Nat Rev Clin Oncol. 2020;17:204–32. doi: 10.1038/s41571-019-0293-2
5. Walsh LA, Quail DF. Decoding the tumor microenvironment with spatial technologies. Nat Immunol. 2023;24:1982–93. doi: 10.1038/s41590-023-01678-9
6. Kanzaki R, Pietras K. Heterogeneity of cancer-associated fibroblasts: opportunities for precision medicine. Cancer Sci. 2020;111:2708–17. doi: 10.1111/cas.14537
7. Parker JS, Mullins M, Cheang MC, Leung S, Voduc D, Vickery T, et al. Supervised risk predictor of breast cancer based on intrinsic subtypes. J Clin Oncol. 2009;27:1160–7. doi: 10.1200/JCO.2008.18.1370
8. Cardoso F, Kyriakides S, Ohno S, Penault-Llorca F, Poortmans P, Rubio IT, et al. Early breast cancer: ESMO Clinical Practice Guidelines for diagnosis, treatment and follow-up. Ann Oncol. 2019;30:1674.
9. Colleoni M, Sun Z, Price KN, Karlsson P, Forbes JF, Thurlimann B, et al. Annual hazard rates of recurrence for breast cancer during 24 years of follow-up: results from the international breast cancer study group trials I to V. J Clin Oncol. 2016;34:927–35. doi: 10.1200/JCO.2015.62.3504
10. Lindstrom LS, Karlsson E, Wilking UM, Johansson U, Hartman J, Lidbrink EK, et al. Clinically used breast cancer markers such as estrogen receptor, progesterone receptor, and human epidermal growth factor receptor 2 are unstable throughout tumor progression. J Clin Oncol. 2012;30:2601–8. doi: 10.1200/JCO.2011.37.2482
11. Lim E, Vaillant F, Wu D, Forrest NC, Pal B, Hart AH, et al. Aberrant luminal progenitors as the candidate target population for basal tumor development in BRCA1 mutation carriers. Nat Med. 2009;15:907–13. doi: 10.1038/nm.2000
12. Molyneux G, Geyer FC, Magnay FA, McCarthy A, Kendrick H, Natrajan R, et al. BRCA1 basal-like breast cancers originate from luminal epithelial progenitors and not from basal stem cells. Cell Stem Cell. 2010;7:403–17.
13. Yamamoto S, Wu Z, Russnes HG, Takagi S, Peluffo G, Vaske C, et al. JARID1B is a luminal lineage-driving oncogene in breast cancer. Cancer Cell. 2014;25:762–77.
14. Su Y, Subedee A, Bloushtain-Qimron N, Savova V, Krzystanek M, Li L, et al. Somatic cell fusions reveal extensive heterogeneity in basal-like breast cancer. Cell Rep. 2015;11:1549–63. doi: 10.1016/j.celrep.2015.05.011
15. Vulin M, Jehanno C, Sethi A, Correia AL, Obradovic MMS, Couto JP, et al. A high-throughput drug screen reveals means to differentiate triple-negative breast cancer. Oncogene. 2022;41:4459–73. doi: 10.1038/s41388-022-02429-0
16. Zhang H, Diab A, Fan H, Mani SK, Hullinger R, Merle P, et al. PLK1 and HOTAIR accelerate proteasomal degradation of SUZ12 and ZNF198 during Hepatitis B virus-induced liver carcinogenesis. Cancer Res. 2015;75:2363–74. doi: 10.1158/0008-5472.CAN-14-2928
17. Roswall P, Bocci M, Bartoschek M, Li H, Kristiansen G, Jansson S, et al. Microenvironmental control of breast cancer subtype elicited through paracrine platelet-derived growth factor-CC signaling. Nat Med. 2018;24:463–73.
18. Reid SE, Pantaleo J, Bolivar P, Bocci M, Sjolund J, Morsing M, et al. Cancer-associated fibroblasts rewire the estrogen receptor response in luminal breast cancer, enabling estrogen independence. Oncogene. 2024. doi: 10.1038/s41388-024-02973-x
19. Brechbuhl HM, Finlay-Schultz J, Yamamoto TM, Gillen AE, Cittelly DM, Tan AC, et al. Fibroblast subtypes regulate responsiveness of luminal breast cancer to estrogen. Clin Cancer Res. 2017;23:1710–21.
20. Peyvandi S, Bulliard M, Yilmaz A, Kauzlaric A, Marcone R, Haerri L, et al. Tumor-educated Gr1+CD11b+ cells drive breast cancer metastasis via OSM/IL6-JAK-induced cancer cell plasticity. J Clin Invest. 2024;134:e166847
21. Ohlund D, Handly-Santana A, Biffi G, Elyada E, Almeida AS, Ponz-Sarvise M, et al. Distinct populations of inflammatory fibroblasts and myofibroblasts in pancreatic cancer. J Exp Med. 2017;214:579–96. doi: 10.1084/jem.20162024
22. Bartoschek M, Oskolkov N, Bocci M, Lovrot J, Larsson C, Sommarin M, et al. Spatially and functionally distinct subclasses of breast cancer-associated fibroblasts revealed by single cell RNA sequencing. Nat Commun. 2018;9:5150.
23. Friedman G, Levi-Galibov O, David E, Bornstein C, Giladi A, Dadiani M, et al. Cancer-associated fibroblast compositions change with breast cancer progression linking the ratio of S100A4(+) and PDPN(+) CAFs to clinical outcome. Nat Cancer. 2020;1:692–708. doi: 10.1038/s43018-020-0082-y
24. Costa A, Kieffer Y, Scholer-Dahirel A, Pelon F, Bourachot B, Cardon M, et al. Fibroblast heterogeneity and immunosuppressive environment in human breast cancer. Cancer Cell. 2018;33:463–79.e10.
25. Kieffer Y, Hocine HR, Gentric G, Pelon F, Bernard C, Bourachot B, et al. Single-cell analysis reveals fibroblast clusters linked to immunotherapy resistance in cancer. Cancer Discov. 2020;10:1330–51. doi: 10.1158/2159-8290.CD-19-1384
26. Wu SZ, Al-Eryani G, Roden DL, Junankar S, Harvey K, Andersson A, et al. A single-cell and spatially resolved atlas of human breast cancers. Nat Genet. 2021;53:1334–47.
27. Azizi E, Carr AJ, Plitas G, Cornish AE, Konopacki C, Prabhakaran S, et al. Single-cell map of diverse immune phenotypes in the breast tumor microenvironment. Cell. 2018;174:1293–308.e36. doi: 10.1016/j.cell.2018.05.060
28. Shackleton M, Quintana E, Fearon ER, Morrison SJ. Heterogeneity in cancer: cancer stem cells versus clonal evolution. Cell. 2009;138:822–9.
29. Batlle E, Clevers H. Cancer stem cells revisited. Nat Med. 2017;23:1124–34. doi: 10.1038/nm.4409
30. Schubert M, Klinger B, Klunemann M, Sieber A, Uhlitz F, Sauer S, et al. Perturbation-response genes reveal signaling footprints in cancer gene expression. Nat Commun. 2018;9:20. doi: 10.1038/s41467-017-02391-6
31. Iwamoto C, Ohuchida K, Shinkawa T, Okuda S, Otsubo Y, Okumura T, et al. Bone marrow-derived macrophages converted into cancer-associated fibroblast-like cells promote pancreatic cancer progression. Cancer Lett. 2021;512:15–27. doi: 10.1016/j.canlet.2021.04.013
32. Tang PC, Chung JY, Xue VW, Xiao J, Meng XM, Huang XR, et al. Smad3 Promotes Cancer-Associated Fibroblasts Generation via Macrophage-Myofibroblast Transition. Adv Sci (Weinh). 2022;9:e2101235. doi: 10.1002/advs.202101235
2. Pietras K, Ostman A. Hallmarks of cancer: interactions with the tumor stroma. Exp Cell Res. 2010;316:1324–31. doi: 10.1016/j.yexcr.2010.02.045
3. Bejarano L, Jordao MJC, Joyce JA. Therapeutic targeting of the tumor microenvironment. Cancer Discov. 2021;11:933–59. doi: 10.1158/2159-8290.CD-20-1808
4. Clara JA, Monge C, Yang Y, Takebe N. Targeting signalling pathways and the immune microenvironment of cancer stem cells – a clinical update. Nat Rev Clin Oncol. 2020;17:204–32. doi: 10.1038/s41571-019-0293-2
5. Walsh LA, Quail DF. Decoding the tumor microenvironment with spatial technologies. Nat Immunol. 2023;24:1982–93. doi: 10.1038/s41590-023-01678-9
6. Kanzaki R, Pietras K. Heterogeneity of cancer-associated fibroblasts: opportunities for precision medicine. Cancer Sci. 2020;111:2708–17. doi: 10.1111/cas.14537
7. Parker JS, Mullins M, Cheang MC, Leung S, Voduc D, Vickery T, et al. Supervised risk predictor of breast cancer based on intrinsic subtypes. J Clin Oncol. 2009;27:1160–7. doi: 10.1200/JCO.2008.18.1370
8. Cardoso F, Kyriakides S, Ohno S, Penault-Llorca F, Poortmans P, Rubio IT, et al. Early breast cancer: ESMO Clinical Practice Guidelines for diagnosis, treatment and follow-up. Ann Oncol. 2019;30:1674.
9. Colleoni M, Sun Z, Price KN, Karlsson P, Forbes JF, Thurlimann B, et al. Annual hazard rates of recurrence for breast cancer during 24 years of follow-up: results from the international breast cancer study group trials I to V. J Clin Oncol. 2016;34:927–35. doi: 10.1200/JCO.2015.62.3504
10. Lindstrom LS, Karlsson E, Wilking UM, Johansson U, Hartman J, Lidbrink EK, et al. Clinically used breast cancer markers such as estrogen receptor, progesterone receptor, and human epidermal growth factor receptor 2 are unstable throughout tumor progression. J Clin Oncol. 2012;30:2601–8. doi: 10.1200/JCO.2011.37.2482
11. Lim E, Vaillant F, Wu D, Forrest NC, Pal B, Hart AH, et al. Aberrant luminal progenitors as the candidate target population for basal tumor development in BRCA1 mutation carriers. Nat Med. 2009;15:907–13. doi: 10.1038/nm.2000
12. Molyneux G, Geyer FC, Magnay FA, McCarthy A, Kendrick H, Natrajan R, et al. BRCA1 basal-like breast cancers originate from luminal epithelial progenitors and not from basal stem cells. Cell Stem Cell. 2010;7:403–17.
13. Yamamoto S, Wu Z, Russnes HG, Takagi S, Peluffo G, Vaske C, et al. JARID1B is a luminal lineage-driving oncogene in breast cancer. Cancer Cell. 2014;25:762–77.
14. Su Y, Subedee A, Bloushtain-Qimron N, Savova V, Krzystanek M, Li L, et al. Somatic cell fusions reveal extensive heterogeneity in basal-like breast cancer. Cell Rep. 2015;11:1549–63. doi: 10.1016/j.celrep.2015.05.011
15. Vulin M, Jehanno C, Sethi A, Correia AL, Obradovic MMS, Couto JP, et al. A high-throughput drug screen reveals means to differentiate triple-negative breast cancer. Oncogene. 2022;41:4459–73. doi: 10.1038/s41388-022-02429-0
16. Zhang H, Diab A, Fan H, Mani SK, Hullinger R, Merle P, et al. PLK1 and HOTAIR accelerate proteasomal degradation of SUZ12 and ZNF198 during Hepatitis B virus-induced liver carcinogenesis. Cancer Res. 2015;75:2363–74. doi: 10.1158/0008-5472.CAN-14-2928
17. Roswall P, Bocci M, Bartoschek M, Li H, Kristiansen G, Jansson S, et al. Microenvironmental control of breast cancer subtype elicited through paracrine platelet-derived growth factor-CC signaling. Nat Med. 2018;24:463–73.
18. Reid SE, Pantaleo J, Bolivar P, Bocci M, Sjolund J, Morsing M, et al. Cancer-associated fibroblasts rewire the estrogen receptor response in luminal breast cancer, enabling estrogen independence. Oncogene. 2024. doi: 10.1038/s41388-024-02973-x
19. Brechbuhl HM, Finlay-Schultz J, Yamamoto TM, Gillen AE, Cittelly DM, Tan AC, et al. Fibroblast subtypes regulate responsiveness of luminal breast cancer to estrogen. Clin Cancer Res. 2017;23:1710–21.
20. Peyvandi S, Bulliard M, Yilmaz A, Kauzlaric A, Marcone R, Haerri L, et al. Tumor-educated Gr1+CD11b+ cells drive breast cancer metastasis via OSM/IL6-JAK-induced cancer cell plasticity. J Clin Invest. 2024;134:e166847
21. Ohlund D, Handly-Santana A, Biffi G, Elyada E, Almeida AS, Ponz-Sarvise M, et al. Distinct populations of inflammatory fibroblasts and myofibroblasts in pancreatic cancer. J Exp Med. 2017;214:579–96. doi: 10.1084/jem.20162024
22. Bartoschek M, Oskolkov N, Bocci M, Lovrot J, Larsson C, Sommarin M, et al. Spatially and functionally distinct subclasses of breast cancer-associated fibroblasts revealed by single cell RNA sequencing. Nat Commun. 2018;9:5150.
23. Friedman G, Levi-Galibov O, David E, Bornstein C, Giladi A, Dadiani M, et al. Cancer-associated fibroblast compositions change with breast cancer progression linking the ratio of S100A4(+) and PDPN(+) CAFs to clinical outcome. Nat Cancer. 2020;1:692–708. doi: 10.1038/s43018-020-0082-y
24. Costa A, Kieffer Y, Scholer-Dahirel A, Pelon F, Bourachot B, Cardon M, et al. Fibroblast heterogeneity and immunosuppressive environment in human breast cancer. Cancer Cell. 2018;33:463–79.e10.
25. Kieffer Y, Hocine HR, Gentric G, Pelon F, Bernard C, Bourachot B, et al. Single-cell analysis reveals fibroblast clusters linked to immunotherapy resistance in cancer. Cancer Discov. 2020;10:1330–51. doi: 10.1158/2159-8290.CD-19-1384
26. Wu SZ, Al-Eryani G, Roden DL, Junankar S, Harvey K, Andersson A, et al. A single-cell and spatially resolved atlas of human breast cancers. Nat Genet. 2021;53:1334–47.
27. Azizi E, Carr AJ, Plitas G, Cornish AE, Konopacki C, Prabhakaran S, et al. Single-cell map of diverse immune phenotypes in the breast tumor microenvironment. Cell. 2018;174:1293–308.e36. doi: 10.1016/j.cell.2018.05.060
28. Shackleton M, Quintana E, Fearon ER, Morrison SJ. Heterogeneity in cancer: cancer stem cells versus clonal evolution. Cell. 2009;138:822–9.
29. Batlle E, Clevers H. Cancer stem cells revisited. Nat Med. 2017;23:1124–34. doi: 10.1038/nm.4409
30. Schubert M, Klinger B, Klunemann M, Sieber A, Uhlitz F, Sauer S, et al. Perturbation-response genes reveal signaling footprints in cancer gene expression. Nat Commun. 2018;9:20. doi: 10.1038/s41467-017-02391-6
31. Iwamoto C, Ohuchida K, Shinkawa T, Okuda S, Otsubo Y, Okumura T, et al. Bone marrow-derived macrophages converted into cancer-associated fibroblast-like cells promote pancreatic cancer progression. Cancer Lett. 2021;512:15–27. doi: 10.1016/j.canlet.2021.04.013
32. Tang PC, Chung JY, Xue VW, Xiao J, Meng XM, Huang XR, et al. Smad3 Promotes Cancer-Associated Fibroblasts Generation via Macrophage-Myofibroblast Transition. Adv Sci (Weinh). 2022;9:e2101235. doi: 10.1002/advs.202101235
Published
2024-04-02
How to Cite
Pietras K., & Sjölund J. (2024). Cellular plasticity in the breast cancer ecosystem. Upsala Journal of Medical Sciences, 129(S1), e10629. https://doi.org/10.48101/ujms.v129.10629
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Section
Review Articles
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