2. Academic Validation
  3. Dynamic altruistic cooperation within breast tumors

Dynamic altruistic cooperation within breast tumors

  • Mol Cancer. 2023 Dec 14;22(1):206. doi: 10.1186/s12943-023-01896-7.
Muhammad Sufyan Bin Masroni # 1,  Kee Wah Lee # 1 2,  Victor Kwan Min Lee 1 3,  Siok Bian Ng 1 3,  Chao Teng Law 1,  Kok Siong Poon 1,  Bernett Teck-Kwong Lee 4,  Zhehao Liu 1 2,  Yuen Peng Tan 1,  Wee Ling Chng 1,  Steven Tucker 5,  Lynette Su-Mien Ngo 6 7,  George Wai Cheong Yip 2 3,  Min En Nga 8,  Susan Swee Shan Hue 8 9,  Thomas Choudary Putti 1,  Boon Huat Bay 2,  Qingsong Lin 10,  Lihan Zhou 11,  Mikael Hartman 12,  Tze Ping Loh 13,  Manikandan Lakshmanan 9,  Sook Yee Lee 9,  Vinay Tergaonkar 3 9,  Huiwen Chua 1,  Adeline Voon Hui Lee 1,  Eric Yew Meng Yeo 1,  Mo-Huang Li 14,  Chan Fong Chang 15,  Zizheng Kee 1,  Karen Mei-Ling Tan 16 17,  Soo Yong Tan 18 19 20 21,  Evelyn Siew-Chuan Koay 22 23,  Marco Archetti 24,  Sai Mun Leong 25 26
Affiliations

Affiliations

  • 1 Department of Pathology, Yong Loo Lin School of Medicine, National University of Singapore, Level 3 NUH Main Building, 21 Lower Kent Ridge Road, Singapore, 119077, Singapore.
  • 2 Department of Anatomy, Yong Loo Lin School of Medicine, National University of Singapore, MD10, 4 Medical Drive, Singapore, 117594, Singapore.
  • 3 NUS Centre for Cancer Research (N2CR), MD6, Centre for Translational Medicine, National University of Singapore, 14 Medical Drive, #12-01, Singapore, 117599, Singapore.
  • 4 Centre for Biomedical Informatics, Lee Kong Chian School of Medicine, Nanyang Technological University, Experimental Medicine Building, NTU Main Campus, 59 Nanyang Drive, Level 4, Singapore, 636921, Singapore.
  • 5 Tucker Medical Pte Ltd, Novena Specialist Centre, 8 Sinaran Drive #04-03, Singapore, 307470, Singapore.
  • 6 Raffles Cancer Centre, Raffles Hospital, 585 North Bridge Road, Singapore, 188770, Singapore.
  • 7 Current address: Curie Oncology Pte Ltd, Mount Elizabeth Novena Specialist Centre, 38 Irrawaddy Road, Level 8, #08-29/30, Singapore, 329563, Singapore.
  • 8 Department of Pathology, National University Hospital, Level 3 NUH Main Building, 21 Lower Kent Ridge Road, Singapore, 119077, Singapore.
  • 9 Institute of Molecular and Cell Biology, Agency for Science, Technology and Research (A*STAR), Proteos, 61 Biopolis Drive, Singapore, 138673, Singapore.
  • 10 Department of Biological Sciences, Faculty of Science, National University of Singapore, 14 Science Drive 4, Singapore, 117543, Singapore.
  • 11 MiRXES Pte Ltd, JTC MedTech Hub, 2 Tukang Innovation Grove #08-01, Singapore, 618305, Singapore.
  • 12 Department of Surgery, Yong Loo Lin School of Medicine, National University of Singapore, 1E Kent Ridge Road, NUHS Tower Block, Level 8, Singapore, 119228, Singapore.
  • 13 Department of Laboratory Medicine, National University Hospital, Level 3 NUH Main Building, 5 Lower Kent Ridge Road, Singapore, 119074, Singapore.
  • 14 CellSievo Pte Ltd, Block 289A, Bukit Batok Street 25, #15-218, Singapore, 650289, Singapore.
  • 15 Department of Biochemistry, Yong Loo Lin School of Medicine, National University of Singapore, 8 Medical Drive, Singapore, 117594, Singapore.
  • 16 Department of Laboratory Medicine, National University Hospital, Level 3 NUH Main Building, 5 Lower Kent Ridge Road, Singapore, 119074, Singapore. [email protected].
  • 17 Singapore Institute For Clinical Sciences, Brenner Centre for Molecular Medicine, 30 Medical Drive, Singapore, 117609, Singapore. [email protected].
  • 18 Department of Pathology, Yong Loo Lin School of Medicine, National University of Singapore, Level 3 NUH Main Building, 21 Lower Kent Ridge Road, Singapore, 119077, Singapore. [email protected].
  • 19 NUS Centre for Cancer Research (N2CR), MD6, Centre for Translational Medicine, National University of Singapore, 14 Medical Drive, #12-01, Singapore, 117599, Singapore. [email protected].
  • 20 Department of Pathology, National University Hospital, Level 3 NUH Main Building, 21 Lower Kent Ridge Road, Singapore, 119077, Singapore. [email protected].
  • 21 Institute of Molecular and Cell Biology, Agency for Science, Technology and Research (A*STAR), Proteos, 61 Biopolis Drive, Singapore, 138673, Singapore. [email protected].
  • 22 Department of Pathology, Yong Loo Lin School of Medicine, National University of Singapore, Level 3 NUH Main Building, 21 Lower Kent Ridge Road, Singapore, 119077, Singapore. [email protected].
  • 23 Department of Laboratory Medicine, National University Hospital, Level 3 NUH Main Building, 5 Lower Kent Ridge Road, Singapore, 119074, Singapore. [email protected].
  • 24 Department of Biology, Pennsylvania State University, W210 Millennium Science Complex, University Park, PA, 16802, USA. [email protected].
  • 25 Department of Pathology, Yong Loo Lin School of Medicine, National University of Singapore, Level 3 NUH Main Building, 21 Lower Kent Ridge Road, Singapore, 119077, Singapore. [email protected].
  • 26 NUS Centre for Cancer Research (N2CR), MD6, Centre for Translational Medicine, National University of Singapore, 14 Medical Drive, #12-01, Singapore, 117599, Singapore. [email protected].
  • # Contributed equally.
PMID: 38093346 DOI: 10.1186/s12943-023-01896-7
Abstract

Background: Social behaviors such as altruism, where one self-sacrifices for collective benefits, critically influence an organism's survival and responses to the environment. Such behaviors are widely exemplified in nature but have been underexplored in Cancer cells which are conventionally seen as selfish competitive players. This multidisciplinary study explores altruism and its mechanism in breast Cancer cells and its contribution to chemoresistance.

Methods: MicroRNA profiling was performed on circulating tumor cells collected from the blood of treated breast Cancer patients. Cancer cell lines ectopically expressing candidate miRNA were used in co-culture experiments and treated with docetaxel. Ecological parameters like relative survival and relative fitness were assessed using flow cytometry. Functional studies and characterization performed in vitro and in vivo include proliferation, iTRAQ-mass spectrometry, RNA sequencing, inhibition by small molecules and Antibodies, siRNA knockdown, CRISPR/dCas9 inhibition and fluorescence imaging of promoter reporter-expressing cells. Mathematical modeling based on evolutionary game theory was performed to simulate spatial organization of Cancer cells.

Results: Opposing Cancer processes underlie altruism: an oncogenic process involving secretion of IGFBP2 and CCL28 by the altruists to induce survival benefits in neighboring cells under taxane exposure, and a self-sacrificial tumor suppressive process impeding proliferation of altruists via cell cycle arrest. Both processes are regulated concurrently in the altruists by miR-125b, via differential NF-κB signaling specifically through IKKβ. Altruistic cells persist in the tumor despite their self-sacrifice, as they can regenerate epigenetically from non-altruists via a KLF2/PCAF-mediated mechanism. The altruists maintain a sparse spatial organization by inhibiting surrounding cells from adopting the altruistic fate via a lateral inhibition mechanism involving a GAB1-PI3K-AKT-miR-125b signaling circuit.

Conclusions: Our data reveal molecular mechanisms underlying manifestation, persistence and spatial spread of Cancer cell altruism. A minor population behave altruistically at a cost to itself producing a collective benefit for the tumor, suggesting tumors to be dynamic social systems governed by the same rules of cooperation in social organisms. Understanding Cancer cell altruism may lead to more holistic models of tumor evolution and drug response, as well as therapeutic paradigms that account for social interactions. Cancer cells constitute tractable experimental models for fields beyond oncology, like evolutionary ecology and game theory.

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