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Yi Fan, M.D., Ph.D.
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Richard H. Chamberlain Professor in Research Oncology II
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Member, Abramson Cancer Center, University of Pennsylvania
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Member, Institute for Immunology, University of Pennsylvania
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Member, Cardiovascular Institute, University of Pennsylvania
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Department: Radiation Oncology
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Graduate Group Affiliations
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Contact information
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Smilow Center for Translational Research, Room 8-132
23 University of Pennsylvania
24 Perelman School of Medicine
49 3400 Civic Center Blvd., Bldg 421
Philadelphia, PA 19104-5156
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23 University of Pennsylvania
24 Perelman School of Medicine
49 3400 Civic Center Blvd., Bldg 421
Philadelphia, PA 19104-5156
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Office: 215-898-9291
32 Fax: 215-898-0090
32 Lab: 215-573-0039
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32 Fax: 215-898-0090
32 Lab: 215-573-0039
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Email:
yi.fan@uphs.upenn.edu
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yi.fan@uphs.upenn.edu
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Publications
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Education:
21 9 M.D. 15 (Medicine) c
4c Shanghai University of Traditional Chinese Medicine, 1999.
21 a Ph.D. 17 (Pathology ) c
4b Case Western Reserve University School of Medicine, 2009.
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Permanent link21 9 M.D. 15 (Medicine) c
4c Shanghai University of Traditional Chinese Medicine, 1999.
21 a Ph.D. 17 (Pathology ) c
4b Case Western Reserve University School of Medicine, 2009.
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1ec We work on cancer and regenerative medicine. As a prominent example of malignant solid tumors, glioblastoma (GBM) is among the most deadly human malignancies, largely due to its high resistance to standard therapies. The ultimate objective of our research is to develop efficient therapies against diseases by targeting the tissue microenvironment. We aim to reprogram the microenvironment to block cancer progression, activate anti-tumor immunity, and fuel post-injury tissue repair.
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1f Vascular transformation
44f Aberrant vascularization is a hallmark of cancer and cardiovascular diseases. However, current anti- and pro- vascular therapies that primarily target angiogenic factors, albeit initially groundbreaking, have encountered major difficulties and failures in treating most cancers and ischemic heart diseases, respectively. We propose that endothelial transformation alternatively drives vessel abnormalities and vascular microenvironment-mediated pathogenesis. Our work reveals that tumor-associated endothelial cells undergo mesenchymal transformation, driving aberrant vascularization and therapeutic resistance (Huang et al, JCI 2016). We uncover that endothelial transformation downregulates VEGFR2 expression, rendering tumor resistance to anti-VEGF treatment (Liu et al, Nature Comm 2018), and that endothelial transformation induces vascular niche-mediated chemoresistance (Huang et al, Science Transl Med 2020). Based on these studies, we propose a new therapeutic concept, namely, “vascular de-transformation” as a next-generation strategy against cancer (Fan, Trends in Cancer 2019).
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15 Immunotherapy
4df Immunotherapy holds great promise for cancer treatment. However, current immunotherapy of solid tumors remains a big challenge, largely due to the immunosuppressive microenvironment that inhibits T cell infiltration and activation. We are particularly interested in reversal of immune suppression by reprogramming the tumor microenvironment. Our work reveals that vascular niche-derived IL-6 induces alternative macrophage polarization and tumor immunosuppression in GBM (Wang et al, Nature Comm 2018; Yang et al, manuscript in revision). By using whole genome/kinome-wide functional screen approaches, we identified several drivers that modulate T cell infiltration across tumor vasculature, serving as potential targets to improve CAR T immunotherapy (Ma et al, manuscript in revision). The overall goal of our study in this area is to lay the groundwork for the development of microenvironment-targeted treatments, which are expected to activate pro-tumor immunity and to overcome cancer resistance to immune checkpoint blockade and CAR T immunotherapy in solid tumors. We are also interested in deciphering the role of immune microenvironment in tissue repair and are dedicated to develop new immunotherapy for promoting tissue repair.
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19 Cancer stem cells
3ca Cancer stem cells, also known as tumor-initiating cells or tumor-propagating cells, are highly tumorigenic and therapy resistant, which are able to repopulate a tumor after treatment. We are interested in cancer stem cell-mediated tumor resistance to chemotherapy and radiation, emphasizing the mechanisms that control DNA repair and telomere function. We identify that dynamic DNA-PK activation after radiation induces genomic instability in glioma stem cells, leading to therapy resistance (Wang et al, JCI Insight 2018). We reveal a Wnt-mediated mechanism that drives therapy resistance in circulating glioma cells (Liu et al, Cancer Res 2018). In addition, we show that proton radiation exhibits more therapeutic efficacy against glioma stem cells than photon radiation (Mitteer et al, Sci Rep 2015). The goal of our work here is to develop new therapies that specifically eradicate cancer stem cells to overcome therapy resistance and prevent cancer relapse.
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Description of Research Expertise
81 Research Interests: Brain tumor; Angiogenesis; Tissue repar; Immunotherapy; Cancer stem cells; Proton radiation.8
1ec We work on cancer and regenerative medicine. As a prominent example of malignant solid tumors, glioblastoma (GBM) is among the most deadly human malignancies, largely due to its high resistance to standard therapies. The ultimate objective of our research is to develop efficient therapies against diseases by targeting the tissue microenvironment. We aim to reprogram the microenvironment to block cancer progression, activate anti-tumor immunity, and fuel post-injury tissue repair.
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1f Vascular transformation
44f Aberrant vascularization is a hallmark of cancer and cardiovascular diseases. However, current anti- and pro- vascular therapies that primarily target angiogenic factors, albeit initially groundbreaking, have encountered major difficulties and failures in treating most cancers and ischemic heart diseases, respectively. We propose that endothelial transformation alternatively drives vessel abnormalities and vascular microenvironment-mediated pathogenesis. Our work reveals that tumor-associated endothelial cells undergo mesenchymal transformation, driving aberrant vascularization and therapeutic resistance (Huang et al, JCI 2016). We uncover that endothelial transformation downregulates VEGFR2 expression, rendering tumor resistance to anti-VEGF treatment (Liu et al, Nature Comm 2018), and that endothelial transformation induces vascular niche-mediated chemoresistance (Huang et al, Science Transl Med 2020). Based on these studies, we propose a new therapeutic concept, namely, “vascular de-transformation” as a next-generation strategy against cancer (Fan, Trends in Cancer 2019).
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15 Immunotherapy
4df Immunotherapy holds great promise for cancer treatment. However, current immunotherapy of solid tumors remains a big challenge, largely due to the immunosuppressive microenvironment that inhibits T cell infiltration and activation. We are particularly interested in reversal of immune suppression by reprogramming the tumor microenvironment. Our work reveals that vascular niche-derived IL-6 induces alternative macrophage polarization and tumor immunosuppression in GBM (Wang et al, Nature Comm 2018; Yang et al, manuscript in revision). By using whole genome/kinome-wide functional screen approaches, we identified several drivers that modulate T cell infiltration across tumor vasculature, serving as potential targets to improve CAR T immunotherapy (Ma et al, manuscript in revision). The overall goal of our study in this area is to lay the groundwork for the development of microenvironment-targeted treatments, which are expected to activate pro-tumor immunity and to overcome cancer resistance to immune checkpoint blockade and CAR T immunotherapy in solid tumors. We are also interested in deciphering the role of immune microenvironment in tissue repair and are dedicated to develop new immunotherapy for promoting tissue repair.
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19 Cancer stem cells
3ca Cancer stem cells, also known as tumor-initiating cells or tumor-propagating cells, are highly tumorigenic and therapy resistant, which are able to repopulate a tumor after treatment. We are interested in cancer stem cell-mediated tumor resistance to chemotherapy and radiation, emphasizing the mechanisms that control DNA repair and telomere function. We identify that dynamic DNA-PK activation after radiation induces genomic instability in glioma stem cells, leading to therapy resistance (Wang et al, JCI Insight 2018). We reveal a Wnt-mediated mechanism that drives therapy resistance in circulating glioma cells (Liu et al, Cancer Res 2018). In addition, we show that proton radiation exhibits more therapeutic efficacy against glioma stem cells than photon radiation (Mitteer et al, Sci Rep 2015). The goal of our work here is to develop new therapies that specifically eradicate cancer stem cells to overcome therapy resistance and prevent cancer relapse.
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e3 Lamplugh ZL, Wellhausen N, June CH, Fan Y.: Microenvironmental regulation of solid tumour resistance to CAR T cell therapy. Nature Review Immunology 2025.
f2 Cleveland AH, Fan Y.: Reprogramming endothelial cells to empower cancer immunotherapy. Trends in Molecular Medcine 30(2): 126-135. Feb 2024 Notes: Peer reviewed opinion.
10d Zhao X, Williamson T, Gong Y*, Epstein J*, Fan Y*.: Immunomodulatory therapy for ischemic heart disease. Circulation 150(13): 1050-1058, Sept 2024 Notes: *Co-senior author. peer-reviewed opinion.
19c Yang F, Akhtar N, Zhang D, El-Mayta R, Shin J, Dorsey JF, Zhang L, Xu X, Guo W, Bagley SJ, Fuchs SY, Koumenis C, Lathia JD, Mitchell MJ, Gong Y*, & Fan Y*.: An immunosuppressive vascular niche drives macrophage polarization and immunotherapy resistance in glioblastoma. Science Advances 10(9): eadj4678, Mar 2024 Notes: *Co-senior authors.
149 Zhang D, Cleveland AH, Krimitza E, Han K, Yi C, Stout AL, Zou W, Dorsey JF, Gong Y*, Fan Y*.: Spatial analysis of tissue immunity and vascularity by light sheet fluorescence microscopy. Nature Protocols 19(4): 1053-1082, Apr 2024 Notes: *Co-senior authors.
13b Yang F, Zhang D, Jiang H, Ye J, Zhang L, Winkler J, Gong Y, & Fan Y.: Small-molecule reversal of macrophage-mediated immunosuppression overcomes glioblastoma resistance to immunotherapy. Science Translational Medicine 15: eabq3558, Feb 2023.
174 Zhang D, Li A, Huang M, Yang F, Zhang L, Wellen KE, Xu X, Conn CS, Zou W, Kahn M, Rhoades SD, Weljie AM, Amankulor N, Yoshor D, Ye J, Koumenis C, Gong Y, & Fan Y. : PHGDH-mediated endothelial metabolism drives glioblastoma resistance to CAR T cell immunotherapy. Cell Metabolism 35: 1-18, Feb 2023.
18a Huang M, Yang F, Zhang D, Lin M, Duan H, EI-Mayta R, Zhang L, Qin L, Shewale S, Pei L, Mitchell M, Rader D, Fan Y*, Gong Y*.: : Endothelial plasticity drives aberrant vascularization and impedes cardiac repair after myocardial infarction. Nature Cardiovascular Research 1(4): 372–388, Apr 2022 Notes: *Co-senior author.
178 Ma W, Wang Y, Zhang R, Yang F, Zhang D, Huang M, Zhang L, Dorsey JF, Binder ZA, O’Rourke DM, Fraietta JA, Gong Y*, Fan Y*.: Targeting PAK4 to reprogram vascular microenvironment and improve CAR T immunotherapy for glioblastoma. Nature Cancer 2: 83–97, February 2021 Notes: *Co-corresponding authors.
189 Yang F, He Z, Duan H, Zhang D, Li J, Yang H, Dorsey JF, Zou W, Nabavizadeh SA, Bagley SJ, Abdullah K, Brem S, Zhang L, Xu X, Byrne KT, Vonderheide RH*, Gong Y*, & Fan Y*.: Synergistic immunotherapy of glioblastoma by dual targeting of IL-6 and CD40. Nature Comm. 12(1): 3424, June 2021 Notes: *Co-corresponding authors.
188 Huang M, Zhang D, Wu JY, Xing K, Yeo E, Li C, Zhang L, Holland E, Yao L, Qin L, Binder ZA, O’Rourke DM, Brem S, Koumenis C, Gong Y, and Fan Y. : Wnt-mediated endothelial transformation into mesenchymal stem cell-like cells induces chemoresistance in glioblastoma. Science Transl Medicine 12(532): eaay7522, Feb 2020.
aa Fan Y: Vascular Detransformation for Cancer Therapy. Trends in Cancer 5(8): 460-463, August 2019.
14c Wang Q, He Z, Huang M, Liu T, Xu H, Ma P, Zhang L, Zamvil SS, Hidalgo J, Zhang Z, O’Rourke DM, Dahmane N, Brem S, Gong Y, & Fan Y: Vascular niche IL-6 induces macrophage M2 polarization in gliomblastoma through HIF-2α. Nature Comm 9(1): 559, February 2018.
159 Liu T, Xu H, Huang M, Ma W, Saxena D, Lustig RA, Alonso-Basanta M, Zhang Z, O’Rourke DM, Zhang L, Gong Y, Kao GD, Dorsey JF*, & Fan Y*: Circulating glioma cells exhibit stem cell-like properties. Cancer Res 78(23): 6632-6642, December 2018 Notes: *corresponding authors.
149 Liu T, Ma W, Xu H, Huang M, Zhang D, He Z, Zhang L, Brem S, O'Rourke DM, Gong Y, Mou Y, Zhang Z, and Fan Y: PDGF-mediated mesenchymal transformation renders endothelial resistance to anti-VEGF treatment in glioblastoma. Nature Comm 9(1): 3439, August 2018.
13a Wang Y, Xu H, Liu T, Huang M, Butter P, Li C, Zhang L, Kao G, Gong Y, Maity A, Koumenis C, & Fan Y: Temporal DNA-PK activation drives genomic instability and therapy resistance in glioma stem cells. JCI Insight 3(3): pii98096, February 2018.
181 Huang M, T Liu, Ma P, Mitteer RA, Zhang Z, Kim HJ, Yeo E, Zhang D, Cai P, Li C, Zhang L, Zhao B, Roccograndi L, O’Rourke DM, Dahmane N, Gong Y, Koumenis C, Fan Y: c-Met-mediated endothelial plasticity drives aberrant vascularization and chemoresistance in glioblastoma. J Clin Invest 126(5): 1801-14, May 2016.
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Selected Publications
20b Ni H, Reitman ZJ, Zou W, Akhtar MN, Paul R, Huang M, Zhang D, Zheng H, Zhang R, Ma R, Ngo G, Zhang L, Diffenderfer ES, Motlagh SAO, Kim MM, Minn AJ, Dorsey JF, Foster JB, Metz J, Koumenis C, Kirsch DG*, Gong Y*, Fan Y*. : FLASH radiation stimulates proinflammatory macrophage polarization and sensitizes medulloblastoma to CAR-T cell immunotherapy. Nature Cancer Page: doi.org/10.1038/s43018-025-00905-6, Feb 2025 Notes: *, co-corresponding authors.e3 Lamplugh ZL, Wellhausen N, June CH, Fan Y.: Microenvironmental regulation of solid tumour resistance to CAR T cell therapy. Nature Review Immunology 2025.
f2 Cleveland AH, Fan Y.: Reprogramming endothelial cells to empower cancer immunotherapy. Trends in Molecular Medcine 30(2): 126-135. Feb 2024 Notes: Peer reviewed opinion.
10d Zhao X, Williamson T, Gong Y*, Epstein J*, Fan Y*.: Immunomodulatory therapy for ischemic heart disease. Circulation 150(13): 1050-1058, Sept 2024 Notes: *Co-senior author. peer-reviewed opinion.
19c Yang F, Akhtar N, Zhang D, El-Mayta R, Shin J, Dorsey JF, Zhang L, Xu X, Guo W, Bagley SJ, Fuchs SY, Koumenis C, Lathia JD, Mitchell MJ, Gong Y*, & Fan Y*.: An immunosuppressive vascular niche drives macrophage polarization and immunotherapy resistance in glioblastoma. Science Advances 10(9): eadj4678, Mar 2024 Notes: *Co-senior authors.
149 Zhang D, Cleveland AH, Krimitza E, Han K, Yi C, Stout AL, Zou W, Dorsey JF, Gong Y*, Fan Y*.: Spatial analysis of tissue immunity and vascularity by light sheet fluorescence microscopy. Nature Protocols 19(4): 1053-1082, Apr 2024 Notes: *Co-senior authors.
13b Yang F, Zhang D, Jiang H, Ye J, Zhang L, Winkler J, Gong Y, & Fan Y.: Small-molecule reversal of macrophage-mediated immunosuppression overcomes glioblastoma resistance to immunotherapy. Science Translational Medicine 15: eabq3558, Feb 2023.
174 Zhang D, Li A, Huang M, Yang F, Zhang L, Wellen KE, Xu X, Conn CS, Zou W, Kahn M, Rhoades SD, Weljie AM, Amankulor N, Yoshor D, Ye J, Koumenis C, Gong Y, & Fan Y. : PHGDH-mediated endothelial metabolism drives glioblastoma resistance to CAR T cell immunotherapy. Cell Metabolism 35: 1-18, Feb 2023.
18a Huang M, Yang F, Zhang D, Lin M, Duan H, EI-Mayta R, Zhang L, Qin L, Shewale S, Pei L, Mitchell M, Rader D, Fan Y*, Gong Y*.: : Endothelial plasticity drives aberrant vascularization and impedes cardiac repair after myocardial infarction. Nature Cardiovascular Research 1(4): 372–388, Apr 2022 Notes: *Co-senior author.
178 Ma W, Wang Y, Zhang R, Yang F, Zhang D, Huang M, Zhang L, Dorsey JF, Binder ZA, O’Rourke DM, Fraietta JA, Gong Y*, Fan Y*.: Targeting PAK4 to reprogram vascular microenvironment and improve CAR T immunotherapy for glioblastoma. Nature Cancer 2: 83–97, February 2021 Notes: *Co-corresponding authors.
189 Yang F, He Z, Duan H, Zhang D, Li J, Yang H, Dorsey JF, Zou W, Nabavizadeh SA, Bagley SJ, Abdullah K, Brem S, Zhang L, Xu X, Byrne KT, Vonderheide RH*, Gong Y*, & Fan Y*.: Synergistic immunotherapy of glioblastoma by dual targeting of IL-6 and CD40. Nature Comm. 12(1): 3424, June 2021 Notes: *Co-corresponding authors.
188 Huang M, Zhang D, Wu JY, Xing K, Yeo E, Li C, Zhang L, Holland E, Yao L, Qin L, Binder ZA, O’Rourke DM, Brem S, Koumenis C, Gong Y, and Fan Y. : Wnt-mediated endothelial transformation into mesenchymal stem cell-like cells induces chemoresistance in glioblastoma. Science Transl Medicine 12(532): eaay7522, Feb 2020.
aa Fan Y: Vascular Detransformation for Cancer Therapy. Trends in Cancer 5(8): 460-463, August 2019.
14c Wang Q, He Z, Huang M, Liu T, Xu H, Ma P, Zhang L, Zamvil SS, Hidalgo J, Zhang Z, O’Rourke DM, Dahmane N, Brem S, Gong Y, & Fan Y: Vascular niche IL-6 induces macrophage M2 polarization in gliomblastoma through HIF-2α. Nature Comm 9(1): 559, February 2018.
159 Liu T, Xu H, Huang M, Ma W, Saxena D, Lustig RA, Alonso-Basanta M, Zhang Z, O’Rourke DM, Zhang L, Gong Y, Kao GD, Dorsey JF*, & Fan Y*: Circulating glioma cells exhibit stem cell-like properties. Cancer Res 78(23): 6632-6642, December 2018 Notes: *corresponding authors.
149 Liu T, Ma W, Xu H, Huang M, Zhang D, He Z, Zhang L, Brem S, O'Rourke DM, Gong Y, Mou Y, Zhang Z, and Fan Y: PDGF-mediated mesenchymal transformation renders endothelial resistance to anti-VEGF treatment in glioblastoma. Nature Comm 9(1): 3439, August 2018.
13a Wang Y, Xu H, Liu T, Huang M, Butter P, Li C, Zhang L, Kao G, Gong Y, Maity A, Koumenis C, & Fan Y: Temporal DNA-PK activation drives genomic instability and therapy resistance in glioma stem cells. JCI Insight 3(3): pii98096, February 2018.
181 Huang M, T Liu, Ma P, Mitteer RA, Zhang Z, Kim HJ, Yeo E, Zhang D, Cai P, Li C, Zhang L, Zhao B, Roccograndi L, O’Rourke DM, Dahmane N, Gong Y, Koumenis C, Fan Y: c-Met-mediated endothelial plasticity drives aberrant vascularization and chemoresistance in glioblastoma. J Clin Invest 126(5): 1801-14, May 2016.
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