Patient-derived skin tumor organoids with immune cells respond to metformin

Yanghua Shi^{¹^,^§}, Jiping Liu^{¹^,^§}, Lanyang Li^¹, Chen Wang^¹, Jian Zhang^¹, Mingjie Rong^¹, Yamin Rao^², Xiaobo Zhou^³, Di Sun^⁴, Jun Chen^³(), Chunhui Cai^¹(), Xinxin Han^{¹^,⁵}()

1Shanghai Lisheng Biotech, Shanghai 200092, China

2Department of Pathology, Shanghai Ninth People’s Hospital, affiliated to Shanghai Jiao Tong University School of Medicine, Shanghai 200011, China

3Department of Dermatology and Dermatologic Surgery, Shanghai Ninth People’s Hospital, affiliated to Shanghai Jiao Tong University School of Medicine, Shanghai 200011, China

4Department of Plastic and Reconstructive Surgery, Shanghai Ninth People’s Hospital, affiliated to Shanghai Jiao Tong University School of Medicine, Shanghai 200011, China

5Organ Regeneration X Lab, LiSheng East China Institute of Biotechnology, Peking University, Nantong 226299, China

^§ Yanghua Shi and Jiping Liu contributed equally to this work.

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Highlights

• Patient-derived skin tumor organoids replicate clinical tissue characteristic

• Single-cell sequencing identifies 11 distinct cell types in skin organoids

• Bermatofibrosarcoma protuberans (DFSP) organoids used to test responses to imatinib and metformin

• Metformin inhibits the growth of DFSP organoids via immune signaling pathway

Graphical Abstract

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Here, we developed patient-derived skin tumor organoids mimicking clinical tissues, showcasing diverse cell types and immune interactions. Single-cell sequencing identified 11 cell types, highlighting fidelity to in vivo counterparts. Bermatofibrosarcoma protuberans (DFSP) organoids revealed metformin's unique immune signaling modulation, aiding drug testing and mechanistic exploration.

Abstract

Surgery is the primary treatment for skin tumors, but it can result in scarring and distress for patients. Developing alternative therapeutic methods necessitates suitable in vitro models, which are currently limited in accurately representing the in vivo cell types and microenvironment of skin tumors. Here, we present a practical approach for creating patient-derived skin tumor organoids that effectively replicate the histological characteristics and mutational profiles observed in clinical tissues. Utilizing single-cell sequencing, we identified up to 11 distinct cell types within the organoid samples, encompassing various skin system cells and immune cells. Furthermore, we demonstrate the applicability of bermatofibrosarcoma protuberans (DFSP) organoids for assessing their responses to imatinib and metformin. Our findings reveal that metformin, in contrast to imatinib, can modulate the expression of downstream genes through immune signaling pathways. Our results underscore the ability of DFSP organoids to preserve key features of clinical tissues, including the presence of multiple cell types, especially immune cells. Importantly, our organoids provide a convenient approach for investigating the effects of drugs and elucidating underlying molecular mechanisms.

Keywords

skin tumor keloid dermatofibrosarcoma protuberans (DFSP)patient-derived organoid (PDO)drug screening immune cells therapy metformin imatinib

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References

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Tay, S. S., Roediger, B., Tong, P. L., Tikoo, S., Weninger, W. The skin-resident immune network. Current Dermatology Reports, 2014, 3(1): 13–22. https://doi.org/10.1007/s13671-013-0063-9