Lamins regulate cancer cell plasticity and chemosensitivity

Guofang Chen¹Tingyi Wei²Ao Huang¹Junwei Shen¹Furong Ju³Shichao Huang⁴Haisen Li^5*

• ¹Tongji University, Shanghai, Shanghai Municipality, China
• ²Shanghai Jiao Tong University, Shanghai, Shanghai Municipality, China
• ³City University of Hong Kong, Kowloon, Hong Kong, SAR China
• ⁴Center for Excellence in Molecular Cell Science, Chinese Academy of Sciences (CAS), Shanghai, Shanghai Municipality, China
• ⁵Fudan University, Shanghai, China

Stem cell plasticity plays key roles in mammalian organogenesis, tissue homeostasis, and carcinogenesis. Given its tolerance to anti-tumor therapy and its promotion on immunosuppressive microenvironment, cancer cell plasticity is a major contributor to cancer recurrence and metastasis. It is necessary to explore novel avenues to resolve the limitations of current treatments. Herein, we found that all lamin knockdown disrupts cancer cell plasticity and impairs tumor progression. The deficiency of all lamin subtypes impaired the stemness and cell cycle transition of cancer cell. Lamin knockdown modulated genomic damage and repair pathways, inhibited mitochondrial function, and triggered cellular senescence. Moreover, lamin knockdown within cancer cell suppressed cancer growth in vivo by enhancing the infiltration and activation of functional T cells. Mechanistically, lamin knockdown reduced the expression of inhibitory immune checkpoints and inflammatory factors in cancer cell via the HIF-1 signaling pathway, which led to the increased sensitivity of cancer cells to chemotherapy. Overall, our findings characterize the significance of nuclear lamins in cancer cell plasticity and offer an attractive way to improve the effectiveness of anti-cancer therapy.