mProX™ Human LPAR5 Stable Cell Line

Konen JM, et al. "Autotaxin suppresses cytotoxic T cells via LPAR5 to promote anti-PD-1 resistance ." The Journal of clinical investigation, 2023.
The study focuses on the identification of novel tumor-driven resistance mechanisms in non-small cell lung cancers harboring concurrent KRAS and TP53 mutations (KP mutations). The research team developed a panel of KP murine lung cancer models with intrinsic resistance to anti-PD-1 and analyzed the differential gene expression between these tumors and anti-PD-1-sensitive tumors. Their findings showed that the enzyme autotaxin (ATX) and its product, lysophosphatidic acid (LPA), were significantly upregulated in resistant tumors. Additionally, ATX was found to directly modulate antitumor immunity and its expression was negatively correlated with total and effector tumor-infiltrating CD8+ T cells. The team also found that pharmacological inhibition of ATX or its downstream receptor LPAR5, in combination with anti-PD-1, effectively controlled lung tumor growth in multiple KP tumor models by restoring the antitumor immune response. Furthermore, the study revealed that ATX was significantly correlated with inflammatory gene signatures, including a CD8+ cytolytic score, in multiple lung adenocarcinoma patient data sets, indicating that the activated tumor-immune microenvironment upregulates ATX and provides a potential target for preventing acquired resistance to anti-PD-1 treatment. Overall, the study highlights the ATX/LPA axis as an immunosuppressive pathway that diminishes the response to immune checkpoint blockade in lung cancer.
Pubmed: 37655662   DOI: 10.1172/JCI163128

Sun X, et al. "PARP1 modulates METTL3 promoter chromatin accessibility and associated LPAR5 RNA ." Molecular therapy : the journal of the American Society of Gene Therapy, 2023.
In most eukaryotic bioprocesses, chromatin remodeling and N(6)-methyladenosine (m(6)A) modification are essential in controlling gene expression and DNA damage signaling. Recent research has revealed the role of poly(ADP-ribose) polymerase 1 (PARP1) in regulating the accessibility of METTL3, an m(6)A methyltransferase, to its promoter. Upon DNA damage induced by radiation, PARP1 dissociates from the METTL3 promoter, leading to decreased levels of transcription factors NFIC and TBP, reduced METTL3 expression, and suppressed m(6)A methylation of poly(A)(+) RNA. The Lysophosphatidic Acid Receptor 5 (LPAR5) mRNA was identified as a target of METTL3, with the m(6)A methylation site located at A1881. This study also demonstrates the potential of METTL3-targeted small-molecule inhibitors as a valuable therapeutic strategy for PARP1 inhibitors in oncology.
Pubmed: 37482682   DOI: 10.1016/j.ymthe.2023.07.018