LAUSR

Background: Malignant pleural mesothelioma (MPM) is a highly aggressive tumor linked to loss of tumor suppressorsBAP1, NF2, andTRP53and accompanied by malignant pleural effusion (MPE). Aim: To develop novel mouse models of MPM with MPE. Methods: Intercrosses of conditional mutantKRAS (LoxP-STOP-LoxP.KRASG12D; K) andTRP53-deleted (LoxP.Trp53.LoxP; P) mice received intrapleural adenovirus-Cre. Pleural tumors were molecularly phenotyped and cultured to isolate cell lines, which were inoculated into the pleurae of naive mice. Results: K mice developed lethal epithelioid MPM (median, 95%CI survival: 339, 285-379 days). KP mice succumbed to sarcomatoid MPM (median, 95%CI survival 40, 38-72 days) accompanied by MPE (mean±SD volume 349±269 µL). KP mice also developed peritoneal mesothelioma upon intraperitoneal adenovirus-Cre. Mouse MPMs expressed calretinin, podoplanin, and osteopontin, but not surfactant protein C. MPM cell lines were isolated from KP MPM, which transplanted MPM to naiveC57BL/6mice causing their death (median, 95%CI survival 26, 25-28 days) by MPE induction (mean±SD volume 387±180 µL). The models harbored secondary BAP1, NF2 and CDKN2 mutations. Treatment of KP mice with a KRAS inhibitor resulted in increased survival and halted MPM growth and MPE formation. Conclusions: We developed multiple models of primary and transplantable MPM that show thatKRASandTP53mutations can initiate the disease and cause secondaryBAP1andNF2loss. Funding ERC Grants #260524 and #679345.