Murray, Nicole R.

Abstract Lung squamous cell carcinoma (LUSC) is a devastating disease, accounting for ~30% of all lung cancer diagnoses and ~40,000 deaths annually in the United States alone. LUSC patients suffer from high prevalence of relapse and a dismal 5-year survival of only ~24%. The lack of animal models that reflect the salient features of human disease to assess the safety and efficacy of drugs, and to explore the underlying molecular mechanisms of LUSC tumor biology, is a major impediment for LUSC patients. We have identified concomitant 3q26 copy number gain (CNG) and TP53 loss as a defining genetic alteration present in ~90% of LUSC tumors. Furthermore, we have identified and characterized three 3q26 oncogenes (PRKCI, ECT2 and SOX2) that genetically and biochemically collaborate to drive LUSC tumor formation. Using syngeneic mouse modeling, we have demonstrated that coordinate overexpression of Prkci, Ect2 and Sox2, and loss of Trp53 in ex vivo cultures of lung basal stem cells (LBSCs; a cell of origin for LUSC) drives transformation of these cells into tumors of exclusively LUSC histopathology. These findings lead to the hypothesis that PRKCI, ECT2 and SOX2 represent a multigenic driver of 3q26 CNG-driven LUSC, which we term the 3q26 OncCassette. Based in these findings, we have developed and begun characterizing the first autochthonous genetically engineered mouse model (GEMM) to study 3q26 OncCassette-driven tumorigenesis. Our novel immune competent GEMM will provide critical insight into tumor initiation and progression of preneoplastic lesions to malignant LUSC and allow characterization of the immune landscape in these tumors. Citation Format: Kayleah M. Meneses, Yi Liu, Capella R. Weems, Lee Jamieson, Duy T. Nguyen, Verline Justilien, Nicole R. Murray, Alan P. Fields. Modeling the 3q26 OncCassette using genetically engineered mice [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2024; Part 1 (Regular Abstracts); 2024 Apr 5-10; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2024;84(6_Suppl):Abstract nr 1434.

Abstract Lung adenocarcinoma (LUAD), the most prevalent subtype of lung cancer, can arise from two different cell populations: alveolar type 2 (AT2) cells and bronchiolar club cells. By utilizing genomic data from the cancer genome atlas program, human LUAD cell lines, and the well-characterized LSL-KrasG12D/Trp53-/- (KP) mouse model, we demonstrated that tumors arising from club cells are much more aggressive and follow a different trajectory of tumorigenesis when compared to those arising from AT2 cells. Intriguingly, our data strongly suggest that expression and signaling activity of protein kinase C iota (PKCι) can profoundly affect the cell of origin and oncogenic signaling pathways employed by resultant tumors. Specifically, KP-mediated transformation of club cells appears to be dependent on PKCι-ELF3-NOTCH3 and PKCι-YAP1 signaling axes, while AT2 cell malignancy is dependent on the PKCι-independent WNT signaling. In addition, club-cell-origin tumors exhibit an enrichment of cancer stem cells and increased infiltration of immunosuppressive myeloid cells in comparison to AT2-cell-origin tumors. This results in accelerated progression and increased likelihood of metastasis by LUAD tumors that originate from club cells. Taken together, our results indicate that PKCι expression and signaling activity can profoundly influence the cells of origin, tumor trajectories, and therapeutic vulnerabilities of LUAD tumors. Citation Format: Duy T. Nguyen, Ning Yin, Capella R. Weems, Lee Jamieson, Kayleah Meneses, Yi Liu, Nicole R. Murray, Alan P. Fields. A lineage-specific role of oncogenic protein kinase Cι in lung adenocarcinoma [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2024; Part 1 (Regular Abstracts); 2024 Apr 5-10; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2024;84(6_Suppl):Abstract nr 4299.

Protein kinase C ι (PKCι) has been implicated in Ras signaling, however, a role for PKCι in oncogenic Ras-mediated transformation has not been established. Here, we show that PKCι is a critical downstream effector of oncogenic Ras in the colonic epithelium. Transgenic mice expressing constitutively active PKCι in the colon are highly susceptible to carcinogen-induced colon carcinogenesis, whereas mice expressing kinase-deficient PKCι (kdPKCι) are resistant to both carcinogen- and oncogenic Ras-mediated carcinogenesis. Expression of kdPKCι in Ras-transformed rat intestinal epithelial cells blocks oncogenic Ras-mediated activation of Rac1, cellular invasion, and anchorage-independent growth. Constitutively active Rac1 (RacV12) restores invasiveness and anchorage-independent growth in Ras-transformed rat intestinal epithelial cells expressing kdPKCι. Our data demonstrate that PKCι is required for oncogenic Ras- and carcinogen-mediated colon carcinogenesis in vivo and define a procarcinogenic signaling axis consisting of Ras, PKCι, and Rac1.