Evaluating Lung Cancer Therapies with KRAS G12D Mouse Models
In this issue, we introduce the KS mouse model of lung cancer, based on the most common cancer-associated K-Ras mutant, K-Ras(G12D). Lung cancer is the most common cancer worldwide, with over 2.2 million new cases reported globally in 2020. According to data released by the Chinese National Cancer Center, lung cancer had already become the leading cause of morbidity and mortality among all malignant tumors in China by 2015. In 2023, the United States’ NIH National Cancer Institute estimates that lung cancer remains the cause of 12.2% of all new cancer cases nationwide.[7] The high incidence and mortality rates of lung cancer pose a significant burden on global public health, underscoring the urgent need for more clinical and preclinical research.
Genetic mutations and the onset of lung cancer
Lung cancer is divided into two histological subtypes: non-small cell lung cancer (NSCLC) and small cell lung cancer (SCLC), with NSCLC accounting for approximately 85% of all lung cancers and SCLC for 15%. NSCLC can be further classified into lung adenocarcinoma (LUAD), lung squamous cell carcinoma (LSCC), and large cell lung cancer (LCC). KRAS is the most common oncogene in NSCLC, with K-Ras(G12D) being the most common cancer-associated K-Ras mutant. In normal cells, K-Ras (KRAS) protein acts as a central hub for cell growth signaling pathways to exert a tumor-suppressing effect. Mutations can lead to KRAS being in a constantly activated state, resulting in uncontrolled cell proliferation and the development of adenocarcinoma within NSCLC. The KRAS G12D mutation is common in lung cancer, and many lung cancer models are based on mice overexpressing KRAS G12D.[2-3]
Recently, Ferone and colleagues summarized the characteristics of different lung cancer mouse models, discovering that tumor heterogeneity, invasiveness, and responses to treatment/resistance in these mouse models are determined by a combination of the cell of origin and genetic mutations. For example, the studies highlighted that type II alveolar cells carrying KRAS or EGFR oncogenic mutations are the primary origin of LUAD, while the proliferation of mutated club cells more frequently exhibits a papillary tumor phenotype.[4-5]
KS Mouse Model: Cell-specific Expression of KRAS G12D
SFTPC is a marker gene for type II alveolar cells. Cyagen produced offspring by crossbreeding conditionally overexpressing KRAS G12D mutant Lox-Stop-Lox (LSL)-K-ras G12D mice (Product Number: C001064) with Sftpc-MerCreMer mice (Product Number: C001501). Through tamoxifen induction, they obtained the KS lung cancer mouse model characterized by the expression of the mutant KRAS G12D oncogenic protein originating from SFTPC-positive type II alveolar cells (Product Number: C001514). This strain may be useful in studies of cancer and development of therapeutics.
KS Mouse Model for Lung Cancer Research
The KS mouse model developed for lung cancer research has demonstrated expression of K-ras G12D, a point mutation allele commonly associated with human cancer, from SFTPC-positive type II alveolar cells. Model validation experiments have been performed with the following results, which are indicative of the model’s potential utility in oncology and therapeutic research.
Six weeks after tamoxifen treatment, the lungs of the KS mice showed significant tumor tissue infiltration
For early detection of lung cancers, low-dose spiral CT is the screening technique recommended by the "Chinese Lung Cancer Screening Standards".[6] Cyagen conducted lung CT scans on early-stage KS mouse models to determine the occurrence of tumors. The results showed that six weeks after tamoxifen treatment, significant tumor tissue infiltration had already appeared in the mouse lungs.
KS mice exhibit abnormal growth and development
Growth and survival curve data indicate that the body weight of tamoxifen-treated KS mice is significantly lower than that of wild-type (WT) mice, a trend observed in both females and males. Furthermore, the survival rate of KS mice begins to decline in the ninth week after tamoxifen induction, and all mice die after 13 weeks of induction, consistent with survival times reported in the literature.[5]
KS mice exhibit abnormalities in the lungs and spleen
Observations of the lungs from KS mice at various time points after induction completion show that, compared with wild-type (WT) mice, tumor cell invasion in the lungs of KS mice is evident as early as six weeks after induction completion, with the lungs presenting a dense and enlarged structure. By the 12th week after induction completion, the spleens of KS mice exhibit abnormal hyperplasia.
Pathological conditions of other tissues
H&E staining was performed on the spleen, kidney, liver, and pancreas tissues of KS mice 12 weeks after induction completion. The results show that compared to the control group, the kidneys, liver, and pancreas showed no abnormalities, but their spleens exhibited abnormal hyperplasia of the white pulp.
Conclusion
The KS mouse model provides a more suitable preclinical tool for evaluating therapies targeting the KRAS G12D mutation. KS mice begin to lose weight six weeks after tamoxifen induction, exhibit symptoms of respiratory distress as they age, and all die 13 weeks post-induction. Pathologically, significant tumor cell infiltration starts in the lungs of KS mice six weeks after induction, with the lungs becoming expanded and deformed, presenting a dense structure and reddish appearance, and reaching advanced stages by week 12. Therefore, while ensuring the efficient and rapid development of tumors, KS mice offer an extended experimental window for mechanism research and drug development.
In addition to the KS lung cancer mouse model, Cyagen also offers a variety of spontaneous, induced, or CDX (Cell-Derived Xenograft) tumor models, including those for liver cancer, pancreatic cancer, breast cancer, and gastrointestinal cancer. They can also customize or co-develop models according to researchers' needs. If you are interested in our models, or wish to collaborate with us to develop models that meet your research needs, please contact us immediately!
References
[1] Sun D, Li H, Cao M, He S, Lei L, Peng J, Chen W. Cancer burden in China: trends, risk factors and prevention. Cancer Biol Med. 2020 Nov 15;17(4):879-895.
[2] Kwon MC, Berns A. Mouse models for lung cancer. Mol Oncol. 2013 Apr;7(2):165-77.
[3] WebMD. (2023, December 19). Gene Mutations in Non-Small-Cell Lung Cancer. Retrieved from https://www.webmd.com/lung-cancer/story/nsclc-gene-mutations
[4] Ferone G, Lee MC, Sage J, Berns A. Cells of origin of lung cancers: lessons from mouse studies. Genes Dev. 2020 Aug 1;34(15-16):1017-1032.
[5] Xu X, Rock JR, Lu Y, Futtner C, Schwab B, Guinney J, Hogan BL, Onaitis MW. Evidence for type II cells as cells of origin of K-Ras-induced distal lung adenocarcinoma. Proc Natl Acad Sci U S A. 2012 Mar 27;109(13):4910-5.
[6] China National Cancer Prevention and Control Network. (2023, December 19). Guide Standard Detail. Retrieved from http://www.chinancpcn.org.cn/guideStandardDetail?id=6
[7] “Cancer of the Lung and Bronchus - Cancer Stat Facts.” Surveillance, Epidemiology, and End Results Program, National Cancer Institute, National Institutes of Health, seer.cancer.gov/statfacts/html/lungb.html. Accessed 14 Mar. 2024.
