Abstract 6139: Sex-dependent development of anal squamous cell carcinoma in Kras-mutant mice

Abstract

Abstract A historical over-reliance on male animals in research studies has clouded sex differences in pathologic diseases. This led to a mandate from the NIH requiring the use of both male and female animals in preclinical studies. Our study began with the aim to evaluate both sexes of KC mice (LSL-KrasG12D/+; Pdx1-Cre), a standard pre-clinical model for pancreatic ductal adenocarcinoma (PDAC). This was because previous characterization of this model to advanced age (9-12 months) only included males, and evaluating both sexes was an essential foundation for subsequent studies of PDAC progression. Twenty-eight KC mice have been evaluated, comprised of 15 males and 13 females. KC mice developed the expected pancreatic cancer pre-cursor lesions called PanINs (100% PanIN1, 7% PanIN 2 and 7% PanIN 3) and PDAC (14%) at an established time point (age 9 months). Surprisingly, female KC mice developed anal lesions, a finding that has not previously been described. Histopathologic analysis demonstrated anal squamous cell carcinoma (SCC), with all 13 KC females developing anal SCC compared to 0/15 in KC males and 0/83 control mice (Table 1). Genotyping for activated Kras mutation confirmed the presence of KrasG12D, indicating Pdx1 expression (Pdx1-Cre) in the anal tumor tissue. To understand the distinct sex differences and connection to sex-dependent steroids (estrogen and testosterone), female mice were ovariectomized (n = 5) and males castrated (n = 6). Remarkably, while 5/5 females developed anal SCC (i.e. unchanged phenotype), 6/6 males developed anal SCC, a stark contrast to the absence of tumor development in non-castrated KC males. This suggests a novel mechanism in which Kras driven anal SCC tumor development is suppressed through testosterone / dihydrotestosterone (DHT) exposure. Follow-up studies will focus on the mechanism by which testosterone or DHT suppresses Kras-driven anal SCC formation. These findings may ultimately have therapeutic implications for the subset of patients with Kras-mutant anal SCC. Table 1:Characterization and Incidence of Anal SCC TumorsGroupMouseAnal SCC IncidenceControlC57Bl6 Male (n=12)0/12 (0%)ControlC57Bl6 female (n=11)0/11 (0%)ControlKrasG12D/+ Female (n=9)0/9 (0%)ControlKrasG12D/+ Male (n=18)0/18 (0%)ControlPDX1-Cre male (n=10)0/10 (0%)ControlPDX1-Cre Female (n=23)0/23 (0%)KC MiceKC Male (n=15)0/15 (0%)KC MiceKC Female (n=13)13/13 (100%)Study KC MiceCastrated KC Male (n=6)6/6 (100%)Study KC MiceOvariectomized KC Female (n=5)5/5 (100%) Citation Format: Morgan Walcheck, Jessica Noel, Manabu Nukaya, Kristina Matkowskyj, Sean Ronnekleiv-Kelly. Sex-dependent development of anal squamous cell carcinoma in Kras-mutant mice [abstract]. In: Proceedings of the Annual Meeting of the American Association for Cancer Research 2020; 2020 Apr 27-28 and Jun 22-24. Philadelphia (PA): AACR; Cancer Res 2020;80(16 Suppl):Abstract nr 6139.