Timothy Brown

GPR81 is a G-protein-coupled receptor for lactate, which is upregulated in breast cancer and plays an autocrine role to promote tumor growth by tumor cell-derived lactate. Here we asked whether lactate has any paracrine role via activation of GPR81 in cells present in tumor microenvironment to help tumor growth. First, we showed that deletion of Gpr81 suppresses breast cancer growth in a constitutive breast cancer mouse model (MMTV-PyMT-Tg). We then used a syngeneic transplant model by monitoring tumor growth from a mouse breast cancer cell line (AT-3, Gpr81-negative) implanted in mammary fat pad of wild-type mice and Gpr81-null mice. Tumor growth was suppressed in Gpr81-null mice compared with wild-type mice. There were more tumor-infiltrating T cells and MHCIIhi-immune cells in tumors from Gpr81-null mice compared with tumors from wild-type mice. RNA-seq analysis of tumors indicated involvement of immune cells and antigen presentation in Gpr81-dependent tumor growth. Antigen-presenting dendritic cells expressed Gpr81 and activation of this receptor by lactate suppressed cell-surface presentation of MHCII. Activation of Gpr81 in dendritic cells was associated with decreased cAMP, IL-6 and IL-12. These findings suggest that tumor cell-derived lactate activates GPR81 in dendritic cells and prevents presentation of tumor-specific antigens to other immune cells. This paracrine mechanism is complementary to the recently discovered autocrine mechanism in which lactate induces PD-L1 in tumor cells via activation of GPR81 in tumor cells, thus providing an effective means for tumor cells to evade immune system. As such, blockade of GPR81 signaling could boost cancer immunotherapy.

SLC6A14 is a Na+/Cl--coupled transporter for neutral and cationic amino acids. It is expressed at basal levels in the normal colon but is up-regulated in colon cancer. However, the relevance of this up-regulation to cancer progression and the mechanisms involved in the up-regulation remain unknown. Here, we show that SLC6A14 is essential for colon cancer and that its up-regulation involves, at least partly, Wnt signaling. The up-regulation of the transporter is evident in most human colon cancer cell lines and also in a majority of patient-derived xenografts. These findings are supported by publicly available TCGA (The Cancer Genome Atlas) database. Treatment of colon cancer cells with α-methyltryptophan (α-MT), a blocker of SLC6A14, induces amino acid deprivation, decreases mTOR activity, increases autophagy, promotes apoptosis, and suppresses cell proliferation and invasion. In xenograft and syngeneic mouse tumor models, silencing of SLC6A14 by shRNA or blocking its function by α-MT reduces tumor growth. Similarly, the deletion of Slc6a14 in mice protects against colon cancer in two different experimental models (inflammation-associated colon cancer and genetically driven colon cancer). In colon cancer cells, expression of the transporter is reduced by Wnt antagonist or by silencing of β-catenin whereas Wnt agonist or overexpression of β-catenin shows the opposite effect. Finally, SLC6A14 as a target for β-catenin is confirmed by chromatin immunoprecipitation. These studies demonstrate that SLC6A14 plays a critical role in the promotion of colon cancer and that its up-regulation in cancer involves Wnt signaling. These findings identify SLC6A14 as a promising drug target for the treatment of colon cancer.

This study explores the interpersonal faculty development interactions of university faculty as a function of their demographic representation (with regard to gender and ethnicity) in their home departments. For one academic semester, a small sample of 30 tenure-track junior faculty participated in a weekly diary checklist study in which they logged all their mentoring and professional development communications, noting the status of those involved in the interaction and the content. Demographically privileged faculty (whose gender and ethnicity were not underrepresented in their departments) reported more interactions overall, more with higher status colleagues, and more on content critical to retention. Extrapolating from the disparities revealed in this single semester (which benefitted demographically privileged faculty with an average of 13 more faculty development interactions), a gap amounting to 130 faculty development interactions could accumulate favoring privileged over underrepresented faculty by the end of a typical 10-semester tenure probationary period. Results warn of the need to attend to subtle accumulating privilege in the interpersonal professional development opportunities available in the academy. It must be a question of the well-being and opportunities not of a few but for all. -Paul Robeson, 1949 Effective mentoring has been increasingly recognized as an important professional development resource (Blackwell, 1989; Boice, 1992; Frierson, 1997; Gonzales, 2003; Holloway, 2001; Moss, 2008; Santos & Reigadas, 2002). The faculty development interactions that socialize faculty into the academy involve more than just a mentoring relationship in the traditional sense. To survive, faculty members may receive mentoring and professional development advice from a wide range of interpersonal interactions, covering a range of content. One of the strengths of mentoring is its highly varied, interpersonal, and often informal nature (Boice, 1993; Bova, 1995; Johnsrud & Atwater, 1993; Sorcinelli, & Yun, 2007; Turner & Thompson, 1993; Ragins & Scandura, 1997). In its broadest sense, mentoring is interpersonally communicated professional guidance on a wide range of professional topics through interaction with fellow junior colleagues, in social get-togethers, and in consultation with senior colleagues, chairs, administrators, and mentors (Gaskin, Lumpkin, & Tennant, 2003; Johnson-Bailey & Cervero, 2002; Sandler, 1993; Turner, 2003). As a boost to professional development, access to a wide range of mentoring interactions can help level the playing field for women and ethnic minority faculty, providing necessary information to help encourage productivity, retention, and advancement (Sorcinelli, & Yun, 2007; Williams & Blackburn, 1988). Regretfully, research suggests that faculty development via interpersonal interactions may occur unevenly across faculty demographic groups, putting certain faculty at a serious disadvantage. For instance, women in male dominated environments report difficulties in accessing mentoring (Feist-Price, 1994; Gibbons, 1993; Gibson, 2006; Gilbert & Rossman, 1992; Noe, 1988b; Rios & Longnion, 2000). This is partly due to women being less likely to develop a comfortable rapport with potential senior ranking men over shared hobbies or interests (Ragins & Scandura, 1997) or senior men's fears that informal crosssex interactions might lead to gossip or rumors (Burke & McKeen, 1996; Clawson & Kram, 1984; Hansman, 1998, 2002, & 2003). The availability of mentoring via other faculty women may be delayed if senior ranking women simply do not exist or if those women who are senior fear over-identifying with junior women or are already overextended (Hansman, 1998, 2002, & 2003). Similarly, ethnic minority faculty may lack mentoring experiences (Cabezas, Tan, Lowe, Wong, «Sc Turner, 1989; Crawford & Smith, 2005; Evans & Cokley, 2008; Guanipa, Santa Cruz, & Chao, 2003; Sands, Parson, & Duane, 1991; Smith, Smith, & Markham, 2000; Thomas, 1990; Turner, 2003; Turner, Gonzalez, «Sc Wood, 2008). …