Highlights from Recent Cancer Literature
Journal: Cancer Research (2022)

Although BRCA1/2 pathogenic variants are well known to increase risk of female breast and ovarian cancers, the risk of other malignancies has not been well characterized due to small sample sizes tested. Here, Li and colleagues analyzed data from 3,184 BRCA1 and 2,157 BRCA2 carrier families from the Consortium of Investigators of Modifiers of BRCA1/2, identifying numerous differences in the spectrum of cancers. Carriers of BRCA1 pathogenic variants had significantly increased incidence of male breast, gallbladder, stomach, and colorectal cancers, without an increase in prostate cancer, while those with BRCA2 pathogenic variants had dramatically increased relative incidence of male breast cancer, along with significant increases in the incidence of stomach, pancreatic, and prostate cancer. Age-specific absolute risks were calculated across cancers separately for both BRCA1 and BRCA2.Expert Commentary: This large study of BRCA1/2 families provides a detailed risk for cancers in addition to breast and ovarian cancers, generating crucial baseline data to design age- and mutation-specific surveillance protocols.Li S, Silvestri V, Leslie G, Rebbeck TR, Neuhausen SL, Hopper JL, et al. Cancer risks associated with BRCA1 and BRCA2 pathogenic variants. Journal of Clinical Oncology; Published online January 25, 2022; doi: 10.1200/JCO.21.02112.Tumoral heterogeneity allows for resistant tumor cell clones to survive during cancer therapy, leading to relapse. Karabacak and colleagues used single cell mass cytometry on PTEN-deleted mouse models of prostate cancer to determine the evolution of kinase activities in different tumor compartments during metastasis or following drug treatment. Bone lesions in a metastatic model of prostate cancer displayed elevated PI3K/mTOR activity and overexpressed the c-Met receptor tyrosine kinase as compared with primary tumors, circulating tumor cells, and metastases. These metastases were uniquely sensitive to inhibition of c-MET as compared with metastases in other tissues. The authors also expanded on the importance of intratumoral heterogeneity by demonstrating PI3K/mTOR activity was elevated in epithelial cancer cells and diminished in mesenchymal cells within a single tumor, which was confirmed in prostate and breast patient–derived circulating tumor cells. These findings suggest differential sensitivity of different cell states to PI3K/mTOR inhibitors and provide insights into how the epithelial-to-mesenchymal transition promotes drug resistance.Expert Commentary: This study highlights intertumoral and intratumoral differences in kinase activity (PI3K/mTOR) in a mouse model of prostate cancer and suggests using combination therapies to target the differing therapeutic vulnerabilities of cancer cells in different tissue compartments.Karabacak NM, Zheng Y, Dubash TD, Burr R, Micalizzi DS, Wittner BS, et al. Differential kinase activity across tumor compartments defines sensitivity to target inhibition. Cancer Res 2022;82:1084–97.Multiple cancer types are dependent upon glutamine for survival as a key component of tumor cell metabolism and energy production. In a recent study, Huang and colleagues identified a previously unrecognized role for glutamine in cancer by demonstrating glutamine is used in γ-aminobutyric acid (GABA) production, which has mostly been studied in neuronal signaling. GABA and GAD1, the enzymes responsible for conversion of glutamine to GABA, were found to be overexpressed in lung and colorectal cancer and correlated with poor outcomes. GABA, through a GAD1- and β-catenin–dependent pathway, promoted tumor growth and suppressed CD8+ T-cell infiltration. Targeting the GABA receptor or GAD1 overcame resistance to anti-PD-1 therapy.Expert Commentary: This study suggests that targeting the GABA pathway may be an effective therapeutic strategy for a subset of cancer patients.Huang D, Wang Y, Thompson JW, Yin T, Alexander PB, Qin D, et al. Cancer-cell-derived GABA promotes β-catenin–mediated tumour growth and immunosuppression. Nat Cell Biol 2022;24:230–41.Disparities in survival outcomes exist between Black and Hispanic patients and non-Hispanic white patients. Abraham and colleagues examined biological, clinical, and socioeconomic variables in six Chicago area hospitals, assessing outcomes in acute myeloid leukemia, an aggressive hematologic cancer. While patient age and specific mutations were favorable indicators in the white population, this was not the case for other populations. Using census tract information to generate measures of racial and economic segregation, the authors assembled an outcomes dataset that included these data and other known variables. Other studies have suggested that nonbiologic factors can independently affect survival in acute myeloid leukemia. Here the variables considered to represent structural racism accounted for nearly all the disparity in survival outcomes among the defined racial groups.Expert Commentary: This study highlights the urgent need to consider structural and historic factors including socioeconomic status, neighborhood segregation and affluence, and access to community support resources when seeking to improve cancer outcomes.Abraham I, Rauscher G, Patel A, Pearse W, Rajakumar P, Burkart M, et al. Structural racism is a mediator of disparities in acute myeloid leukemia outcomes. Blood; Published online January 21, 2022; doi: 10.1182/blood.2021012830.Cancer-associated fibroblasts (CAF) are now known to have both tumor-promoting and tumor-suppressive properties, which complicates the design of therapies targeting CAFs. Prostaglandin E2 (PGE2), a lipid mediator, is known to promote tumor initiation and growth, and suppresses antitumor immunity, however, Elsakeel and colleagues further defined the role of PGE2 by studying its impact on CAF activation. Knockout of microsomal prostaglandin E synthase-1 (mPGES-1) in PyMT mice or prostanoid E receptor 3 (EP3) in CAFs constrained PGE2 signaling to inhibit mammary tumor growth, however, these changes promoted robust CAF proliferation. Disruption of PGE2 signaling in CAFs caused epithelial-to-mesenchymal transition in cancer organoids and stimulated metastasis in mice. Mechanistically, these effects were associated with a reduction in TGFβ-activated kinase–like protein (TAK1L), a negative regulator of p38 MAPK activation. Interestingly, high TAK1L expression in CAFs correlated with reduced metastasis and enhanced survival in breast cancer patients.Expert Commentary: This study suggests that PGE2 functions as a double-edged mediator, promoting tumor growth at the primary site while restricting metastasis. PGE2 targeting strategies in breast cancer may potentially benefit from EP3-selective approaches.Elsakeel E, Brüggemann M, Wagih J, Lityagina O, Elewa MAF, Han Y, et al. Disruption of prostaglandin E2 signaling in cancer-associated fibroblasts limits mammary carcinoma growth but promotes metastasis. Cancer Res 2022:82:1380–95.Ferroptosis is a cell death pathway known to be regulated by fatty acid metabolism, but the specific species of fatty acids that can induce this process are not well defined. Liao and colleagues screened which fatty acids could trigger ferroptosis in cancer cells in vitro, specifically in combination with IFNγ. Only arachidonic acid induced cell death, which could be suppressed by ferrostatin 1. Arachidonic acid–mediated cell death required ACSL4, an essential enzyme in generating phospholipids from polyunsaturated fatty acids, which, when oxidized, can induce ferroptosis. Interestingly, ACSL4-deficient tumor cells were resistant to immune control and these tumors exhibited reduced T-cell infiltration and function, and the authors observed that induction of ferroptosis required T cells. Therapeutically, systemic arachidonic acid administration enhanced tumor control when combined with checkpoint blockade therapy. In cancer patients, higher expression of ACSL4 correlated with improved response to checkpoint blockade.Expert Commentary: T cells can induce cancer cell ferroptosis through producing IFNγ in the presence of the long chain fatty acid arachidonic acid. Arachidonic acid administration may improve the efficacy of checkpoint blockade therapy.Liao P, Wang W, Wang W, Kryczek I, Li X, Bian Y, et al. CD8+ T cells and fatty acids orchestrate tumor ferroptosis and immunity via ACSL4. Cancer Cell; Published online February 15, 2022; doi: 10.1016/j.ccell.2022.02.003.Note: Breaking Insights are written by Cancer Research editors. Readers are encouraged to consult the articles referred to in each item for full details on the findings described.