Highlights from Recent Cancer Literature

Abstract

Non-small cell lung cancer (NSCLC) is an aggressive disease with high rates of metastasis and poor survival, and while immunotherapy has been trialed for this tumor type, the improvements have been limited. In order to provide a framework for the stratification of patients who may best respond to this therapy, Lehtiö and colleagues performed mass spectrometry–based proteogenomics on a collection of 141 NSCLC tumors representing the spectrum of histological presentations for this disease. This analysis revealed six different subtypes that had unique immune cell compositions and expression of antigen processing proteins. The study also highlighted differences in neoantigen expression across the subtypes, which was influenced by epigenetic alterations, and showed differences in expression of immune checkpoint proteins such as FGL1 and B7-H4, which could be informative for determining the appropriate therapy. Finally, the authors developed a data-independent acquisition-based mass spectrometry classifier, which was able to reproduce the six subtypes in additional NSCLC cohorts of early or late-stage disease.Expert Commentary: This classifier has future clinical promise for classification of NSCLC patients for therapeutic intervention.Lehtiö J, Arslan T, Siavelis I, Pan Y, Socciarelli F, Berkovska O, et al. Proteogenomics of non-small cell lung cancer reveals molecular subtypes associated with specific therapeutic targets and immune evasion mechanisms. Nat Cancer 2021:1224–42.Metastatic progression involves escape of circulating tumor cells (CTC) into the bloodstream, attachment to the vasculature, and finally growth in distant organs. Scheidmann and colleagues applied a two-step, CRISPR-based screen in human CTC-derived xenografts to identify genes essential for this process. Transplanted metastasis-derived CTCs produced consistent metastatic lesions in tissues reflective of the patients' underlying disease. This approach enabled identification of previously unrecognized genes regulating CTC cluster formation, as well as genes that regulated intravasation of both single and clustered CTCs, and organ-specific metastasis. In particular, PLK1 was shown to be critical for entry of cancer cells into the bloodstream, as opposed to roles in tumor growth or metastatic colonization, and a PLK1 inhibitor prevented CTC intravasation. In the context of brain metastases, pharmacological inhibition of histone deacetylases or RhoA/C GTPases significantly reduced brain metastasis.Expert Commentary: This study highlights a new CTC-based tool to study breast cancer metastasis in a clinically relevant manner, enabling a loss-of-function CRISPR-screen, which uncovered treatment opportunities for metastatic breast cancers.Scheidmann MC, Castro-Giner F, Strittmatter K, Krol I, Paasinen-Sohns A, Scherrer R, et al. An in vivo CRISPR screen identifies stepwise genetic dependencies of metastatic progression. Cancer Res 2022;82:681–94.Bone is a frequent site of metastasis in patients with breast cancer, resulting in severe bone pain and poor quality of life. The unique bone vasculature provides a permissive site for early metastatic colonization of breast cancer cells. Using mouse models of mammary cancer and 3D imaging, Yip and colleagues identified distinct vascular niches, composed of type H capillaries, that were remodeled by tumor cells to promote bone metastatic growth. Mechanistically, this was driven via tumor cell secretion of granulocyte colony–stimulating factor (G-CSF). Both molecular and pharmacological intervention of G-CSF signaling reduced bone metastatic outgrowth.Expert Commentary: The role of G-CSF in this model is independent of its known effects on hematopoietic cells, and it will be important to unravel the mechanisms involved to understand whether patients may benefit from G-CSF targeting.Yip RKH, Rimes JS, Capaldo BD, Vaillant F, Mouchemore KA, Pal B, et al. Mammary tumour cells remodel the bone marrow vascular microenvironment to support metastasis. Nat Commun 2021;12:6920. doi: 10.1038/s41467-021-26556-6.Glioblastoma is characterized by numerous mechanisms of immunosuppression, which have limited the efficacy of immune checkpoint blockade as a therapy for treating patients with this tumor. In order to improve the clinical assessment of patient response, Arrieta and colleagues identified signaling features correlated with outcome in recurrent glioblastoma tumors treated with the immune checkpoint inhibitor anti-PD-1. Building on prior work implicating dysregulation of MAPK signaling, the authors showed that patients whose tumors contained a high density of cells with detectable phosphorylated ERK (pERK) were more likely to have a pronounced response to PD-1 blockade and thus longer survival. Multiplexed imaging showed high pERK staining primarily in SOX2-positive tumor cells and corresponded with increased myeloid cell infiltration. These myeloid cells had increased expression of MHC class II, suggesting effective antigen presentation was critical for the effectiveness of immunotherapy.Expert Commentary: This work reveals a predictor of response to PD-1 blockade in glioblastoma, however, the mechanism by which pERK in tumor cells evokes increased immune cell activity will require further investigation. This study also highlights the importance of timing in measuring predictive biomarkers, as tissue collected close to the start of checkpoint blockade provided the most effective predictor of outcome.Arrieta VA, Chen AX, Kane JR, Kang SJ, Kassab C, Dmello C, et al. ERK1/2 phosphorylation predicts survival following anti-PD-1 immunotherapy in recurrent glioblastoma. Nat Cancer 2021;1372–86. https://doi.org/10.1038/s43018-021-00260-2.Aberrant enhancer function and chromatin remodeling are critical for transcription factor–dependent malignancies, however, strategies to disrupt enhancer-driven oncogene overexpression are lacking. To address this, Xiao and colleagues developed AU-15330, a proteolysis-targeting chimera (PROTAC) degrader of the switch/sucrose non-fermentable (SWI/SNF) components SMARCA2, SMARCA4, and PBRM1. Androgen receptor (AR) and FOXA1-driven, estrogen receptor–positive or MYC overexpressing cancer cells were sensitive to AU-15330 treatment. AU-15330 led to rapid loss of chromatin accessibility at enhancer regions and AR, FOXA1, and ERG chromatin binding, with subsequent decreased expression of these transcription factors and their target genes. AU-15330 was effective in vivo in prostate cancer models alone or in combination with the nonsteroidal antiandrogen enzalutamide, without notable toxicity.Expert Commentary: This proof-of-principle study demonstrated that targeting SWI/SNF components may be an effective therapeutic approach for transcription factor–addicted malignancies.Xiao L, Parolia A, Qiao Y, Bawa P, Eyunni S, Mannan R, et al. Targeting SWI/SNF ATPases in enhancer-addicted prostate cancer. Nature 2022;601:434–9.Gastric cancer is known to be driven by a diverse range of signaling pathways, including Wnt, p53, and Ras, but how these pathways uniquely regulate tumor progression has not been studied in a comparative setting. Fatehullah and colleagues developed a novel mouse model of gastric cancer using a gastric epithelium–specific CreERT2 driver to introduce mutations in key gastric cancer genes into relevant regions of the stomach, validating their model-based tumor morphology, molecular biomarkers, and metastatic progression. The authors simultaneously developed an orthotopic gastric cancer organoid transplantation model that demonstrated the importance of LGR5+ cancer stem cells in vivo to drive metastatic gastric cancer. Ablated LGR5+ cancer stem cells were rapidly repopulated by new LGR5+ cancer stem cells supporting metastasis and recurrence. A combination of fluorouracil and a reduction of LGR5+ cancer stem cells resulted in sustained tumor growth reduction.Expert Commentary: This paper highlights the importance of targeting LGR5+ cancer stem cells and general gastric cancer debulking to prevent the reemergence of cancer stem cells in gastric cancer.Fatehullah A, Terakado Y, Sagiraju S, Tan TL, Sheng T, Tan SH, et al. A tumour-resident Lgr5+ stem-cell-like pool drives the establishment and progression of advanced gastric cancers. Nat Cell Biol 2021;23:1299–1313.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.