Highlights from Recent Cancer Literature

Molecular predictors of response to anti-PD-1 therapy are lacking. Two independent approaches (whole exome sequencing and a genetic screen) demonstrated that mutations in PBRM1 or other alterations in SWI/SNF chromatin remodeling complex members (PBAF subtype) correlated with response in renal cell carcinoma (RCC) and could sensitize to checkpoint inhibitors in melanoma preclinically. In RCC, PBRM1 mutations correlated with response to monotherapy or combination immune checkpoint therapy (1), while inactivation of PBAF complex members (Pbrm1, Arid2, Brd7) increased antitumor T-cell cytotoxicity and sensitized to immune checkpoint therapy in melanoma preclinically (2).

Expert Commentary: These studies provide the first molecular markers of response to immune checkpoint therapy and may have significant impact on patient selection.

1. Miao D, Margolis CA, Gao W, Voss MH, Li W, Martini DJ, et al. Genomic correlates of response to immune checkpoint therapies in clear cell renal cell carcinoma. Science; Published online January 4, 2018; doi: 10.1126/science.aan5951.

2. Pan D, Kobayashi A, Jiang P, Ferrari De Andrade L, Tay RE, Luoma A, et al. A major chromatin regulator determines resistance of tumor cells to T cell–mediated killing. Science; Published online January 4, 2018; doi: 10.1126/science.aao1710.

Amplification and overexpression of EGFR or EGFRvIII (a constitutively active mutant) occur commonly in glioma. Sang and colleagues show that EGFR signaling upregulates tripartite motif-containing protein 59 (TRIM59) through SOX9, enhancing interactions between TRIM59 and nuclear STAT3. This interaction prevents STAT3 dephosphorylation by nuclear T-cell protein tyrosine phosphatase (TC45), thereby promoting tumorigenesis. Silencing TRIM59 suppressed proliferation, migration, and xenograft brain tumor formation of GBM and glioma stem cells.

Expert Commentary: This study reveals a previously unknown signal relay by which TRIM59 mediates EGFR stimulation of STAT3 by inhibiting TC45-driven dephosphorylation of STAT3 in the nucleus. The newly established roles of TRIM59 in EGFR-driven gliomagenesis suggest TRIM59 as a novel prognostic marker and a potential target.

Sang Y, Li Y, Song L, Alvarez AA, Zhang W, Lv D, et al. TRIM59 promotes gliomagenesis by inhibiting TC45 dephosphorylation of STAT3. Cancer Research; Published OnlineFirst January 31, 2018; doi: 10.1158/0008-5472.CAN-17-2774.

The transcription factor Myc plays a major role in hematopoiesis and is frequently deregulated in many types of human lymphoma and leukemia. Bahr and colleagues found that an evolutionarily conserved region located 1.7 megabases downstream of the MYC gene was crucial for regulation of MYC expression in both normal hematopoietic and leukemic stem cell hierarchies in mice and humans. This element comprised multiple enhancer modules with selective activity that recruited transcription factors GFI1b, RUNX1, and MYB. Deletion of individual enhancer modules in mice suggested that expression levels of MYC throughout the hematopoietic hierarchy were controlled by the combinatorial and additive activity of individual enhancer modules, collectively functioning as a ‘blood enhancer cluster’ (BENC). A BENC module showed increased chromatin accessibility in human acute myeloid leukemia stem cells compared with blasts. This difference correlated with MYC expression and patient outcome.

Expert Commentary: Identification of the role of super enhancers in human hematopoietic malignancies suggests that these could serve as targets for novel treatments.

Bahr C, von Paleske L, Uslu VV, Remeseiro S, Takayama N, Nq SW, et al. A Myc enhancer cluster regulates normal and leukaemic haematopoietic stem cell hierarchies. Nature 2018;553:515–20.

Tumor cells undergo transcriptional reprogramming to adapt to the microenvironment of the metastatic site. Morrow and colleagues performed epigenomic profiling of osteosarcoma, a bone tumor that commonly metastasizes to the lung, to assess contributions of enhancer elements to the metastatic phenotype. The authors identified loci with differential enhancer activity in primary versus metastatic tumors, termed metastatic variant enhancer loci (Met-VEL). Notably, disruption of Met-VEL–associated genes through chemical inhibition, genetic knockdown of transcription factor complexes, depletion of specific genes, or of individual Met-VELs themselves, inhibited metastatic colonization. Thus, disruption of Met-VEL activity provides a strategy for treating metastases.

Expert Commentary: This study demonstrates for the first time that the activity of enhancer elements in metastatic osteosarcoma is distinct from that in primary tumors, adding to the growing body of evidence for enhancer activity playing a functional role in progression and emphasizing the importance of the tumor microenvironment in metastasis.

Morrow JJ, Bayles I, Funnell APW, Miller TE, Saiakhova A, Lizardo MM, et al. Positively selected enhancer elements endow osteosarcoma cells with metastatic competence. Nat Med 2017;24:176–85.

FERMT1 (encoding for Kindlin-1 protein) is in a six-gene signature that distinguishes breast tumors with high likelihood for metastasis independently of molecular subtype. Kindlin-1 supports tumor growth and lung metastasis in an orthotopic mouse model of breast cancer. Sarvi and colleagues found that Kindlin-1 facilitated early pulmonary metastasis by inducing activation of integrin cell surface receptors and enhancing α4 integrin-mediated adhesion of mammary tumor cells to VCAM on the surface of endothelial cells. Inhibiting VCAM-1 reduced early pulmonary arrest of tumor cells. Kindlin-1 may also contribute to a metastatic niche, as depletion reduced secretion of metastasis-related proteins, including tenascin-C. These findings, and previous work implicating integrins as regulators of metastasis, demonstrate that integrin activity regulators contribute to metastasis in multiple ways.

Expert Commentary: These studies in Kindlin-1–deficient mice provide important mechanistic insight into the established link between Kindlin-1 expression and poor patient outcome.

Sarvi S, Patel H, Li J, Dodd GL, Creedon H, Muir M, et al. Kindlin-1 promotes pulmonary breast cancer metastasis. Cancer Res 2018;78:1484–96.

Although Hedgehog inhibitors such as vismodegib exhibit dramatic efficacy against basal cell carcinoma (BCC), resistant cells persist to drive recurrence. Eberl and colleagues identified two spatially, histologically, and functionally distinct populations of cells in BCC, one of which consisted of vismodegib-resistant basal cells and the other of more loosely organized interior cells (suprabasal) that were vismodegib sensitive. These two populations of cells differed in their Hedgehog and Notch activities. The suprabasal Hedgehog^Low;Notch^High cells marked the population of vismodegib-sensitive cells and the basal Hedgehog^High;Notch^Low cells marked the population of vismodegib-resistant cells that drove recurrence. Loss of Notch activity led to increased BCC persistence without increased vismodegib resistance. However, increased Notch activity could induce regression of established BCC.

Expert Commentary: This manuscript demonstrates the importance of three-dimensional tumor architecture to BCC persistence upon vismodegib treatment, via modulation of Notch and Hedgehog activities.

Eberl M, Mangelberger D, Swanson JB, Verhaegen ME, Harms PW, Frohm ML, et al. Tumor Architecture and Notch Signaling Modulate Drug Response in Basal Cell Carcinoma. Cancer Cell 2018;33:229–43.

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.