Highlights from Recent Cancer Literature
Journal: Cancer Research (2021)

The pancreatic tumor microenvironment is highly inflammatory, but the contribution of inflammation to the early development of pancreatic cancer is still not well defined. Del Poggetto and colleagues demonstrated that inflammation-induced changes primed acinar cells for pancreatic cancer development. Using an inducible allele of oncogenic Kras in mice and the pancreatic inflammatory mediator caerulein, the authors demonstrated that long after the inflammatory response had cleared, acinar cells retained altered gene expression and chromatin profiles that heightened susceptibility to transformation. The EGR1 transcription factor was critical for accelerated tumorigenesis with KRAS activation, and its expression was induced by coculture with immune cells from the inflamed pancreas via IL6 signaling. Activation of the Ras–MAPK pathway was shown as an adaptive response to inflammation to reduce tissue damage. Inflammation promoted Ras–MAPK-driven acinar-to-ductal cell state changes to reduce production of acinar zymogens that promoted cell death. Thus, pancreatic epithelial changes that protect the tissue from damage ultimately promote cancer.Expert Commentary: Pancreatic inflammation drives a long-lasting tissue damage protective response by priming the Ras–MAPK pathway, increasing susceptibility to KRAS-mediated transformation.Del Poggetto E, Ho IL, Balestrieri C, Yen EY, Zhang S, Citron F, et al. Epithelial memory of inflammation limits tissue damage while promoting pancreatic tumorigenesis. Science 2021;373:eabj0486.The H3K9 methyltransferase SETDB1 epigenetically silences expression of endogenous retroviral elements (ERV), whose expression in cancer cells generates antigenic epitopes recognizable by T cells. Zhang and colleagues reported that the lysine demethylase KDM5B is critical for enabling SETDB1 to restrain ERV expression and limit immune responses in tumors. KDM5B expression correlated inversely with immune cell signatures and response of melanoma patients to checkpoint blockade immunotherapy. CRISPR-mediated deletion of Kdm5b in mouse tumor cells led to complete rejection of transplanted tumors, dependent on adaptive immunity. Kdm5b deletion activated both RNA (MDA5/MAVS)- and DNA (cGAS/STING)-dependent sensors, inducing interferon-stimulated genes to initiate an immune response driven by the endogenous retrovirus MMLV30. Interestingly, demethylase activity of KDM5B was not required to suppress ERVs. Instead, KDM3B bound the H3K9 methyltransferase SETDB1, guiding it to silence target sites.Expert Commentary: The demethylase KDM5B provides a crucial link for epigenetic silencing of ERVs in cancer cells by directing the H3K9 methyltransferase SETDB1 throughout the genome.Zhang SM, Cai WL, Liu X, Thakral D, Luo J, Chan LH, et al. KDM5B promotes immune evasion by recruiting SETDB1 to silence retroelements. Nature 2021;598:682–7.Human gliomas frequently exhibit tumor cells with transcriptionally unique cell states, which cannot be accounted for by genetic diversity, suggesting that epigenetic mechanisms may be an important contributor to plasticity. Chaligne and colleagues used combined methylomics and transcriptomics in single cells to reveal patterns of methylation that differ between stem-like and differentiated cells in brain tumors. These patterns also differed by mutational class, with glioblastomas exhibiting hypomethylation of PRC2 targets in stem-like cells and IDH1/2-mutant gliomas distinguished by hypermethylation of enhancers in differentiated cells. These data suggest distinct cellular trajectories occur during tumor growth. Using heritable, stochastic DNA methylation changes as a “clock,” the authors constructed lineage trees for individual tumors and found that glioblastoma cells had a higher capacity to dedifferentiate than IDH1/2-mutant gliomas, which exhibited more self-renewal of stem-like cells.Expert Commentary: These findings begin to connect epigenetic, transcriptional, and functional cell states in gliomas, demonstrating that many heterogeneous states are present and underscoring the unique lineages that exist between IDH-mutant gliomas and glioblastoma.Chaligne R, Gaiti F, Silverbush D, Schiffman JS, Weisman HR, Kluegel L, et al. Epigenetic encoding, heritability and plasticity of glioma transcriptional cell states. Nature Genetics 2021;53:1469–79.The tumor microenvironment (TME) plays a pivotal role in regulating tumor progression and response to therapy. Recent studies have highlighted the cellular complexity within the TME, and Grünwald and colleagues have identified distinct TME phenotypes that can co-occur within the same tumor in a spatially confined manner, depending on the presence of different categories of cancer-associated fibroblasts. Two main stromal microenvironments with distinct tumor-promoting and chemoprotective roles were identified in pancreatic ductal adenocarcinoma (PDAC), where sub-tumor microenvironment co-occurrence was linked to poor patient survival. The two main categories of TME characterized were a chemosensitive reactive subTME with high immune cell signatures and tumor-promoting properties, and a chemo-protective extracellular matrix–rich deserted subTME.Expert Commentary: This study suggests that different sub-tumor microenvironments within a tumor act in concert to drive aggressive tumor phenotypes. Further definition of these microenvironments and whether they exist in other tumor types is now required.Grünwald BT, Devisme A, Andrieux G, Vyas F, Aliar K, McCloskey CW, et al. Spatially confined sub-tumor microenvironments in pancreatic cancer. Cell 2021;184:5577–92.e18.Cytology for malignant cells, a mainstay of staging and monitoring in medulloblastoma, is relatively insensitive and lacks genomic correlates. To determine the utility of minimally invasive monitoring in medulloblastoma, Liu and colleagues performed an integrated genomic study of cell-free DNA (cfDNA) derived from cerebrospinal fluid, including longitudinal samples. Low coverage whole-genome sequencing revealed that minimal residual disease after therapy correlated inversely with outcome, irrespective of molecular subgroup or the presence of metastatic disease at diagnosis. In several instances, high-risk features such as MYC amplification were detected in cfDNA but not in the primary tumor, supporting dissemination of early clones. Moreover, cfDNA profiles of recurrent disease were in many cases disparate from the primary tumor, further supporting previous observations of drastic clonal divergence at recurrence.Expert Commentary: Current cytological methods are crude and lack sensitivity. This elegant study changes the landscape of medulloblastoma and opens the possibility of incorporating leukemia-style surveillance and maintenance therapy into routine clinical care.Liu APY, Smith KS, Kumar R, Paul L, Bihannic L, Lin T, et al. Serial assessment of measurable residual disease in medulloblastoma liquid biopsies. Cancer Cell 2021;39:1519–1530.e4.Many pediatric neuroblastomas amplify MYCN in sympathetic progenitors and also feature a super-enhancer–driven core regulatory circuit (CRC) of transcription factors, which define the neuroblastoma cell identity. The vitamin A derivate retinoic acid (RA) inhibits growth and induces differentiation in neuroblastomas with an adrenergic CRC identity. Zimmerman and colleagues combined transcriptional and chromatin assays to show that RA reprogrammed the super-enhancer landscape via altering histone acetylation and methylation in MYCN-amplified neuroblastoma. The new “retino-sympathetic” CRC downregulated MYCN, GATA3, PHOX2B, and ASCL1 and induced MEIS1 and SOX4, blocking proliferation and inducing differentiation. The authors also demonstrated that tumors driven by “enhancer-hijacked” MYCN failed to downregulate MYCN and these tumors were resistant to RA treatment.Expert Commentary: This study provides mechanisms of action for retinoic acid treatment, explains why some high-risk patients benefit while others do not, and opens novel strategies to overcome therapy resistance.Zimmerman MW, Durbin AD, He S, Oppel F, Tao T, Li Z, et al. Retinoic acid rewires the adrenergic core regulatory circuitry of childhood neuroblastoma. Sci Adv. 2021;7:eabe0834.