Functional diversity and cooperativity between subclonal populations of pediatric glioblastoma and diffuse intrinsic pontine glioma cells

Abstract

The failure to develop effective therapies for pediatric glioblastoma (pGBM) and diffuse intrinsic pontine glioma (DIPG) is in part due to their intrinsic heterogeneity. We aimed to quantitatively assess the extent to which this was present in these tumors through subclonal genomic analyses and to determine whether distinct tumor subpopulations may interact to promote tumorigenesis by generating subclonal patient-derived models in vitro and in vivo. Analysis of 142 sequenced tumors revealed multiple tumor subclones, spatially and temporally coexisting in a stable manner as observed by multiple sampling strategies. We isolated genotypically and phenotypically distinct subpopulations that we propose cooperate to enhance tumorigenicity and resistance to therapy. Inactivating mutations in the H4K20 histone methyltransferase KMT5B (SUV420H1), present in <1% of cells, abrogate DNA repair and confer increased invasion and migration on neighboring cells, in vitro and in vivo, through chemokine signaling and modulation of integrins. These data indicate that even rare tumor subpopulations may exert profound effects on tumorigenesis as a whole and may represent a new avenue for therapeutic development. Unraveling the mechanisms of subclonal diversity and communication in pGBM and DIPG will be an important step toward overcoming barriers to effective treatments.

Modulating autophagy as a therapeutic strategy for the treatment of paediatric high‐grade glioma

“…These data raised the interesting hypothesis that pHGG tumors have a requirement on a basal level of autophagy to provide sufficient energy and metabolic precursors for their continued growth and division. These observations and hypotheses are supported by published data that glial tumors exploit low level autophagy for nutrient cycling, whereas healthy brain tissues do not . This proposed reliance on basal autophagy represents an important therapeutic vulnerability, and a possible route to sensitizing glioma cells to therapeutic interventions.…”

Branched evolution and genomic intratumor heterogeneity in the pathogenesis of cutaneous T-cell lymphoma

“…It is likely that such ancestor clones may become extinct during the progression of the tumor and are no longer detectable, a phenomenon which was described during the evolution of another highly heterogeneous tumor, the glioblastoma. 44 Finally, we would like to propose a model for the pathogenesis of MF that accounts for the previously found clonotypic heterogeneity [19][20][21] and the ITH described here (Fig 7) . ITH is readily detectable in ESP, which testifies to the history of mutational tumor evolution before seeding of neoplastic cells in the skin.…”

“…However, it is worthwhile to mention here that even subclonal mutations may present with drug targeting opportunities if the given subclone is important for the progression of the entire tumor. Cooperativity between distinct subclones was described for some metastasizing tumors [42][43][44] , and it was proposed that disruption of clonal cooperation might be an interesting therapeutic approach. Especially the targeting of Wnt and Hedgehog seems to be promising 42 , the pathway which we show here to be frequently mutated in MF (genes MACF1 , PTCH1 , RNF43 ).…”

Transient Commensal Clonal Interactions Can Drive Tumor Metastasis

“…Several studies in mouse models and in Drosophila have demonstrated that subpopulations of cells can cooperate to induce tumor growth [7][8][9] and metastasis [10][11][12][13][14][15] . In diffuse intrinsic pontine glioma, Vinci and colleagues 16 identified a cooperative mechanism between H4K20 methyltransferase-wild-type and -mutant subpopulations that promotes invasion. In all of the aforementioned studies, either specific tumor subpopulations with pre-defined markers or genetically-engineered subclonal populations were examined.…”