Astrocytic trans-Differentiation Completes a Multicellular Paracrine Feedback Loop Required for Medulloblastoma Tumor Growth

Abstract

The tumor microenvironment (TME) is critical for tumor progression. However, the establishment and function of the TME remain obscure because of its complex cellular composition. Using a mouse genetic system called mosaic analysis with double markers (MADMs), we delineated TME evolution at single-cell resolution in sonic hedgehog (SHH)-activated medulloblastomas that originate from unipotent granule neuron progenitors in the brain. First, we found that astrocytes within the TME (TuAstrocytes) were trans-differentiated from tumor granule neuron precursors (GNPs), which normally never differentiate into astrocytes. Second, we identified that TME-derived IGF1 promotes tumor progression. Third, we uncovered that insulin-like growth factor 1 (IGF1) is produced by tumor-associated microglia in response to interleukin-4 (IL-4) stimulation. Finally, we found that IL-4 is secreted by TuAstrocytes. Collectively, our studies reveal an evolutionary process that produces a multi-lateral network within the TME of medulloblastoma: a fraction of tumor cells trans-differentiate into TuAstrocytes, which, in turn, produce IL-4 that stimulates microglia to produce IGF1 to promote tumor progression.

Fragmentation of Small-cell Lung Cancer Regulatory States in Heterotypic Microenvironments

“…The documented cell-state changes upon liver colonization could simply reflect the injury-like state of tumors and metastases (12). Alternatively, the reprogramming events could provide trophic support to the cellular ecosystem (7,18). The candidate heterogeneities identified by stochastic profiling and 10cRNA-seq create a resource to guide future functional studies that perturb specific emergent heterogeneities in vivo.…”

“…Within normal tissues, single cells differ by lineage type and regulatory state (2). These distinctions blur, however, when cells lose their proper context because of tissue damage (3,4), transformation (5)(6)(7), or metastatic colonization (8,9). The details of such adaptive heterogeneity are expected to depend heavily on the originating cell type, the state of the cell when perturbed, and the local microenvironment where the cell resides.…”

A Genome-wide Library of MADM Mice for Single-Cell Genetic Mosaic Analysis

“…Most prominently, tumor formation and the delineation of cancer cell of origin at single cell level upon the introduction of mutations in tumor suppressor genes and/or loss of heterozygosity has been studied (Gonzalez et al 2018;Liu et al 2011;Muzumdar et al 2016;Muzumdar et al 2007;Yao et al 2020).…”

“…Cells that are homozygous mutant for a candidate tumor suppressor gene are uniquely labeled and can be followed dynamically in vivo to study tumor progression and metastasis and/or to assay for the effects of therapeutic agents. As such, MADM has been used for the analysis of tumor formation and the delineation of cancer cell of origin at single cell level in the brain and distinct organs (Gonzalez et al 2018;Liu et al 2011;Muzumdar et al 2016;Muzumdar et al 2007;Yao et al 2020). MADM could in principle be exploited to systematically study the loss of any tumor suppressor in the entire genome and for identifying the cellular origins of a wide variety of cancers.…”

PremalignantNf1, Trp53-null Oligodendrocyte Precursor Cells Become Stalled in a Heterogeneous State of Replication Stress Before Gliomagenesis

“…However, an earlier attempt to enrich OPCs by flow sorting (28) yielded fewer transcript alignments compared to other methods (18). Therefore, we used fluorescence-guided LCM under conditions of cryoembedding, sectioning, and fixation that retained tdTomato fluorescence and RNA integrity in labeled cells (18,29). Nf1-Trp53 deletion should cause not only population-wide changes in gene expression compared to control OPCs by bulk analysis, but also single-cell variations in transcript abundance requiring the stochastic-profiling method developed by our group (17,19).…”