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A Modular Master Regulator Landscape Controls Cancer Transcriptional Identity

Paul et al., Cell. 2021.

https://www.sciencedirect.com/science/article/pii/S0092867420316172

The mechanisms linking genomic alterations to transcriptional identity of cancer cells remain elusive. Integrative genomic analysis, using a network-based approach, identified 407 master regulator (MR) proteins responsible for canalizing the genetics of individual samples from 20 cohorts in The Cancer Genome Atlas into 112 transcriptionally distinct tumor subtypes. MR proteins could be further organized into 24 pan-cancer, MR block modules (MRBs), each regulating key cancer hallmarks and predictive of patient outcome in multiple cohorts. Of all somatic alterations detected in each individual sample, >50% were predicted to induce aberrant MR activity, yielding insight into mechanisms linking tumor genetics and transcriptional identity and establishing non-oncogene dependencies. Genetic and pharmacological validation assays confirmed the predicted effect of upstream mutations and MR activity on downstream cellular identity and phenotype. Thus, co-analysis of mutational and gene expression profiles identified elusive subtypes and provided testable hypothesis for mechanisms mediating the effect of genetic alterations. Supported by ORIP (S10OD012351 and S10OD021764) and NCI.

Intra-Strain Genetic Variation of Platyfish (Xiphophorus maculatus) Strains Determines Tumorigenic Trajectory

Lu et al., Frontiers in Genetics . 2020.

https://www.frontiersin.org/articles/10.3389/fgene.2020.562594/full

Xiphophorus interspecies hybrids represent a valuable model system to study heritable tumorigenesis. Although the ancestors of the two X. maculatus parental lines, Jp163 A and Jp163 B, were siblings produced by the same mother, backcross interspecies hybrid progeny between X. hellerii and X. maculatus Jp163 A develop spontaneous melanoma initiating at the dorsal fin due to a regulator encoded by the X. maculatus genome; the backcross hybrid progeny with X. hellerii or X. couchianus and Jp163 B exhibit melanoma on their flanks. Comparative genomic analyses revealed genetic differences are associated with pathways highlighting fundamental cellular functions. Disruption of these baselines may give rise to spontaneous or inducible tumorigenesis. Supported by ORIP (R24OD011120), NCI, and NIGMS.

Induction and Characterization of Pancreatic Cancer in a Transgenic Pig Model

Boas et al., PLOS One. 2020.

https://journals.plos.org/plosone/article?id=10.1371/journal.pone.0239391

Preclinical testing of new therapies for pancreatic cancer has been challenging due to lack of a suitable large animal model. Pigs, however, have similar physiology and immune response to humans. Boas et al report the development of a porcine model for pancreatic cancer. H&E and immunohistochemical stains revealed undifferentiated carcinomas, like those of human pancreatobiliary systems. In several pigs, angiographies revealed that the artery supplying the pancreatic tumor could be catheterized using a 2.4 F microcatheter. In summary, pancreatic cancer can be induced in a transgenic pig, and intra-arterial procedures using catheters designed for human interventions were feasible in this model. Supported by ORIP (U42OD011140) and NCI.