DISEASE MODELS
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We recently built a new mouse model that combines early genetic alterations with disease-relevant dietary carcinogens to study gastric premalignancy. Using this model, we learned that early TP53 alterations ultimately lead to premalignant lesions that have a selective pressure to alter a cell cycle regulator. Although this second alteration enabled disease progression, it also yielded a therapeutic vulnerability.
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After realizing that hypoxia transcriptional programs may be heightened in p53 mutant gastric and esophageal adenocarcinomas, we designed an in vivo system to measure hypoxia activity in real-time during xenograft tumor growth. Using this system, we were able to identify a new dependency in these deadly cancers. |
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Background: As the most regenerative epithelium in the human body, the intestine requires rapidly dividing stem cells to give rise to differentiated cell types that serve digestive functions before dying. Genomic alterations that encourage stem cell activity and hinder proper maturation are central to the development of colorectal cancer (CRC). Key molecular mediators that promote these malignant properties require further elucidation to galvanize translational advances. We identified and characterized a key factor that blocks intestinal differentiation, defined its transcriptional and epigenetic program, and provided preclinical evidence for therapeutic targeting in CRC.
Findings: We demonstrated that SRY-box transcription factor 9 (SOX9) promotes CRC by activating a stem cell–like program that hinders intestinal differentiation. Intestinal adenomas and colorectal adenocarcinomas from mouse models and patients demonstrated ectopic and elevated expression of SOX9. Functional experiments indicated that SOX9 is a dependency human CRC cell lines and engineered neoplastic organoids. SOX9 is necessary and sufficient to block differentiation in CRC models. By binding to genome wide enhancers, SOX9 directly activated genes associated with Paneth and stem cell activity, including prominin 1 (PROM1). SOX9 directly activated PROM1 expression via a WNT-responsive intronic enhancer. A pentaspan transmembrane protein, PROM1 uses its first intracellular domain to support stem cell signaling, at least in part through SOX9, reinforcing a PROM1-SOX9 positive feedback loop. Genetic suppression of SOX9 or its downstream target PROM1 impaired primary tumor growth in vivo by inducing intestinal differentiation. Significance: Our findings uncover fundamental molecular mechanisms driving cancer initiation within the rapidly renewing epithelium of the colon. We identify SOX9 as a master regulator of an enhancer-driven stem cell-like program, orchestrating a transcriptional network that actively suppresses intestinal differentiation. By delineating the key molecular players of this self-reinforcing circuit, we position SOX9 as a pivotal therapeutic target. These insights have broader implications for the development of novel treatment strategies aimed at overcoming differentiation defects in CRC. Liang et al., Gastroenterology, 2022 |
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Background: Cell state plasticity, the ability of cells to acquire new states via differentiation programs, is a critical cellular feature of embryogenesis, allowing for tissue specification during development, and adult homeostasis, enabling tissue repair and regeneration. Recent studies have highlighted that unrestricted cellular plasticity underlies neoplastic initiation, molecular heterogeneity, and suboptimal response to therapy, earning recognition as a new hallmark of cancer. The aberrant expansion of the normally restricted capability for cell state plasticity in neoplasia is poorly defined.
Findings: Using genetically engineered and carcinogen-induced mouse models of intestinal neoplasia, we observed that impaired differentiation is a conserved event preceding cancer development. Single-cell RNA sequencing (scRNA-seq) of premalignant lesions from mouse models and a patient with hereditary polyposis revealed that cancer initiates by adopting an aberrant transcriptional state characterized by regenerative activity, marked by Ly6a (Sca-1), and reactivation of fetal intestinal genes, including Tacstd2 (Trop2). Genetic inactivation of Sox9 in a mouse model of CRC initiation prevented adenoma formation, obstructed the emergence of regenerative and fetal programs, and restored multilineage differentiation by scRNA-seq. Expanded chromatin accessibility at regeneration and fetal genes upon Apc inactivation was reduced by concomitant Sox9 suppression. SOX9 demonstrates greater genome-wide occupancy at stem cell and fetal genes in paired adenoma compared to normal organoids derived from a patient with hereditary polyposis. Suppression of SOX9 in patient-derived adenoma organoids interfered with fetal gene expression and promoted differentiation. Significance: Our study reveals that the reactivation of a fetal intestinal program is a pivotal driver of an aberrant transcriptional state that impairs differentiation and enhances cell state plasticity prior to cancer development. By establishing that SOX9 is indispensable for orchestrating this fetal reprogramming, we further validate its role as a compelling therapeutic target in CRC, offering new opportunities to disrupt early disease progression. Bala*, Rennhack et al., Science Advances, 2023 |
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