Faculty Publications

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    An Enhancer-Driven Stem Cell–Like Program Mediated by SOX9 Blocks Intestinal Differentiation in Colorectal Cancer
    (W.B. Saunders, 2022) Liang, X.; Duronio, G.N.; Yang, Y.; Bala, P.; Hebbar, P.; Spisák, S.; Sahgal, P.; Singh, H.; Zhang, Y.; Xie, Y.; Cejas, P.; Long, H.W.; Bass, A.J.; Sethi, N.S.
    Background and Aims: 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 therefore aimed to characterize a key factor that blocks intestinal differentiation, define its transcriptional and epigenetic program, and provide preclinical evidence for therapeutic targeting in CRC. Methods: Intestinal tissue from transgenic mice and patients were analyzed by means of histopathology and immunostaining. Human CRC cells and neoplastic murine organoids were genetically manipulated for functional studies. Gene expression profiling was obtained through RNA sequencing. Histone modifications and transcription factor binding were determined with the use of chromatin immunoprecipitation sequencing. Results: We demonstrate 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 demonstrate ectopic and elevated expression of SOX9. Functional experiments indicate a requirement for SOX9 in human CRC cell lines and engineered neoplastic organoids. Disrupting SOX9 activity impairs primary CRC tumor growth by inducing intestinal differentiation. By binding to genome wide enhancers, SOX9 directly activates genes associated with Paneth and stem cell activity, including prominin 1 (PROM1). SOX9 up-regulates PROM1 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. Conclusions: These studies establish SOX9 as a central regulator of an enhancer-driven stem cell–like program and carry important implications for developing therapeutics directed at overcoming differentiation defects in CRC. © 2022
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    Amidated pectin and gum Arabic aldehyde-based pH-sensitive hydrogel for targeted colonic treatment
    (Elsevier B.V., 2025) Singh, H.; JagadeeshBabu, J.; Mohan Balakrishnan, R.
    In this study, a novel pH-responsive hydrogel was developed by crosslinking amidated pectin(AmPec) with oxidised gum Arabic(GAA) by hydrogen and hemiacetal bonding without the need for toxic crosslinkers for oral delivery of doxorubicin to treat colon cancer. FTIR and NMR confirmed the amidation of pectin and oxidation of Gum Arabic. FTIR confirmed the formation of hydrogen and hemiacetal bonds in the hydrogel. X-ray diffraction(XRD) spectra showed the amorphous characteristic of AmPec-GAA hydrogels compared to their polymer precursors, confirming the formation of a crosslinked hydrogel. AmPec-GAA15 hydrogel swelled around 655 %±39.90 at pH 7.4 compared to 181 %±7.94 swelling at pH 1.2 after 72 h. The release of doxorubicin also followed the same trend, with only 4.48 % ±0.89 doxorubicin release at pH 1.2, while the drug release increased to 68.10 %±3.73 at pH 7.4 after 48 h. SEM micrographs revealed the macroporous and interconnected hydrogel structure with fewer pores in the hydrogel swelled in pH 1.2 compared with pH 7.4, where more visible pores were observed, indicating the pH-sensitive behaviour of the hydrogel. Hydrogel possessed excellent thermal and mechanical stability as revealed by TGA and rheology study, which can also be explored for tissue engineering applications. MTT assay on L929 cells showed cell viability above 95.1 %±,0.0074, demonstrating hydrogels' non-toxic and biocompatible behaviour. Meanwhile, Dox-loaded hydrogel induced higher cytotoxicity against HT-29 cells than free Dox in a dose-dependent manner. Therefore, the developed hydrogel can be used as an effective oral carrier to deliver doxorubicin to colon cancer while hindering its release in the stomach and thus preventing associated toxicity. © 2025 Elsevier B.V.