GYF-pixel/Pp1-87B-PPP1CA-Induced-Tumor-Promoting-Cell-Competition: Tumors Exploit Interclonal Hedgehog-Wnt Crosstalk to Drive Tumor-Promoting Cell Competition

Engineering notes

https://www.ncbi.nlm.nih.gov/bioproject/PRJNA1259382/ Full Changelog: https://github.com/GYF-pixel/Pp1-87B-PPP1CA-Induced-Tumor-Promoting-Cell-Competition/commits/Inter-clonal

Chinese explanation / 中文解读

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Original abstract

Tumors Exploit Interclonal Hedgehog-Wnt Crosstalk to Drive Tumor-Promoting Cell Competition Summary: Intratumoral heterogeneity (ITH) is a hallmark of cancer that drives progression, therapy resistance, and relapse. While single-cell technologies have illuminated interactions between tumor cells and their microenvironment, the mechanisms by which genetically distinct subclones cooperate to exploit competition for oncogenic advantage remain elusive. Here, using Drosophila genetics and mammalian models, we reveal how tumors hijack interclonal Hedgehog (Hh)-Wnt signaling to convert competition into a tumor-progressive force. In Drosophila eye epithelia, clonal depletion of the phosphatase Pp1-87B in RAS-mutant cells triggers a competitive hierarchy: Pp1-87B-deficient "loser" clones activate Hh signaling, driving their elimination via JNK-mediated apoptosis while secreting Wingless (Wg) to hyperactivate β-catenin in neighboring RAS "winner" clones. This Hh-Wnt crosstalk reprograms "winners" into hyperproliferative, motile super-competitors that fuel tissue invasion. Strikingly, this mechanism is conserved in human cancer. Depletion of PPP1CA, the mammalian Pp1-87B ortholog, in KRAS-mutant pancreatic ductal adenocarcinoma (PDAC) cells induces analogous Hh-Wnt synergy, accelerating tumor growth in xenograft models. Together, our study elucidates an uncharacterized paradoxical role for cell competition in ITH, wherein distinct tumor clones exploit conserved Hh-Wnt signaling to transform competition into a tumor progressive force. These findings reveal therapeutic vulnerabilities in heterotypic tumor ecosystems and position interclonal signaling pathways as potential targets to dismantle oncogenic cooperation. Keywords: Intratumoral heterogeneity, Interclonal communication, Tumor-promoting cell competition, Drosophila, Ras, Hedgehog, WNT, Pp1-87B/PPP1CA, PDAC Multi-omics data analysis encompasses: 1. Drosophila FACS Bulk RNA-seq FACS-sorted GFP+ and GFP− cells were isolated from WT//WT, WT//Ras, and WT//Ras+Pp1-87B intercellular crosstalk-induced non-cell-autonomous overgrowth models for bulk RNA-seq analysis. 2. Drosophila FACS Bulk ATAC-seq FACS-sorted GFP+ and GFP− cells were isolated from WT//WT, WT//Ras, and WT//Ras+Pp1-87B intercellular crosstalk-induced non-cell-autonomous overgrowth models for bulk ATAC-seq analysis. 3. Human cancer cell FACS PDX Bulk RNA-seq Genetically engineered human PDAC cell lines were subcutaneously implanted, and GFP+ and mCherry+ cancer cells were harvested via FACS for bulk RNA-seq analysis. 4. Human cancer cell PDX scRNA-seq Genetically engineered human PDAC cell lines were subcutaneously implanted, and whole tummors were harvested for scRNA-seq analysis. For more information, please read our paper: The sequencing data can be downloaded freely, and codes developed for this study are provided. https://www.ncbi.nlm.nih.gov/bioproject/PRJNA1259382/ Full Changelog: https://github.com/GYF-pixel/Pp1-87B-PPP1CA-Induced-Tumor-Promoting-Cell-Competition/commits/Inter-clonal

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