Therapeutic manipulation and spatial quantification of the tumor microenvironment in colorectal cancer
Eoghan J. Mulholland-Illingworth, Joshua W. Moore, Muyang Lin, Raheleh Amirkhah, Lucile Grzesiak, Amelia Ligeza, Joshua A. Bull, Joseph Boen, Gabriel N. Valbuena, Michael A. Gillespie, Tamsin R.M. Lannagan, Kathryn Gilroy, Megan L. Mills, Shania M. Corry, Rachel A. Ridgway
TL;DR
The study identifies two main types of cancer-associated fibroblasts in colorectal cancer and shows how targeting TGFβ signaling can reshape the tumor environment to improve immune response.
Contribution
A simplified framework for CAF classification and a method to measure therapeutic response through spatial metrics in CRC.
Findings
TGFβ signaling drives transitions between PDGFRA+ and ACTA2+ fibroblast states.
ALK5 inhibition shifts CAF composition and enhances T-cell presence.
Multiscale spatial analysis detects stromal drug response without tumor shrinkage.
Abstract
Colorectal cancer (CRC) is a complex ecosystem shaped by bidirectional interactions between epithelium and the tumor microenvironment, prominently mediated by TGFβ signaling. Cancer-associated fibroblasts (CAFs) are regulators of epithelial plasticity and immune cell recruitment; yet, their diversity has impacted translationally applicable spatial analysis. Here, we distil the fibroblast continuum into two overarching CAF populations that are largely transcriptomically distinct and are marked by PDGFRA+ and ACTA2+ expression, enabling robust spatial identification using single immunohistochemical markers. We show that TGFβ signaling drives dynamic transitions between these states. In a preclinical model, selective ALK5 inhibition remodels CAF composition in vivo, reconfiguring local immune neighborhoods and indirectly altering epithelial stem cell states. Finally, we demonstrate that…
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Taxonomy
TopicsCancer Cells and Metastasis · Cancer Research and Treatments · Colorectal Cancer Treatments and Studies