Fascinating paper on the connections between fibrotic colon tissue and early onset (EO) CRC. The authors discuss "early and widespread biomechanical remodeling, suggesting that a fibrotic and stiffened tissue microenvironment may orchestrate EO CRC tumor initiation." Looks like leronlimab can add another MOA to it's already substantial toolkit against the various instigators of colorectal cancer. From the abstract:
"This study tests the hypothesis that fibrotic remodeling and biomechanical stiffening of colorectal tissues represent measurable hallmarks and potential drivers of EO CRC. Using primary human tissues, this work shows that EO CRC is associated with changes in collagen microstructure, increased stiffness, and elevated viscosity of primary tumors. Spatial transcriptional profiling and immunostaining reveal pro-fibrotic signatures in stromal cells, alongside enhanced Yes-associated protein (YAP) mechanotransduction and proliferation in epithelial cells of EO CRC tissues. Mechanistically, increasing matrix stiffness in vitro promotes proliferation of epithelial cells in 2D and 3D colorectal cancer models. Together, these findings establish EO CRC as a disease marked by early and widespread biomechanical remodeling, suggesting that a fibrotic and stiffened tissue microenvironment may orchestrate EO CRC tumor initiation."
Discussion of the "tumor microenvironment" suddenly gets more complex when you start digesting this information. And yet again... leronlimab/CCR5 blockade seems to have an answer for this complexity by inhibiting fibrosis in a "stiffened tissue microenvironment". Who would have thunk? Another argument for utilizing leronlimab in first-line CRC. And they mention a fibrotic element in breast and pancreatic cancer as well. Here's another passage:
"The tumor microenvironment (TME) undergoes profound alterations during colorectal carcinogenesis, with extracellular matrix (ECM) remodeling emerging as a central feature that influences cancer progression. Activation of tissue-resident fibroblasts drives the deposition and reorganization of a collagen-rich ECM, fundamentally altering the biomechanical properties of tissues. These ECM modifications create a mechanically distinct microenvironment characterized by increased tissue stiffness and altered matrix architecture. In breast and pancreatic cancers, such microenvironmental remodeling has been demonstrated to drive malignant phenotypes through mechanotransduction and altered cell-matrix interactions."
Lots of information--that is new to me--in this paper... Like, what's up with YAP, a reference I've come across before--"pro-fibrotic signatures in stromal cells, alongside enhanced Yes-associated protein (YAP) mechanotransduction and proliferation in epithelial cells of EO CRC tissues." Microenvironmental remodeling in breast and pancreatic cancers--any CCR5 connection there, ya think? And discussion of left-handed tumors and right-handed tumors in CRC... Any reason to believe leronlimab works better in one or another? Should Cytodyn be screening for the handedness of the tumor? The paper answers some really important questions about fibrosis and colon cancer... and yet, as breakthrough academic work often does, it brings up additional queries.
With respect to Cytodyn, are they keeping up with this new research and incorporating it into new biomarkers they can introduce into the conversation between leronlimab, colon cancer, and the FDA? How might early onset CRC differ from adult onset CRC, and will leronlimab, via it's multi-faceted MOA, handle both? (With an ICI, of course). Most importantly in my mind, is there a need to screen out early onset CRC patients from adult onset cases in any later clinical trials? Those with left-handed tumors, or right? I don't want to see any surprises AT ALL in our registrational trials... Seems like the biomarkers are there for the measuring...
"In this study, we identify tissue stiffening and fibrotic remodeling as consistent biophysically measurable hallmarks of EO CRC. Furthermore, we link these mechanical changes to collagen remodeling in the colonic stroma and to mechanobiological changes in the colonic epithelium."
Huning et al in the Dec 1st 2025 issue of "Advanced Science"
https://advanced.onlinelibrary.wiley.com/doi/....202514693
"This study tests the hypothesis that fibrotic remodeling and biomechanical stiffening of colorectal tissues represent measurable hallmarks and potential drivers of EO CRC. Using primary human tissues, this work shows that EO CRC is associated with changes in collagen microstructure, increased stiffness, and elevated viscosity of primary tumors. Spatial transcriptional profiling and immunostaining reveal pro-fibrotic signatures in stromal cells, alongside enhanced Yes-associated protein (YAP) mechanotransduction and proliferation in epithelial cells of EO CRC tissues. Mechanistically, increasing matrix stiffness in vitro promotes proliferation of epithelial cells in 2D and 3D colorectal cancer models. Together, these findings establish EO CRC as a disease marked by early and widespread biomechanical remodeling, suggesting that a fibrotic and stiffened tissue microenvironment may orchestrate EO CRC tumor initiation."
Discussion of the "tumor microenvironment" suddenly gets more complex when you start digesting this information. And yet again... leronlimab/CCR5 blockade seems to have an answer for this complexity by inhibiting fibrosis in a "stiffened tissue microenvironment". Who would have thunk? Another argument for utilizing leronlimab in first-line CRC. And they mention a fibrotic element in breast and pancreatic cancer as well. Here's another passage:
"The tumor microenvironment (TME) undergoes profound alterations during colorectal carcinogenesis, with extracellular matrix (ECM) remodeling emerging as a central feature that influences cancer progression. Activation of tissue-resident fibroblasts drives the deposition and reorganization of a collagen-rich ECM, fundamentally altering the biomechanical properties of tissues. These ECM modifications create a mechanically distinct microenvironment characterized by increased tissue stiffness and altered matrix architecture. In breast and pancreatic cancers, such microenvironmental remodeling has been demonstrated to drive malignant phenotypes through mechanotransduction and altered cell-matrix interactions."
Lots of information--that is new to me--in this paper... Like, what's up with YAP, a reference I've come across before--"pro-fibrotic signatures in stromal cells, alongside enhanced Yes-associated protein (YAP) mechanotransduction and proliferation in epithelial cells of EO CRC tissues." Microenvironmental remodeling in breast and pancreatic cancers--any CCR5 connection there, ya think? And discussion of left-handed tumors and right-handed tumors in CRC... Any reason to believe leronlimab works better in one or another? Should Cytodyn be screening for the handedness of the tumor? The paper answers some really important questions about fibrosis and colon cancer... and yet, as breakthrough academic work often does, it brings up additional queries.
With respect to Cytodyn, are they keeping up with this new research and incorporating it into new biomarkers they can introduce into the conversation between leronlimab, colon cancer, and the FDA? How might early onset CRC differ from adult onset CRC, and will leronlimab, via it's multi-faceted MOA, handle both? (With an ICI, of course). Most importantly in my mind, is there a need to screen out early onset CRC patients from adult onset cases in any later clinical trials? Those with left-handed tumors, or right? I don't want to see any surprises AT ALL in our registrational trials... Seems like the biomarkers are there for the measuring...
"In this study, we identify tissue stiffening and fibrotic remodeling as consistent biophysically measurable hallmarks of EO CRC. Furthermore, we link these mechanical changes to collagen remodeling in the colonic stroma and to mechanobiological changes in the colonic epithelium."
Huning et al in the Dec 1st 2025 issue of "Advanced Science"
https://advanced.onlinelibrary.wiley.com/doi/....202514693
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