Fibroblast versus cancer cells – who is in control?

Intro

Myofibroblastic cancer-associated fibroblast (myCAF) activity is strongly associated with outcomes in patients with solid tumors. This session will explore the question of what comes first, fibrosis or cancer, and whether we dare to eliminate the barrier. A deep dive into the functions of the barrier generated by myCAFs will highlight its impact on the immune system and discuss how we can best translate these insights to benefit patients.

It’s not who’s in control… It’s what they’re building that matters: The matrix as a determinant of tumour progression and therapy response

Thomas R. Cox, Professor and Head of the Matrix and Metastasis Lab at the Garvan Institute of Medical Research and UNSW Sydney.

Abstract: The question of whether fibroblasts or cancer cells are “in control” presupposes a hierarchical relationship that may fundamentally misrepresent tumour-stroma dynamics. Our work suggests a more nuanced reality: control emerges not from cellular dominance but from the matrix-guided conversation between these populations, where the biochemical and biomechanical properties of the extracellular matrix serve as both the language and the ledger of this exchange.

Through temporal and spatial matrix profiling, we’ve demonstrated that matrix “activity”, characterised by dynamic termporal and spatial remodelling, crosslinking, and architectural reorganisation, regulates disease progression and therapeutic response. Furthermore, the dynamic nature of this becomes critical during therapeutic intervention, where both conventional and contemporary therapies often paradoxically induce tumour fibrosis, creating therapy-resistant, invasion-permissive niches despite apparent tumour regression.

Mechanistically, we’ve revealed that post-translational modifications such as enzymatic crosslinking, alter matrix influence through the generation of new biochemical and biomechanical cues, fundamentally rewiring cellular signalling and metabolism to support aggressive cancer phenotypes. Critically, this matrix-cell dialogue is bidirectional: with cancer cell genotype influencing the matrix produced by stromal populations, thereby creating distinct matrisome signatures, that then feedback to alter cellular phenotype whilst simultaneously modulating therapeutic vulnerability.

The temporal dimension of matrix evolution is also revealing stage-specific architectural transitions that create potentially distinct therapeutic windows. Early deposited matrix proteins establish structural frameworks that later-stage modifications then exploit, generating progressively invasion-permissive microenvironments. This temporal layering explains why assessing remodelling activity, as opposed to simply biochemical composition, may predict outcomes more accurately than cell or matrix abundance.

These implications challenge conventional stromal targeting approaches. Rather than eliminating the “stromal barrier” entirely, which can paradoxically accelerate progression, success will lie in disrupting the matrix-mediated feedback loops that sustain pathological remodelling. Normalising the matrix and/or post-translational modification, softening excessive stiffness, or targeting temporal matrix transitions offer therapeutic precision that bulk stromal depletion cannot achieve. Matrix profiling should thus guide rational co-targeting strategies, transforming the tumour-stromal conversation from pathological collaboration into therapeutic vulnerability.

Tumor-directed reprogramming of the microenvironment drives metastasis and treatment resistance in non-small cell lung cancer

Don L. Gibbons, The Isaiah J. Fidler Professor of Cancer Research, Deputy Chair and Professor at The University of Texas MD Anderson Cancer Center, Co-Leader of the Lung Cancer Moon Shot Program, Director of the Translational Genetic Models Lab

Abstract: The leading cause of cancer-related mortality is non-small cell lung cancer, which is largely due to its strong propensity to metastasize and relative treatment resistance in the metastatic setting. Both its robust metastatic phenotype and treatment resistance are caused in part by reprogramming of the tumor microenvironment to form a fibrotic collagenous extracellular matrix (ECM). During normal tumor progression and in response to many treatment strategies tumor cells undergo dedifferentiation via an epithelial-mesenchymal transition (EMT) that enhances collagen expression, crosslinking and deposition by tumor cells, a differential secretory phenotype and recruitment of cancer-associated fibroblasts. The combined effect of these coordinate tumor cell changes facilitates tumor cell survival, local invasion and distant metastasis. Simultaneously, the remodeled ECM is suppressive of tumor immune surveillance and effector T cell function. We are studying strategies to reverse or block the ECM remodeling or reactivate effector immune cell function despite a hostile ECM environment to improve treatment options for patients with non-small cell lung cancer.