The impact of tumor stromal architecture on therapy response and clinical progression

Abstract

Advances in molecular oncology research culminated in the development of targeted therapies that act on defined molecular targets either on tumor cells directly (such as inhibitors of oncogenic kinases), or indirectly by targeting the tumor microenvironment (such as anti-angiogenesis drugs). These therapies can induce strong clinical responses, when properly matched to patients. Unfortunately, most targeted therapies ultimately fail as tumors evolve resistance. Tumors consist not only of neoplastic cells, but also of stroma, whereby "stroma" is the umbrella term for non-tumor cells and extracellular matrix (ECM) within the tumor microenvironment, possibly excluding immune cells 1 . We know that tumor stroma is an important player in the development of resistance. We also know that stromal architecture is spatially complex, differs from patient to patient and changes with therapy. However, to this date we do not understand the link between spatial and temporal changes in stromal architecture and response of tumors to therapy, in space and time. In this project we sought to address this gap of knowledge using a combination of mathematical and statistical modeling, experimental in vivo studies, and analysis of clinical samples in therapies that target tumor cells directly (in lung and breast cancers) and indirectly (in kidney cancer). This knowledge will inform therapy choices and offer new angles for therapeutic interventions. Our main question is: how does spatial architecture of stroma impact the emergence or evolution of resistance to targeted therapies, and how can we use this knowledge clinically?

Cancer-Associated Fibroblasts: Implications for Cancer Therapy

“…Fibroblasts can influence the vast majority of the mechanisms mentioned above by either (1) supporting specific subpopulations of cancer cells, such as stem-like cancer cells [ 59 , 60 , 61 , 62 , 63 ], (2) rewiring the signalling networks in cancer cells [ 64 , 65 , 66 , 67 ] and (3) modulating the tumour microenvironment, namely immune cells [ 68 ]. Interestingly, spatial analysis has revealed that the close proximity of malignant cells to stromal fibroblasts is associated with an increased cycling capacity of cancer cells after therapy, hinting to a protective role of fibroblasts [ 69 ].…”

Dual Role of Fibroblasts Educated by Tumour in Cancer Behavior and Therapeutic Perspectives

“…Fibroblasts can be of influence by either (i) sustaining specific subtypes of neoplastic cells, such as CSCs [ 267 ], (ii) rewiring the signalling networks in cancer cells [ 80 ], or (iii) modulating immune cells [ 268 ]. All this leads us to the conclusion that both the presence and the amount of CAFs will be determinants in the final outcome in terms of tumour progression, dissemination, and chemoresistance [ 269 ].…”

The impact of the spatial heterogeneity of resistant cells and fibroblasts on treatment response

“…Cancer-associated fibroblasts (CAF) are known to promote cancer cell growth and drug resistance [29][30][31][32][33]. In particular, recent studies revealed the impact of fibroblast location on the outcomes of continuous therapy [30,34,47]. The distribution of CAFs in real tumor tissues is diverse, which is difficult to categorize [32,[35][36][37].…”