Stromagenesis and cancer-associated fibroblast heterogeneity in primary tumors and metastasis: focus in non-small cell lung cancer.

Non-small cell lung cancer (NSCLC) is the most common lung cancer type and one of the deadliest neoplasias worldwide. NSCLC is histologically classified into adenocarcinoma, squamous cell carcinoma, and other less frequent subtypes. Both subtypes and other solid tumors are increasingly regarded as abnormal organs, highlighting the critical role of the desmoplastic tumor stroma rich in cancer-associated fibroblasts (CAFs) in driving tumor progression and therapeutic resistance. This tumor stroma resembles a chronic fibrotic wound and is largely formed by activated/myofibroblast-like α-SMA+ CAFs (myCAFs), which are strongly associated with immunosuppression and poor prognosis. Despite the dominance of the myCAF phenotype, we reported a decade ago phenotypic alterations in NSCLC with a strong dependence on the histologic subtype. Subsequent studies using functional assays, single-cell techniques, and in vivo models have refined these initial observations, enhancing our understanding of the biology of both normal fibroblasts/myofibroblasts and CAFs in NSCLC and other cancer types, including their origins, subclassification, and physiopathologic functions. Notably, increasing evidence supports that CAFs can exhibit tumor-restraining or tumor-promoting effects, and current therapeutic efforts aim to shift the balance towards tumor-restraining phenotypes. Here, we review major advances in our understanding of tumor stromagenesis and CAF heterogeneity in both primary tumors and metastasis, including emerging consensus, with a special focus on NSCLC and its frequent dissemination to the brain. We also highlight the critical role of smoking through epigenetic reprogramming of the TGF-β/SMAD3 pathway. These advances are beginning to delineate how CAF heterogeneity depends on the stage and histologic subtype in NSCLC.