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Pancreatic ductal adenocarcinoma (PDAC) stands as a profoundly heterogeneous and aggressive malignancy, manifesting a discouragingly limited response to conventional therapeutic interventions. Within the intricate tapestry of the tumor microenvironment (TME), cancer-associated fibroblasts (CAFs) emerge as pivotal constituents, wielding the capacity to propel the malignant attributes of neoplastic cells while bolstering their deftness in thwarting treatments. The rapid evolution of nanomedicinal technologies ushers in fresh avenues for therapeutic paradigms meticulously honed to target CAFs. Notably, a recent proposition by Yuan et al. introduces a PDAC treatment strategy metaphorically akin to “shooting fish in a barrel.” By adeptly capitalizing on the spatial distribution of the CAF barricade encircling the tumor, this innovative approach orchestrates a metamorphosis of CAFs, transitioning them from impediments to drug delivery into reservoirs of therapeutic agents. The resultant outcome, an augmentation of chemotherapy and immunotherapy efficacy, attests to the transformative potential of this concept. The study not only bequeaths novel insights and methodologies to surmount barriers in drug delivery for tumor treatment but also holds promise in elevating the precision, efficacy, and safety of tailored therapeutic regimens. Within this discourse, we meticulously evaluate Yuan et al.'s research, scrutinizing its merits and limitations, and cast a forward-looking gaze upon the formulation, validation of efficacy, and clinical translation of nanomedicines targeting CAFs.

Tumor growth and metastases are dependent on interactions between cancer cells and the local environment. Expression of the cell–cell adhesion molecule N-cadherin (Ncad) is associated with highly aggressive cancers, and its expression by osteogenic cells has been proposed to provide a molecular “dock” for disseminated tumor cells to establish in pre-metastatic niches within the bone. To test this biologic model, we conditionally deleted the Ncad gene (Cdh2) in osteolineage cells using Osx-cre (cKO). Contrary to expectations, the metastatic breast cancer cell line PyMT-BO1 was able to form tumors in bone and to induce osteolysis in cKO as well as in control mice. Despite absence of Ncad, bone marrow stromal cells isolated from cKO mice were able to engage in direct cell–cell interactions with tumor cells expressing either N- or E-cadherin. However, subcutaneous PyMT-BO1 and B16F10 tumors grew larger in cKO relative to control littermates. Cell tracking experiments using the Ai9 reporter revealed the presence of Osx+ and Ncad+ cells in the stroma of extra-skeletal tumors and in a small population of lung cells. Gene expression analysis by RNAseq of Osx+ cells isolated from extra-skeletal tumors revealed alterations of pro-tumorigenic signaling pathways in cKO cells relative to control Osx+ cells. Thus, Ncad in Osx+ cells is not necessary for the establishment of bone metastases, but in extra-skeletal tumors it regulates pro-tumorigenic support by the microenvironment.

More than 85% of advanced breast cancer patients suffer from metastatic bone lesions, yet the mechanisms that facilitate these metastases remain poorly understood. Recent studies suggest that tumor-derived factors initiate changes within the tumor microenvironment to facilitate metastasis. However, whether stromal-initiated changes are sufficient to drive increased metastasis in the bone remains an open question. Thus, we developed a model to induce reactive senescent osteoblasts and found that they increased breast cancer colonization of the bone. Analysis of senescent osteoblasts revealed that they failed to mineralize bone matrix and increased local osteoclastogenesis, the latter process being driven by the senescence-associated secretory phenotype factor, IL-6. Neutralization of IL-6 was sufficient to limit senescence-induced osteoclastogenesis and tumor cell localization to bone, thereby reducing tumor burden. Together, these data suggest that a reactive stromal compartment can condition the niche, in the absence of tumor-derived signals, to facilitate metastatic tumor growth in the bone.