Highlights d EMT-derived breast cancer cells can differentiate into postmitotic adipocytes d Adipogenesis disconnects cancer cells from an invasive and oncogenic phenotype d EMT/MET transcription factors and TGF-b signaling regulate cancer adipogenesis d Adipogenesis-inducing drug combinations repress metastasis in preclinical models SUMMARY Cancer cell plasticity facilitates the development of therapy resistance and malignant progression. De-differentiation processes, such as an epithelial-mesenchymal transition (EMT), are known to enhance cellular plasticity.Here, we demonstrate that cancer cell plasticity can be exploited therapeutically by forcing the trans-differentiation of EMT-derived breast cancer cells into post-mitotic and functional adipocytes. Delineation of the molecular pathways underlying such trans-differentiation has motivated a combination therapy with MEK inhibitors and the anti-diabetic drug Rosiglitazone in various mouse models of murine and human breast cancer in vivo. This combination therapy provokes the conversion of invasive and disseminating cancer cells into post-mitotic adipocytes leading to the repression of primary tumor invasion and metastasis formation. SignificanceCancer cell plasticity and EMT are dynamic and can occur during different steps of cancer metastasis. We demonstrate that cellular plasticity acquired by EMT can be exploited to trans-differentiate breast cancer cells into post-mitotic and functional adipocytes. Notably, adipogenic differentiation therapy with a combination of Rosiglitazone and an MEK inhibitor efficiently inhibits cancer cell invasion, dissemination, and metastasis formation in various preclinical mouse models of breast cancer. The results underscore the pivotal role of cancer cell plasticity in malignant tumor progression and reveal the therapeutic potential that lies in the targeting of cellular plasticity, for example by forcing post-mitotic adipogenesis.

Cancer is a systemic heterogeneous disease that can undergo several rounds of latency and activation. Malignant tumors evolve through dynamic responses to microenvironmental signals and development of resistance following therapeutic interventions. Cancer cell adaptation is required for cell survival during metastatic dissemination and outgrowth. Epithelial-mesenchymal transition (EMT) plays a major role in facilitating cell plasticity in cancer and allows cancer cells to escape chemotherapies and targeted therapies through dedifferentiation and signaling adaptation processes. In our recent study, we showed that breast cancer cells that have undergone EMT can be terminally differentiated into adipocytes using the PPARg agonist rosiglitazone combined with the MEK inhibitor trametinib. The conversion of invasive cancer cells into adipocytes repressed primary tumor invasion and metastasis formation in mouse models of breast cancer. The transdifferentiated cancer cell-derived adipocytes were growth-arrested and lost their cellular plasticity. These results indicate the high potential of utilizing the increased cell plasticity inherent to invasive cancer cells for transdifferentiation therapy.

SummaryBone-derived mesenchymal stromal cells (MSCs) differentiate into multiple lineages including chondro- and osteogenic fates and function in establishing the hematopoietic compartment of the bone marrow. Here, we analyze the emergence of different MSC types during mouse limb and long bone development. In particular, PDGFRαposSCA-1pos (PαS) cells and mouse skeletal stem cells (mSSCs) are detected within the PDGFRαposCD51pos (PαCD51) mesenchymal progenitors, which are the most abundant progenitors in early limb buds and developing long bones until birth. Long-bone-derived PαS cells and mSSCs are most prevalent in newborn mice, and molecular analysis shows that they constitute distinct progenitor populations from the earliest stages onward. Differential expression of CD90 and CD73 identifies four PαS subpopulations that display distinct chondro- and osteogenic differentiation potentials. Finally, we show that cartilage constructs generated from CD90pos PαS cells are remodeled into bone organoids encompassing functional endothelial and hematopoietic compartments, which makes these cells suited for bone tissue engineering.