The activity of tertiary lymphoid structures in high grade serous ovarian cancer is governed by site, stroma, and cellular interactions.

Most high grade serous ovarian cancers (HGSOC) originate in the fallopian tube but spread to the ovary and peritoneal cavity, highlighting the need to understand antitumor immunity across HGSOC sites. Using spatial analyses, we discover that tertiary lymphoid structures (TLSs) within ovarian tumors are less developed compared with TLSs in fallopian tube or omental tumors. We reveal transcriptional differences across a spectrum of lymphoid structures, demonstrating that immune cell activity increases when residing in more developed TLSs and produce a prognostic, spatially derived TLS signature from HGSOC tumors. We interrogate TLS-adjacent stroma and assess how normal mesenchymal stem cells MSCs (nMSCs) may support B cell function and TLS, contrary to cancer-educated MSCs (CA-MSCs) which negate the prognostic benefit of our TLS signature, suggesting that pro-tumorigenic stroma could limit TLS formation.

Carcinoma-associated mesenchymal stem cells promote ovarian cancer heterogeneity and metastasis through mitochondrial transfer.

Ovarian cancer is characterized by early metastatic spread. This study demonstrates that carcinoma-associated mesenchymal stromal cells (CA-MSCs) enhance metastasis by increasing tumor cell heterogeneity through mitochondrial donation. CA-MSC mitochondrial donation preferentially occurs in ovarian cancer cells with low levels of mitochondria ("mito poor"). CA-MSC mitochondrial donation rescues the phenotype of mito poor cells, restoring their proliferative capacity, resistance to chemotherapy, and cellular respiration. Receipt of CA-MSC-derived mitochondria induces tumor cell transcriptional changes leading to the secretion of ANGPTL3, which enhances the proliferation of tumor cells without CA-MSC mitochondria, thus amplifying the impact of mitochondrial transfer. Donated CA-MSC mitochondrial DNA persisted in recipient tumor cells for at least 14 days. CA-MSC mitochondrial donation occurs in vivo, enhancing tumor cell heterogeneity and decreasing mouse survival. Collectively, this work identifies CA-MSC mitochondrial transfer as a critical mediator of ovarian cancer cell survival, heterogeneity, and metastasis and presents a unique therapeutic target in ovarian cancer.

Stromal mediated DNA damage promotes high grade serous ovarian cancer initiation.

The fundamental steps in high-grade serous ovarian cancer (HGSOC) initiation are unclear, thus providing critical barriers to the development of prevention or early detection strategies for this deadly disease. Increasing evidence demonstrates most HGSOC starts in the fallopian tube epithelium (FTE). Current models propose HGSOC initiates when FTE cells acquire increasing numbers of mutations allowing cells to evolve into serous tubal intraepithelial carcinoma (STIC) precursors and then to full blown cancer. Here we report that epigenetically altered mesenchymal stem cells (termed high risk MSC-hrMSCs) can be detected prior to the formation of ovarian cancer precursor lesions. These hrMSCs drive DNA damage in the form of DNA double strand breaks in FTE cells while also promoting the survival of FTE cells in the face of DNA damage. Indicating the hrMSC may actually drive cancer initiation, we find hrMSCs induce full malignant transformation of otherwise healthy, primary FTE resulting in metastatic cancer in vivo . Further supporting a role for hrMSCs in cancer initiation in humans, we demonstrate that hrMSCs are highly enriched in BRCA1/2 mutation carriers and increase with age. Combined these findings indicate that hrMSCs may incite ovarian cancer initiation. These findings have important implications for ovarian cancer detection and prevention.

Stromal-Modulated Epithelial-to-Mesenchymal Transition in Cancer Cells.

The ability of cancer cells to detach from the primary site and metastasize is the main cause of cancer- related death among all cancer types. Epithelial-to-mesenchymal transition (EMT) is the first event of the metastatic cascade, resulting in the loss of cell-cell adhesion and the acquisition of motile and stem-like phenotypes. A critical modulator of EMT in cancer cells is the stromal tumor microenvironment (TME), which can promote the acquisition of a mesenchymal phenotype through direct interaction with cancer cells or changes to the broader microenvironment. In this review, we will explore the role of stromal cells in modulating cancer cell EMT, with particular emphasis on the function of mesenchymal stromal/stem cells (MSCs) through the activation of EMT-inducing pathways, extra cellular matrix (ECM) remodeling, immune cell alteration, and metabolic rewiring.